Calcium ion

cross_nutrient

Calcium/Mg substitution at one enzyme site, not whole-body interchangeability.

experimental_model

Recombinant enzyme comparison. Activity was measured using artificial pNPP substrate.

limitations

Site-specific substitution is not evidence that dietary calcium replaces magnesium requirements. This assay does not quantify physiological pyrophosphate turnover or mineral deposition.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Calcium can occupy this magnesium site, but gives a different enzyme response.

primary_references

[mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1479–1489

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme comparison. Activity was measured using artificial pNPP substrate. · source_derived_draft · unverified_draft

### mg-alpl-calcium-partial-substitution Calcium at TNAP site M3 supported about 40% of the activity of Mg/Zn-TNAP at pH 7.4 and 9.8. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium can occupy this magnesium site, but gives a different enzyme response. organism: Homo sapiens tissue_or_cell_type: Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay experimental_model: Recombinant enzyme comparison. Activity was measured using artificial pNPP substrate. limitations: Site-specific substitution is not evidence that dietary calcium replaces magnesium requirements. This assay does not quantify physiological pyrophosphate turnover or mineral deposition. cross_nutrient: Calcium/Mg substitution at one enzyme site, not whole-body interchangeability. [mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

cross_nutrient

Calcium/Zn/Mg interaction depends on site occupancy and local conditions.

experimental_model

Purified TNAP concentration/pH experiment. Activity was measured using artificial pNPP substrate.

limitations

Local experimental concentrations cannot be converted to dietary dose cutoffs. This assay does not quantify physiological pyrophosphate turnover or mineral deposition.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The same calcium ion can activate one site and interfere with another.

primary_references

[mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1491–1501

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified TNAP concentration/pH experiment. Activity was measured using artificial pNPP substrate. · source_derived_draft · unverified_draft

### mg-alpl-high-calcium-zinc-displacement Very high calcium displaced or competed with Zn at TNAP M1/M2 sites and reduced activity; concentrations depended on pH. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same calcium ion can activate one site and interfere with another. organism: Homo sapiens tissue_or_cell_type: Recombinant human TNAP; cell-free p-nitrophenyl phosphate (pNPP) hydrolysis assay experimental_model: Purified TNAP concentration/pH experiment. Activity was measured using artificial pNPP substrate. limitations: Local experimental concentrations cannot be converted to dietary dose cutoffs. This assay does not quantify physiological pyrophosphate turnover or mineral deposition. cross_nutrient: Calcium/Zn/Mg interaction depends on site occupancy and local conditions. [mg-hoylaerts2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

cross_nutrient

Calcium and magnesium effects on a thiamine-dependent enzyme were additive under specified assay conditions.

experimental_model

Purified pig-heart KGDHC, controlled free divalent-ion and cofactor concentrations.

limitations

Additivity depended on concentration; it does not imply Ca replaces Mg at the ThDP site.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Sus scrofa

plain_language

Calcium regulation and magnesium support can act together in the enzyme preparation.

primary_references

[panov-1996-ogdh] Independent modulation of the activity of alpha-ketoglutarate dehydrogenase complex by Ca2+ and Mg2+ (1996). https://pubmed.ncbi.nlm.nih.gov/8555212/ DOI: 10.1021/bi952101t

tissue_or_cell_type

Purified heart mitochondrial enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 687–697

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified pig-heart KGDHC, controlled free divalent-ion and cofactor concentrations. · source_derived_draft · unverified_draft

### mg-ogdh-calcium-additivity Ca and Mg stimulation of purified pig-heart KGDHC was additive over the tested lower free-ion ranges. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium regulation and magnesium support can act together in the enzyme preparation. organism: Sus scrofa tissue_or_cell_type: Purified heart mitochondrial enzyme experimental_model: Purified pig-heart KGDHC, controlled free divalent-ion and cofactor concentrations. limitations: Additivity depended on concentration; it does not imply Ca replaces Mg at the ThDP site. cross_nutrient: Calcium and magnesium effects on a thiamine-dependent enzyme were additive under specified assay conditions. [panov-1996-ogdh] Independent modulation of the activity of alpha-ketoglutarate dehydrogenase complex by Ca2+ and Mg2+ (1996). https://pubmed.ncbi.nlm.nih.gov/8555212/ DOI: 10.1021/bi952101t

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Recombinant human TKT crystallography, kinetics and NMR.

limitations

Ca-supported structural preparation does not quantify native human tissue metal occupancy.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Calcium can anchor the B1-derived cofactor in active human transketolase.

primary_references

[mitschke-2010-tkt] The Crystal Structure of Human Transketolase and New Insights into Its Mode of Action (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC2951230/ DOI: 10.1074/jbc.M110.149955

tissue_or_cell_type

Recombinant TKT crystals

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 589–599

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human TKT crystallography, kinetics and NMR. · source_derived_draft · unverified_draft

### mg-tkt-calcium-thdp-anchor In recombinant human TKT, Ca2+ coordinates the ThDP diphosphate and protein ligands at the active site. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium can anchor the B1-derived cofactor in active human transketolase. organism: Homo sapiens tissue_or_cell_type: Recombinant TKT crystals experimental_model: Recombinant human TKT crystallography, kinetics and NMR. limitations: Ca-supported structural preparation does not quantify native human tissue metal occupancy. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [mitschke-2010-tkt] The Crystal Structure of Human Transketolase and New Insights into Its Mode of Action (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC2951230/ DOI: 10.1074/jbc.M110.149955

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Human erythrocyte transketolase; sulfur-35 ThDP binding and divalent-ion reconstitution.

limitations

Replacement in vitro does not establish physiological substitution during Mg deficiency.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Several divalent metals supported this B1-dependent enzyme; magnesium worked best here.

primary_references

[jung-1988-tkt] Studies on the nature of thiamine pyrophosphate binding and dependency on divalent cations of transketolase from human erythrocytes (1988). https://pubmed.ncbi.nlm.nih.gov/3248678/ DOI: 10.1016/0020-711x(88)90228-5

tissue_or_cell_type

Erythrocyte enzyme

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 565–575

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocyte transketolase; sulfur-35 ThDP binding and divalent-ion reconstitution. · source_derived_draft · unverified_draft

### mg-tkt-other-divalent-cations Reconstituted erythrocyte transketolase activity ranked Co2+ < Mn2+ < Ca2+ < Mg2+ in the tested assay. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several divalent metals supported this B1-dependent enzyme; magnesium worked best here. organism: Homo sapiens tissue_or_cell_type: Erythrocyte enzyme experimental_model: Human erythrocyte transketolase; sulfur-35 ThDP binding and divalent-ion reconstitution. limitations: Replacement in vitro does not establish physiological substitution during Mg deficiency. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [jung-1988-tkt] Studies on the nature of thiamine pyrophosphate binding and dependency on divalent cations of transketolase from human erythrocytes (1988). https://pubmed.ncbi.nlm.nih.gov/3248678/ DOI: 10.1016/0020-711x(88)90228-5

evidence_access

Primary abstract

experimental_model

Human lysosomal sulfatase structure.

limitations

Does not show calcium supplementation reverses vanadate inhibition.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

Calcium and enzyme maturation define the machinery that the inhibitor encounters.

primary_references

Structure of a human lysosomal sulfatase. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9032078/ · DOI 10.1016/s0969-2126(97)00185-8

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 278–284

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lysosomal sulfatase structure. · source_derived_draft · unverified_draft

## vanadium-sulfatase-calcium Calcium and enzyme maturation define the machinery that the inhibitor encounters. Human ARSB crystallography identified calcium coordinated in the sulfate-containing catalytic site and an essential modified Cys91 residue. Model: Human lysosomal sulfatase structure. Limitations: Does not show calcium supplementation reverses vanadate inhibition. Evidence access: Primary abstract Structure of a human lysosomal sulfatase. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9032078/ · DOI 10.1016/s0969-2126(97)00185-8

compartment_description

Cytosolic protein complex

experimental_model

Purified calcium-bound calmodulin and a chicken smooth-muscle myosin light-chain kinase peptide; crystallography

limitations

Structure of a peptide complex; not a measurement of dietary calcium effects or every calmodulin target.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Purified vertebrate proteins

plain_language

Calmodulin carries bound calcium while engaging a target protein.

primary_references

[ca-meador1992] Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex (1992). https://pubmed.ncbi.nlm.nih.gov/1519061/ DOI: 10.1126/science.1519061

research_relationship_category

binding

tissue_or_cell_type

Smooth-muscle target-peptide system

Calcium: mechanism-first literature curation (2026-09-17) · lines 399–410

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified calcium-bound calmodulin and a chicken smooth-muscle myosin light-chain kinase peptide; crystallography · source_derived_draft · unverified_draft

### ca-calmodulin-calcium-complex Calcium-loaded calmodulin forms the Ca2+/CaM regulatory complex resolved with a myosin-light-chain-kinase target peptide. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calmodulin carries bound calcium while engaging a target protein. organism: Purified vertebrate proteins tissue_or_cell_type: Smooth-muscle target-peptide system experimental_model: Purified calcium-bound calmodulin and a chicken smooth-muscle myosin light-chain kinase peptide; crystallography limitations: Structure of a peptide complex; not a measurement of dietary calcium effects or every calmodulin target. research_relationship_category: binding compartment_description: Cytosolic protein complex [ca-meador1992] Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex (1992). https://pubmed.ncbi.nlm.nih.gov/1519061/ DOI: 10.1126/science.1519061

compartment_description

Sarcomeric thin-filament regulatory complex

experimental_model

Purified human cardiac troponin ternary core; crystallography

limitations

Actin-disengagement is a structural model; this is not a direct whole-heart force measurement or a smooth-muscle mechanism.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Troponin C senses calcium to regulate cardiac contraction.

primary_references

[ca-takeda2003] Structure of the core domain of human cardiac troponin in the Ca2+-saturated form (2003). https://pubmed.ncbi.nlm.nih.gov/12840750/ DOI: 10.1038/nature01780

research_relationship_category

binding

tissue_or_cell_type

Cardiac troponin core

Calcium: mechanism-first literature curation (2026-09-17) · lines 770–781

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cardiac troponin ternary core; crystallography · source_derived_draft · unverified_draft

### ca-cardiac-troponin-calcium-switch Calcium binds the regulatory site of cardiac troponin C; the calcium-loaded ternary structure supports altered inhibitory troponin-I interactions with actin. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Troponin C senses calcium to regulate cardiac contraction. organism: Homo sapiens tissue_or_cell_type: Cardiac troponin core experimental_model: Purified human cardiac troponin ternary core; crystallography limitations: Actin-disengagement is a structural model; this is not a direct whole-heart force measurement or a smooth-muscle mechanism. research_relationship_category: binding compartment_description: Sarcomeric thin-filament regulatory complex [ca-takeda2003] Structure of the core domain of human cardiac troponin in the Ca2+-saturated form (2003). https://pubmed.ncbi.nlm.nih.gov/12840750/ DOI: 10.1038/nature01780

compartment_description

Cytosolic regulatory regions of ER channel

experimental_model

Recombinant human ITPR3; cryo-EM in ligand-bound gating states

limitations

Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open.

primary_references

[ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

research_relationship_category

regulation

tissue_or_cell_type

Recombinant ITPR3

Calcium: mechanism-first literature curation (2026-09-17) · lines 492–503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft

### ca-itpr3-calcium-coactivation Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active. research_relationship_category: regulation compartment_description: Cytosolic regulatory regions of ER channel [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

compartment_description

Mitochondrial intermembrane-space regulatory subunits

experimental_model

Human HEK293T MICU1/MICU2 knockout and EF-hand mutant rescue; permeabilized-cell calcium clearance

limitations

Knockout/rescue and permeabilized-cell evidence; numeric thresholds are not universal.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

MICU1 and MICU2 help the uniporter distinguish small calcium levels from a signal.

primary_references

[ca-kamer2014] MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter (2014). https://pubmed.ncbi.nlm.nih.gov/24503055/ DOI: 10.1002/embr.201337946

research_relationship_category

regulation

tissue_or_cell_type

HEK293T cells

Calcium: mechanism-first literature curation (2026-09-17) · lines 732–743

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HEK293T MICU1/MICU2 knockout and EF-hand mutant rescue; permeabilized-cell calcium clearance · source_derived_draft · unverified_draft

### ca-micu12-calcium-sensing Calcium-responsive EF hands in MICU1 and MICU2 allow the uniporter to pass from restrained low-calcium uptake to uptake above a threshold. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MICU1 and MICU2 help the uniporter distinguish small calcium levels from a signal. organism: Homo sapiens tissue_or_cell_type: HEK293T cells experimental_model: Human HEK293T MICU1/MICU2 knockout and EF-hand mutant rescue; permeabilized-cell calcium clearance limitations: Knockout/rescue and permeabilized-cell evidence; numeric thresholds are not universal. research_relationship_category: regulation compartment_description: Mitochondrial intermembrane-space regulatory subunits [ca-kamer2014] MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter (2014). https://pubmed.ncbi.nlm.nih.gov/24503055/ DOI: 10.1002/embr.201337946

compartment_description

Cytosolic regulatory domain of plasma-membrane exchanger

experimental_model

Human cardiac NCX1; cryo-EM and functional exchange assays

limitations

Regulatory calcium binding is distinct from calcium being transported; the measured splice form and assay conditions matter.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Calcium also regulates NCX1 at a site separate from the transported-ion pathway.

primary_references

[ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4

research_relationship_category

regulation

tissue_or_cell_type

Cardiac NCX1 expression system

Calcium: mechanism-first literature curation (2026-09-17) · lines 639–650

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cardiac NCX1; cryo-EM and functional exchange assays · source_derived_draft · unverified_draft

### ca-ncx1-regulatory-calcium Calcium binding to the cytosolic CBD2 regulatory domain disrupts an inactive NCX1 assembly and permits exchange. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium also regulates NCX1 at a site separate from the transported-ion pathway. organism: Homo sapiens tissue_or_cell_type: Cardiac NCX1 expression system experimental_model: Human cardiac NCX1; cryo-EM and functional exchange assays limitations: Regulatory calcium binding is distinct from calcium being transported; the measured splice form and assay conditions matter. research_relationship_category: regulation compartment_description: Cytosolic regulatory domain of plasma-membrane exchanger [ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4

compartment_description

Inner mitochondrial membrane and matrix

experimental_model

Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts

limitations

Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Excess mitochondrial calcium can trigger membrane permeability failure.

primary_references

[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434

research_relationship_category

exposure_response

tissue_or_cell_type

Isolated liver, heart and brain mitochondria

Calcium: mechanism-first literature curation (2026-09-17) · lines 836–847

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft

### ca-overload-permeability-transition Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Excess mitochondrial calcium can trigger membrane permeability failure. organism: Mus musculus tissue_or_cell_type: Isolated liver, heart and brain mitochondria experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore. research_relationship_category: exposure_response compartment_description: Inner mitochondrial membrane and matrix [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434

compartment_description

Cytosolic channel-regulatory region

experimental_model

Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings

limitations

Calcium is both a transported ion and a ligand; caffeine-assisted structures do not imply caffeine is required physiologically.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Oryctolagus cuniculus

plain_language

Calcium helps regulate the RyR1 gate.

primary_references

[ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075

research_relationship_category

regulation

tissue_or_cell_type

Skeletal-muscle channel preparation

Calcium: mechanism-first literature curation (2026-09-17) · lines 666–677

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings · source_derived_draft · unverified_draft

### ca-ryr1-calcium-gating Calcium binds an activating RyR1 site and primes gating; ATP and caffeine increase open-state representation in the experimental preparation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps regulate the RyR1 gate. organism: Oryctolagus cuniculus tissue_or_cell_type: Skeletal-muscle channel preparation experimental_model: Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings limitations: Calcium is both a transported ion and a ligand; caffeine-assisted structures do not imply caffeine is required physiologically. research_relationship_category: regulation compartment_description: Cytosolic channel-regulatory region [ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075

compartment_description

SR and cytosol

experimental_model

Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations

limitations

Experimental intracellular store loading, not dietary intake; normal schema category denotes a mechanistic experiment, not a healthy exposure.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Rattus norvegicus

plain_language

Heavily loaded stores can turn local calcium bursts into spreading waves.

primary_references

[ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594

research_relationship_category

exposure_response

tissue_or_cell_type

Quiescent cardiac myocytes under experimental SR loading

Calcium: mechanism-first literature curation (2026-09-17) · lines 823–834

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations · source_derived_draft · unverified_draft

### ca-sr-overload-propagating-waves Increasing sarcoplasmic-reticulum calcium content raises spontaneous release activity and permits some sparks to initiate propagating calcium waves. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Heavily loaded stores can turn local calcium bursts into spreading waves. organism: Rattus norvegicus tissue_or_cell_type: Quiescent cardiac myocytes under experimental SR loading experimental_model: Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations limitations: Experimental intracellular store loading, not dietary intake; normal schema category denotes a mechanistic experiment, not a healthy exposure. research_relationship_category: exposure_response compartment_description: SR and cytosol [ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594

compartment_description

Presynaptic vesicle-plasma-membrane interface

experimental_model

Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements

limitations

SYT1-dependent evoked release; does not establish the sensor for every secretory cell or all release modes.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Synaptotagmin 1 helps convert a calcium signal into vesicle release.

primary_references

[ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004

research_relationship_category

regulation

tissue_or_cell_type

Cultured neurons

Calcium: mechanism-first literature curation (2026-09-17) · lines 783–794

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements · source_derived_draft · unverified_draft

### ca-synaptotagmin-calcium-release Calcium binding to synaptotagmin 1 participates in triggering evoked neurotransmitter release at mouse synapses. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Synaptotagmin 1 helps convert a calcium signal into vesicle release. organism: Mus musculus tissue_or_cell_type: Cultured neurons experimental_model: Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements limitations: SYT1-dependent evoked release; does not establish the sensor for every secretory cell or all release modes. research_relationship_category: regulation compartment_description: Presynaptic vesicle-plasma-membrane interface [ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004

experimental_model

Bovine parathyroid receptor cDNA; Xenopus oocyte expression

limitations

Heterologous expression; polyvalent ions also activate this receptor.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Bos taurus receptor in Xenopus laevis

plain_language

CaSR senses calcium outside cells.

primary_references

[brown1993] Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid (1993). https://pubmed.ncbi.nlm.nih.gov/8255296/ DOI: 10.1038/366575a0

tissue_or_cell_type

Parathyroid-derived receptor; plasma membrane

Calcium: mechanism-first literature curation (2026-09-17) · lines 14–23

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine parathyroid receptor cDNA; Xenopus oocyte expression · source_derived_draft · unverified_draft

### calcium-activates-casr Extracellular calcium activates cloned bovine CaSR expressed in Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: CaSR senses calcium outside cells. organism: Bos taurus receptor in Xenopus laevis tissue_or_cell_type: Parathyroid-derived receptor; plasma membrane experimental_model: Bovine parathyroid receptor cDNA; Xenopus oocyte expression limitations: Heterologous expression; polyvalent ions also activate this receptor. [brown1993] Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid (1993). https://pubmed.ncbi.nlm.nih.gov/8255296/ DOI: 10.1038/366575a0

compartment_description

Extracellular protein-membrane interface

experimental_model

X-ray crystallography and NMR with lysophosphatidylserine

limitations

The carboxylated Gla domain is a vitamin-K-dependent protein state; calcium binding does not perform gamma-carboxylation.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Bos taurus

plain_language

Protein-bound calcium helps a clotting protein recognize a membrane lipid headgroup.

primary_references

[huang2003] Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins (2003). https://www.nature.com/articles/nsb971 DOI: 10.1038/nsb971

tissue_or_cell_type

Purified prothrombin fragment; blood-protein context

Calcium: mechanism-first literature curation (2026-09-17) · lines 1104–1114

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystallography and NMR with lysophosphatidylserine · source_derived_draft · unverified_draft

### calcium-gla-phosphatidylserine-binding In the bovine prothrombin Gla-domain structure, the lysophosphatidylserine headgroup contacted domain-bound Ca2+ and gamma-carboxyglutamate residues. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protein-bound calcium helps a clotting protein recognize a membrane lipid headgroup. organism: Bos taurus tissue_or_cell_type: Purified prothrombin fragment; blood-protein context experimental_model: X-ray crystallography and NMR with lysophosphatidylserine limitations: The carboxylated Gla domain is a vitamin-K-dependent protein state; calcium binding does not perform gamma-carboxylation. compartment_description: Extracellular protein-membrane interface [huang2003] Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins (2003). https://www.nature.com/articles/nsb971 DOI: 10.1038/nsb971

compartment_description

Extracellular domain

experimental_model

Calcium titration, electron microscopy and trypsin assay

limitations

In-vitro calcium removal is not dietary calcium deficiency; the soluble fragment did not self-associate under these assay conditions.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus protein expressed in insect cells

plain_language

Bound calcium helps keep the adhesion protein folded and resistant to protease attack.

primary_references

[pokutta1994] Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding (1994). https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1994.tb19080.x DOI: 10.1111/j.1432-1033.1994.tb19080.x

tissue_or_cell_type

Purified extracellular domain

Calcium: mechanism-first literature curation (2026-09-17) · lines 1140–1150

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Calcium titration, electron microscopy and trypsin assay · source_derived_draft · unverified_draft

### calcium-protects-e-cadherin-from-proteolysis Calcium binding protected the recombinant mouse E-cadherin ectodomain from tryptic cleavage; calcium depletion caused a reversible conformational change. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bound calcium helps keep the adhesion protein folded and resistant to protease attack. organism: Mus musculus protein expressed in insect cells tissue_or_cell_type: Purified extracellular domain experimental_model: Calcium titration, electron microscopy and trypsin assay limitations: In-vitro calcium removal is not dietary calcium deficiency; the soluble fragment did not self-associate under these assay conditions. compartment_description: Extracellular domain [pokutta1994] Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding (1994). https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1994.tb19080.x DOI: 10.1111/j.1432-1033.1994.tb19080.x

compartment_description

Extracellular domain

experimental_model

Two-domain crystal structure

limitations

The crystallized fragment is not a complete living adherens junction; crystal dimer geometry alone does not define every adhesion contact.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus protein

plain_language

Calcium braces the outside portion of a cell-adhesion protein.

primary_references

[nagar1996] Structural basis of calcium-induced E-cadherin rigidification and dimerization (1996). https://pubmed.ncbi.nlm.nih.gov/8598933/ DOI: 10.1038/380360a0

tissue_or_cell_type

Purified E-cadherin ectodomain

Calcium: mechanism-first literature curation (2026-09-17) · lines 1128–1138

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-domain crystal structure · source_derived_draft · unverified_draft

### calcium-rigidifies-e-cadherin Three Ca2+ ions coordinated at the interface of mouse E-cadherin extracellular domains 1 and 2 support their extended, rigid arrangement. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium braces the outside portion of a cell-adhesion protein. organism: Mus musculus protein tissue_or_cell_type: Purified E-cadherin ectodomain experimental_model: Two-domain crystal structure limitations: The crystallized fragment is not a complete living adherens junction; crystal dimer geometry alone does not define every adhesion contact. compartment_description: Extracellular domain [nagar1996] Structural basis of calcium-induced E-cadherin rigidification and dimerization (1996). https://pubmed.ncbi.nlm.nih.gov/8598933/ DOI: 10.1038/380360a0

evidence_span

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experimental_model

Site-directed mutants, calcium assays and BMP reporters

exposure

Gla and Pro64 alterations, calcium chelation and warfarin

limitations

Binding and calcification in experimental systems; systemic calcium should not be equated with a single binding-site measurement.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

MGP expression systems and calcifying vascular cells

plain_language

The calcium-binding and signaling functions were distinct but functionally connected.

primary_references

[k2-p18369157] Proline and gamma-carboxylated glutamate residues in matrix Gla protein are critical for binding of bone morphogenetic protein-4. (2008). https://pubmed.ncbi.nlm.nih.gov/18369157/ DOI: 10.1161/circresaha.107.166124

tissue_or_cell_type

Calcium/BMP binding and differentiation

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 565–576

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutants, calcium assays and BMP reporters · source_derived_draft · unverified_draft

### k2-mgp-calcium-dependency Calcium chelation or warfarin treatment abolished MGP binding to BMP4 in the tested system. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The calcium-binding and signaling functions were distinct but functionally connected. organism: MGP expression systems and calcifying vascular cells tissue_or_cell_type: Calcium/BMP binding and differentiation experimental_model: Site-directed mutants, calcium assays and BMP reporters limitations: Binding and calcification in experimental systems; systemic calcium should not be equated with a single binding-site measurement. exposure: Gla and Pro64 alterations, calcium chelation and warfarin evidence_span: {"source_cache": "artifacts/k2-research/18369157.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "34c7571f9f3a564647e458dc072113e807c277eaf5f542d6f3ab2e45f71ea5a4", "start_char": 0, "end_char": 1696, "text_sha256": "34c7571f9f3a564647e458dc072113e807c277eaf5f542d6f3ab2e45f71ea5a4"} [k2-p18369157] Proline and gamma-carboxylated glutamate residues in matrix Gla protein are critical for binding of bone morphogenetic protein-4. (2008). https://pubmed.ncbi.nlm.nih.gov/18369157/ DOI: 10.1161/circresaha.107.166124

cross_nutrient

Local calcium availability permits flow-stimulated potassium secretion.

evidence_location

Results; luminal Ca and intracellular buffering experiments.

experimental_model

Luminal Ca removal/BAPTA and flow challenge

limitations

Tests ion availability in vitro, not dietary calcium deficiency; the entry-channel identity was unresolved.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Oryctolagus cuniculus

plain_language

Calcium entry and signaling are required for this flow-driven potassium output.

primary_references

[liu-2007-calcium-flow] Ca2+ dependence of flow-stimulated K secretion in the mammalian cortical collecting duct (2007). https://journals.physiology.org/doi/10.1152/ajprenal.00057.2007 DOI: 10.1152/ajprenal.00057.2007

tissue_or_cell_type

Cortical collecting duct

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 369–380

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Luminal Ca removal/BAPTA and flow challenge · source_derived_draft · unverified_draft

### renal-calcium-entry-supports-flow-k-secretion Removing luminal Ca2+ or buffering intracellular Ca2+ suppressed flow-stimulated K secretion in microperfused rabbit CCDs. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium entry and signaling are required for this flow-driven potassium output. organism: Oryctolagus cuniculus tissue_or_cell_type: Cortical collecting duct experimental_model: Luminal Ca removal/BAPTA and flow challenge limitations: Tests ion availability in vitro, not dietary calcium deficiency; the entry-channel identity was unresolved. cross_nutrient: Local calcium availability permits flow-stimulated potassium secretion. evidence_location: Results; luminal Ca and intracellular buffering experiments. [liu-2007-calcium-flow] Ca2+ dependence of flow-stimulated K secretion in the mammalian cortical collecting duct (2007). https://journals.physiology.org/doi/10.1152/ajprenal.00057.2007 DOI: 10.1152/ajprenal.00057.2007

evidence_access

Primary abstract

experimental_model

Mouse FAH X-ray structure; catalytic roles proposed from structure and mutagenesis.

limitations

This is not evidence that calcium supplementation restores FAH disease.

nutrient_topic

L-Tyrosine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Tyrosine

plain_language

A metal participates in the terminal cleavage chemistry.

primary_references

Crystal structure and mechanism of a carbon-carbon bond hydrolase. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10508789/ · DOI 10.1016/s0969-2126(99)80170-1

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 268–274

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse FAH X-ray structure; catalytic roles proposed from structure and mutagenesis. · source_derived_draft · unverified_draft

## l-tyrosine-fah-calcium A metal participates in the terminal cleavage chemistry. The mouse FAH product complex places acetoacetate at a coordinated calcium ion near a Glu-His catalytic dyad. Model: Mouse FAH X-ray structure; catalytic roles proposed from structure and mutagenesis. Limitations: This is not evidence that calcium supplementation restores FAH disease. Evidence access: Primary abstract Crystal structure and mechanism of a carbon-carbon bond hydrolase. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10508789/ · DOI 10.1016/s0969-2126(99)80170-1

evidence_access

Primary full text

experimental_model

Full-length human PSS1 cryo-EM in apo, calcium-bound and calcium/serine-bound states.

limitations

The proposed chemical mechanism combines structure and mutagenesis; it is not a clinical calcium-response experiment.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

Calcium has a constructive catalytic role in this lipid-building enzyme.

primary_references

Structural basis for catalytic mechanism of human phosphatidylserine synthase 1. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40044636/ · DOI 10.1038/s41421-025-00775-3

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 254–260

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Full-length human PSS1 cryo-EM in apo, calcium-bound and calcium/serine-bound states. · source_derived_draft · unverified_draft

## l-serine-pss1-calcium Calcium has a constructive catalytic role in this lipid-building enzyme. Human PSS1 structures positioned calcium and serine in the catalytic pocket; structural and mutational analysis implicated His172 in the base-exchange mechanism. Model: Full-length human PSS1 cryo-EM in apo, calcium-bound and calcium/serine-bound states. Limitations: The proposed chemical mechanism combines structure and mutagenesis; it is not a clinical calcium-response experiment. Evidence access: Primary full text Structural basis for catalytic mechanism of human phosphatidylserine synthase 1. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40044636/ · DOI 10.1038/s41421-025-00775-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text; Figure 1d and methods

experimental_model

Intracellular calcium buffered with BAPTA; whole-cell recordings.

limitations

This is a local signaling requirement, not evidence of dietary calcium deficiency or benefit from a calcium supplement.

nutrient_topic

Stevia collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Stevia

plain_language

Without the activating calcium signal, potentiation did not turn the channel on.

primary_references

Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28361903/ · DOI 10.1038/ncomms14733

trigger_kind

machinery_impairment Imported condition classification; unverified.

Stevia: glycoside metabolism, taste, ion channels and cross-nutrient mechanisms (2026-09-19) · lines 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Intracellular calcium buffered with BAPTA; whole-cell recordings. · source_derived_draft · unverified_draft

## stevia-calcium-gate Without the activating calcium signal, potentiation did not turn the channel on. Buffering intracellular free calcium prevented stevioside from activating TRPM5 in the expression assay. Model: Intracellular calcium buffered with BAPTA; whole-cell recordings. Limitations: This is a local signaling requirement, not evidence of dietary calcium deficiency or benefit from a calcium supplement. Evidence access: Primary full text; Figure 1d and methods Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28361903/ · DOI 10.1038/ncomms14733

cross_nutrient

true

experimental_model

Recombinant human TNAP and M4 mutants; cell-free enzyme activity and metal reconstitution

exposure

Recombinant TNAP M4-site mutants and metal-dependent activity comparisons at pH 7.4 and 9.8.

limitations

This record states the authors’ mechanistic interpretation; existing M3 calcium substitution and Mg/Zn reconstitution claims remain unchanged. It does not imply dietary calcium is a zinc substitute.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens

plain_language

TNAP metal sites do different jobs: its peripheral calcium site was interpreted as structural.

primary_references

[zinc-enz-tnap-metals2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase. (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

tissue_or_cell_type

Purified protein; cell-free assay

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 820–831

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human TNAP and M4 mutants; cell-free enzyme activity and metal reconstitution · source_derived_draft · unverified_draft

### zinc-enz-tnap-m4-not-catalytic The recombinant TNAP mutant study attributed effects of disrupting calcium site M4 to protein structure rather than direct catalysis by M4-bound calcium. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: TNAP metal sites do different jobs: its peripheral calcium site was interpreted as structural. organism: Homo sapiens tissue_or_cell_type: Purified protein; cell-free assay experimental_model: Recombinant human TNAP and M4 mutants; cell-free enzyme activity and metal reconstitution limitations: This record states the authors’ mechanistic interpretation; existing M3 calcium substitution and Mg/Zn reconstitution claims remain unchanged. It does not imply dietary calcium is a zinc substitute. exposure: Recombinant TNAP M4-site mutants and metal-dependent activity comparisons at pH 7.4 and 9.8. cross_nutrient: true [zinc-enz-tnap-metals2015] Functional significance of calcium binding to tissue-nonspecific alkaline phosphatase. (2015). https://pubmed.ncbi.nlm.nih.gov/25775211/ DOI: 10.1371/journal.pone.0119874

cross_nutrient

true

experimental_model

Purified full-length human ZnT1 in proteoliposomes; supporting HEK293T transport assays

exposure

Proteoliposomes with or without internal calcium, external zinc titration; zinc transport Km 0.38 ± 0.14 micromolar in this assay.

limitations

In vitro transport direction depends on liposome gradients. This does not establish dietary calcium dependence or a fixed physiological Zn/Ca ratio. Calcium versus proton coupling remains incompletely resolved.

nutrient_topic

Zinc research collection; topical membership is not evidence of a direct dietary effect. · Zinc

organism

Homo sapiens protein

plain_language

A calcium gradient helped purified human ZnT1 move zinc; some movement remained without it.

primary_references

[zinc-trans-38669333] Structural insights into the calcium-coupled zinc export of human ZnT1. (2024). https://pubmed.ncbi.nlm.nih.gov/38669333/ DOI: 10.1126/sciadv.adk5128

tissue_or_cell_type

Reconstituted membrane; cultured-cell plasma membrane

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 284–295

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified full-length human ZnT1 in proteoliposomes; supporting HEK293T transport assays · source_derived_draft · unverified_draft

### zinc-trans-znt1-calcium-gradient In reconstituted human ZnT1 proteoliposomes, a transmembrane calcium gradient accelerated zinc transport and zinc addition drove calcium countertransport. Zinc transport persisted at a lower rate without the calcium gradient. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium gradient helped purified human ZnT1 move zinc; some movement remained without it. organism: Homo sapiens protein tissue_or_cell_type: Reconstituted membrane; cultured-cell plasma membrane experimental_model: Purified full-length human ZnT1 in proteoliposomes; supporting HEK293T transport assays limitations: In vitro transport direction depends on liposome gradients. This does not establish dietary calcium dependence or a fixed physiological Zn/Ca ratio. Calcium versus proton coupling remains incompletely resolved. exposure: Proteoliposomes with or without internal calcium, external zinc titration; zinc transport Km 0.38 ± 0.14 micromolar in this assay. cross_nutrient: true [zinc-trans-38669333] Structural insights into the calcium-coupled zinc export of human ZnT1. (2024). https://pubmed.ncbi.nlm.nih.gov/38669333/ DOI: 10.1126/sciadv.adk5128

cross_nutrient

true

experimental_model

Recombinant human proteins; crystal complex at 3.3 angstrom

exposure

Purified complex containing calcium ions

limitations

Does not define a dietary calcium intake target or prove nutritional calcium deficiency causes B12 malabsorption.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium helps intrinsic factor dock with the B12 receptor.

primary_references

[andersen-2010-if-cubn] Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. (2010). https://pubmed.ncbi.nlm.nih.gov/20237569/ DOI: 10.1038/nature08874

tissue_or_cell_type

Extracellular ileal receptor binding site

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 257–268

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human proteins; crystal complex at 3.3 angstrom · source_derived_draft · unverified_draft

### b12-abs-calcium-recognition In the human IF-cobalamin/CUB5-8 structure, calcium-dependent contacts connect cubilin ligand-binding domains to intrinsic factor, providing a molecular basis for calcium-dependent recognition. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps intrinsic factor dock with the B12 receptor. organism: Homo sapiens tissue_or_cell_type: Extracellular ileal receptor binding site experimental_model: Recombinant human proteins; crystal complex at 3.3 angstrom limitations: Does not define a dietary calcium intake target or prove nutritional calcium deficiency causes B12 malabsorption. exposure: Purified complex containing calcium ions cross_nutrient: true [andersen-2010-if-cubn] Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. (2010). https://pubmed.ncbi.nlm.nih.gov/20237569/ DOI: 10.1038/nature08874

cross_nutrient

true

experimental_model

Human kidney cubilin-AMN purification with chelation

exposure

EDTA present during coelution

limitations

Chelation result concerns CUBN-AMN association, not IF-cobalamin docking or whole-body calcium deficiency.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium dependence concerns ligand binding, not every receptor interaction.

primary_references

[fyfe-2004-cubam] The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. (2004). https://pubmed.ncbi.nlm.nih.gov/14576052/ DOI: 10.1182/blood-2003-08-2852

tissue_or_cell_type

Renal epithelial receptor complex

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 231–242

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human kidney cubilin-AMN purification with chelation · source_derived_draft · unverified_draft

### b12-abs-cubam-association-calcium Human renal cubilin and AMN remained associated during coelution in EDTA, indicating that their mutual association did not require calcium under these conditions. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium dependence concerns ligand binding, not every receptor interaction. organism: Homo sapiens tissue_or_cell_type: Renal epithelial receptor complex experimental_model: Human kidney cubilin-AMN purification with chelation limitations: Chelation result concerns CUBN-AMN association, not IF-cobalamin docking or whole-body calcium deficiency. exposure: EDTA present during coelution cross_nutrient: true [fyfe-2004-cubam] The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. (2004). https://pubmed.ncbi.nlm.nih.gov/14576052/ DOI: 10.1182/blood-2003-08-2852

evidence_access

Primary abstract

experimental_model

Receptor uptake assays in defined ionic solutions.

limitations

No dietary calcium–spermidine antagonism established.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

Ions and polyamines can affect each other’s channel passage.

primary_references

Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 462–468

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Receptor uptake assays in defined ionic solutions. · source_derived_draft · unverified_draft

## spermidine-nmda-calcium Ions and polyamines can affect each other’s channel passage. Calcium inhibited spermidine uptake through the tested NMDA receptors. Model: Receptor uptake assays in defined ionic solutions. Limitations: No dietary calcium–spermidine antagonism established. Evidence access: Primary abstract Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+). · 2015 · https://pubmed.ncbi.nlm.nih.gov/26086092/ · DOI 10.1016/j.bbrc.2015.06.081

evidence_span

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experimental_model

Functional expression and reporter-cell coculture

exposure

NOS3 transfection and calcium ionophore A23187

limitations

Heterologous expression; reporter activation supports bioactive NO production, not a clinical calcium supplementation effect.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human NOS3 expressed in NIH3T3 cells; rat reporter fibroblasts

plain_language

Calcium signaling can activate this enzyme; this experiment did not test taking calcium tablets.

primary_references

[citrulline-p1378832] Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. (1992). https://pubmed.ncbi.nlm.nih.gov/1378832/ DOI: 10.1016/s0021-9258(18)42066-2

tissue_or_cell_type

Arginine conversion and NO-dependent reporter guanylate cyclase activity

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 476–487

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Functional expression and reporter-cell coculture · source_derived_draft · unverified_draft

### citrulline-calcium-nos The calcium ionophore A23187 increased arginine-to-citrulline conversion in cells expressing human endothelial NOS. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium signaling can activate this enzyme; this experiment did not test taking calcium tablets. organism: Human NOS3 expressed in NIH3T3 cells; rat reporter fibroblasts tissue_or_cell_type: Arginine conversion and NO-dependent reporter guanylate cyclase activity experimental_model: Functional expression and reporter-cell coculture limitations: Heterologous expression; reporter activation supports bioactive NO production, not a clinical calcium supplementation effect. exposure: NOS3 transfection and calcium ionophore A23187 evidence_span: {"source_cache": "artifacts/citrulline-research/1378832.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "265be186f6d8172b272e7b1e75b4fbae12a6df78c7396cad499bce2b195b1206", "start_char": 0, "end_char": 1652, "text_sha256": "265be186f6d8172b272e7b1e75b4fbae12a6df78c7396cad499bce2b195b1206"} [citrulline-p1378832] Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. (1992). https://pubmed.ncbi.nlm.nih.gov/1378832/ DOI: 10.1016/s0021-9258(18)42066-2

evidence_span

{"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"}

experimental_model

Reconstituted transporter and transfected-cell assays

exposure

Aspartate exchange for glutamate plus proton; external calcium stimulation

limitations

Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human citrin and aralar proteins

plain_language

Calcium is a regulatory signal for the transporter.

primary_references

[citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

tissue_or_cell_type

Inner mitochondrial membrane transport; malate-aspartate shuttle

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 372–383

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transporter and transfected-cell assays · source_derived_draft · unverified_draft

### citrulline-citrin-calcium Calcium on the external side of the inner mitochondrial membrane stimulated citrin-mediated exchange. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium is a regulatory signal for the transporter. organism: Human citrin and aralar proteins tissue_or_cell_type: Inner mitochondrial membrane transport; malate-aspartate shuttle experimental_model: Reconstituted transporter and transfected-cell assays limitations: Cell and liposome experiments; no evidence that calcium supplementation corrects citrin deficiency. exposure: Aspartate exchange for glutamate plus proton; external calcium stimulation evidence_span: {"source_cache": "artifacts/citrulline-research/11566871.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734", "start_char": 0, "end_char": 1249, "text_sha256": "25151a91c1f832fb2e3f86421ef070fb3a7c92390b5b1e7c0038e1db1d6a0734"} [citrulline-p11566871] Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. (2001). https://pubmed.ncbi.nlm.nih.gov/11566871/ DOI: 10.1093/emboj/20.18.5060

evidence_access

Primary abstract

experimental_model

Ex vivo microvillar assays.

limitations

Not evidence that calcium supplements improve tolerance.

nutrient_topic

Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame

plain_language

Calcium availability affected measured enzyme activity.

primary_references

Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ex vivo microvillar assays. · source_derived_draft · unverified_draft

## aspartame-calcium-activation Calcium availability affected measured enzyme activity. CaCl2 increased aspartame hydrolysis 2.9–4.5-fold in the tested human and pig membrane preparations. Model: Ex vivo microvillar assays. Limitations: Not evidence that calcium supplements improve tolerance. Evidence access: Primary abstract Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635

evidence_access

Primary abstract

experimental_model

Purified calf-brain enzyme.

limitations

Free-ion assay concentrations do not establish dietary antagonism.

nutrient_topic

Lithium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Lithium

plain_language

A mineral that activates one enzyme can inhibit another.

primary_references

Inositol polyphosphate 1-phosphatase from calf brain. Purification and inhibition by Li+, Ca2+, and Mn2+. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2824473/

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 64–70

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified calf-brain enzyme. · source_derived_draft · unverified_draft

## lithium-inpp1-calcium-manganese A mineral that activates one enzyme can inhibit another. Calcium and manganese each inhibited the calf-brain enzyme by about half near 6 micromolar under the reported assay conditions. Model: Purified calf-brain enzyme. Limitations: Free-ion assay concentrations do not establish dietary antagonism. Evidence access: Primary abstract Inositol polyphosphate 1-phosphatase from calf brain. Purification and inhibition by Li+, Ca2+, and Mn2+. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2824473/

cross_nutrient

COLGALT1 (affected_protein); UDP-galactose (stabilizing_ligand); Manganese(II) ion (distinct_catalytic_ion)

evidence_span

{"source_cache": "artifacts/manganese-glycosylation-sources/colgalt2025.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "5a42e5928c56f4e312768d79c9a5601b6f9e76a44bcdd9ede4bc8ea0c8985b60", "start_char": 0, "end_char": 1331, "text_sha256": "5a42e5928c56f4e312768d79c9a5601b6f9e76a44bcdd9ede4bc8ea0c8985b60", "text_characters": 1331}

experimental_model

Human COLGALT1 structural and biochemical assays

exposure

Metal substitution and structural-domain comparisons.

limitations

Modification of collagen-bound hydroxylysine does not establish that extra dietary manganese or free lysine improves collagen in a person.

nutrient_topic

Manganese research collection; topical membership is not evidence of a direct dietary effect. · Manganese

organism

Homo sapiens

plain_language

Calcium and the donor sugar also help stabilize a separate part of this manganese enzyme.

primary_references

[mn-gly-colgalt2025] Molecular structure and enzymatic mechanism of the human collagen hydroxylysine galactosyltransferase GLT25D1/COLGALT1. (2025). https://pubmed.ncbi.nlm.nih.gov/40240392/ DOI: 10.1038/s41467-025-59017-5

tissue_or_cell_type

Purified protein and collagen peptides

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 922–934

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human COLGALT1 structural and biochemical assays · source_derived_draft · unverified_draft

### mn-gly-colgalt-gt1-stability Calcium and UDP-galactose bound in COLGALT1’s noncatalytic GT1 domain contribute to folding stability. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium and the donor sugar also help stabilize a separate part of this manganese enzyme. organism: Homo sapiens tissue_or_cell_type: Purified protein and collagen peptides experimental_model: Human COLGALT1 structural and biochemical assays limitations: Modification of collagen-bound hydroxylysine does not establish that extra dietary manganese or free lysine improves collagen in a person. exposure: Metal substitution and structural-domain comparisons. cross_nutrient: COLGALT1 (affected_protein); UDP-galactose (stabilizing_ligand); Manganese(II) ion (distinct_catalytic_ion) evidence_span: {"source_cache": "artifacts/manganese-glycosylation-sources/colgalt2025.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "5a42e5928c56f4e312768d79c9a5601b6f9e76a44bcdd9ede4bc8ea0c8985b60", "start_char": 0, "end_char": 1331, "text_sha256": "5a42e5928c56f4e312768d79c9a5601b6f9e76a44bcdd9ede4bc8ea0c8985b60", "text_characters": 1331} [mn-gly-colgalt2025] Molecular structure and enzymatic mechanism of the human collagen hydroxylysine galactosyltransferase GLT25D1/COLGALT1. (2025). https://pubmed.ncbi.nlm.nih.gov/40240392/ DOI: 10.1038/s41467-025-59017-5

cell_type

· T cell

evidence_scope

Source-derived draft; primary-source verification required

organism

· Human

Selenium in immune cells · lines 30–38

Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription

evidence_span

{"source_cache": "artifacts/pectin-research/29255254.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "514f1ffe2924a1c555e3ecea968fb7260d0f55aa1b22c057697dbc59676c5796", "start_char": 3594, "end_char": 6987, "text_sha256": "73cf8a91e0bec8b92fd78e4630a68e5b8f3e0fe9202fad389959e3de9259167c"}

experimental_model

Purified enzymes, structural biology and targeted bacterial deletions

exposure

Defined pectic substrates; growth media and recombinant-enzyme assays

limitations

Bacterial machinery, not human digestive enzymes. Gene dependence is substrate- and strain-specific; no clinical microbiome threshold follows.

nutrient_topic

Pectin research collection; topical membership is not evidence of a direct dietary effect. · Pectin, structurally heterogeneous plant polysaccharides

organism

Bacteroides thetaiotaomicron

plain_language

Calcium participates in this bacterial cutting mechanism; this does not establish a human calcium requirement for pectin fermentation.

primary_references

[pectin-p29255254] Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides. (2018). https://pubmed.ncbi.nlm.nih.gov/29255254/ DOI: 10.1038/s41564-017-0079-1

tissue_or_cell_type

Cell surface and periplasm

Pectin: metabolism, signaling and nutrient connections (2026-09-17) · lines 126–137

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified enzymes, structural biology and targeted bacterial deletions · source_derived_draft · unverified_draft

### pectin-lyase-calcium The BT4170 catalytic apparatus contained Lys285 and calcium, with substrate specificity determined outside the immediate active site. Condition category: normal nutrient_topic: Pectin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium participates in this bacterial cutting mechanism; this does not establish a human calcium requirement for pectin fermentation. organism: Bacteroides thetaiotaomicron tissue_or_cell_type: Cell surface and periplasm experimental_model: Purified enzymes, structural biology and targeted bacterial deletions limitations: Bacterial machinery, not human digestive enzymes. Gene dependence is substrate- and strain-specific; no clinical microbiome threshold follows. exposure: Defined pectic substrates; growth media and recombinant-enzyme assays evidence_span: {"source_cache": "artifacts/pectin-research/29255254.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "514f1ffe2924a1c555e3ecea968fb7260d0f55aa1b22c057697dbc59676c5796", "start_char": 3594, "end_char": 6987, "text_sha256": "73cf8a91e0bec8b92fd78e4630a68e5b8f3e0fe9202fad389959e3de9259167c"} [pectin-p29255254] Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides. (2018). https://pubmed.ncbi.nlm.nih.gov/29255254/ DOI: 10.1038/s41564-017-0079-1

cross_nutrient

true

evidence_location

Figure 1c

experimental_model

Laser wounding with extracellular calcium control

exposure

200 µM racemic alpha-tocopherol (96% pure) for 24 h; with versus without added extracellular calcium.

limitations

Acute assay calcium removal is not dietary calcium deficiency; does not identify the calcium sensor.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Homo sapiens

plain_language

Vitamin E loading did not eliminate the need for extracellular calcium during membrane repair.

primary_references

[ver-howard2011] Promotion of plasma membrane repair by vitamin E. (2011). https://pubmed.ncbi.nlm.nih.gov/22186893/ DOI: 10.1038/ncomms1594

tissue_or_cell_type

HeLa cells

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 676–688

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Laser wounding with extracellular calcium control · source_derived_draft · unverified_draft

### ver-repair-extracellular-calcium Alpha-tocopherol-loaded HeLa cells still failed to restrict dye entry after laser injury when extracellular calcium was omitted, despite improved repair in calcium-containing buffer. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin E loading did not eliminate the need for extracellular calcium during membrane repair. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Laser wounding with extracellular calcium control limitations: Acute assay calcium removal is not dietary calcium deficiency; does not identify the calcium sensor. exposure: 200 µM racemic alpha-tocopherol (96% pure) for 24 h; with versus without added extracellular calcium. cross_nutrient: true evidence_location: Figure 1c [ver-howard2011] Promotion of plasma membrane repair by vitamin E. (2011). https://pubmed.ncbi.nlm.nih.gov/22186893/ DOI: 10.1038/ncomms1594

evidence_access

Primary full text

experimental_model

Human SLC25A12 structural analysis.

limitations

The transport domain itself was not captured in a complete transport cycle.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

The second mitochondrial aspartate carrier shares a calcium-sensitive regulatory feature.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SLC25A12 structural analysis. · source_derived_draft · unverified_draft

## l-aspartate-aralar-calcium-site The second mitochondrial aspartate carrier shares a calcium-sensitive regulatory feature. Calcium-bound human aralar regulatory-domain structures likewise identified EF-hand 2 as the calcium-binding site. Model: Human SLC25A12 structural analysis. Limitations: The transport domain itself was not captured in a complete transport cycle. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

evidence_access

Primary full text

experimental_model

Human citrin/aralar domain structures and structural model.

limitations

The substrate-access gating mechanism is structure-supported interpretation, not direct observation of an entire transport cycle.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Calcium binding can change access to the transport machinery.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human citrin/aralar domain structures and structural model. · source_derived_draft · unverified_draft

## l-aspartate-carrier-vestibule Calcium binding can change access to the transport machinery. Calcium-associated movement of the mobile regulatory domain opened a vestibule in regulatory-domain structures; the authors proposed that this controls substrate access. Model: Human citrin/aralar domain structures and structural model. Limitations: The substrate-access gating mechanism is structure-supported interpretation, not direct observation of an entire transport cycle. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

evidence_access

Primary full text

experimental_model

Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures.

limitations

Domain structures do not define a dietary calcium threshold or a treatment for citrin deficiency.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Several similarly named structural motifs do not mean several equivalent calcium switches.

primary_references

Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures. · source_derived_draft · unverified_draft

## l-aspartate-citrin-calcium-site Several similarly named structural motifs do not mean several equivalent calcium switches. Human citrin regulatory-domain structures resolved calcium at EF-hand 2; the other EF-hand motifs were not all calcium-binding sites. Model: Human SLC25A13 regulatory-domain crystallography; calcium-bound and calcium-free structures. Limitations: Domain structures do not define a dietary calcium threshold or a treatment for citrin deficiency. Evidence access: Primary full text Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25410934/ · DOI 10.1038/ncomms6491

evidence_span

{"source_cache": "artifacts/inositol-research/8110188.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e", "start_char": 0, "end_char": 940, "text_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e"}

experimental_model

Purification and kinetics of placental PI synthase

exposure

Substrate and ion titrations

limitations

Assay optima and inhibitory concentrations are not dietary advice or proof of in vivo nutrient competition.

nutrient_topic

Inositol research collection; topical membership is not evidence of a direct dietary effect. · Inositol (stereoisomer family)

organism

Homo sapiens

plain_language

Calcium can restrain this isolated lipid-synthesis reaction.

primary_references

[ino-p8110188] Purification and characterization of phosphatidylinositol synthase from human placenta. (1994). https://pubmed.ncbi.nlm.nih.gov/8110188/ DOI: 10.1042/bj2970517

tissue_or_cell_type

Placental microsomal enzyme

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 535–546

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purification and kinetics of placental PI synthase · source_derived_draft · unverified_draft

### ino-cdipt-calcium Ca2+ inhibited purified human placental PI synthase in the tested conditions. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium can restrain this isolated lipid-synthesis reaction. organism: Homo sapiens tissue_or_cell_type: Placental microsomal enzyme experimental_model: Purification and kinetics of placental PI synthase limitations: Assay optima and inhibitory concentrations are not dietary advice or proof of in vivo nutrient competition. exposure: Substrate and ion titrations evidence_span: {"source_cache": "artifacts/inositol-research/8110188.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e", "start_char": 0, "end_char": 940, "text_sha256": "c05bb5272b443bde4f99d4af375d31988a4812150450d6c4462059a59aa8a09e"} [ino-p8110188] Purification and characterization of phosphatidylinositol synthase from human placenta. (1994). https://pubmed.ncbi.nlm.nih.gov/8110188/ DOI: 10.1042/bj2970517

evidence_access

Primary abstract

experimental_model

Consecutive-day dual-tracer tests with standardized meals; ten osteoporosis and seven renal-failure patients.

limitations

Small selected sample; nonlinear relationship and meal/carrier doses matter. Accessed abstract is explicitly truncated.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Strontium can be a calcium tracer surrogate without behaving identically.

primary_references

Stable strontium absorption as a measure of intestinal calcium absorption: comparison with the double-radiotracer calcium absorption test. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7955914/ · DOI 10.1042/cs0870363

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 46–52

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Consecutive-day dual-tracer tests with standardized meals; ten osteoporosis and seven renal-failure patients. · source_derived_draft · unverified_draft

## strontium-absorption-not-identical Strontium can be a calcium tracer surrogate without behaving identically. In 17 patients with osteoporosis or chronic renal failure, mean six-hour fractional absorption was 20.2% for stable strontium versus 37.8% for calcium, despite correlated time courses. Model: Consecutive-day dual-tracer tests with standardized meals; ten osteoporosis and seven renal-failure patients. Limitations: Small selected sample; nonlinear relationship and meal/carrier doses matter. Accessed abstract is explicitly truncated. Evidence access: Primary abstract Stable strontium absorption as a measure of intestinal calcium absorption: comparison with the double-radiotracer calcium absorption test. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7955914/ · DOI 10.1042/cs0870363

duration

Not stated here

evidence_access

RCSB Protein Data Bank entry metadata reviewed. No functional assay is attached to a structure record.

experimental_model

Bacillus subtilis var. natto

exposure

Not applicable

limitations

A deposited crystal structure is not a solution stoichiometry. Calcium occupancy here is what was modelled into density, and no functional calcium requirement is measured by these entries.

organism

Bacillus subtilis var. natto

plain_language

The deposited 1.36 A subtilisin NAT structure models four calcium ions across its two chains, and the 1.74 A native structure is a monomeric assembly of one 275-residue chain.

primary_references

[rcsb-3vyv] RCSB PDB entry 3VYV: crystal structure of subtilisin NAT at 1.36 A. (2013) https://www.rcsb.org/structure/3VYV Not indexed in PubMed.

route

In vitro

tissue

X-ray crystallography

Nattokinase: what the purified enzyme cleaves, what survives being eaten, and the gap between the two (2026-09-23) · lines 92–92

Original AI-assisted curation built from a supplied entity-first document of 105 entities and 129 claims. Every reference in that document was resolved against live PubMed with its abstract read and its DOI cross-checked on 2026-09-23, and the EFSA novel-food opinion was retrieved and read in full. That check corrected two PMIDs that pointed at unrelated papers, two DOIs, and two papers recorded as carrying no erratum that do carry one; it also reversed three findings the supplied document had stated backwards. Two papers carry a published correction, recorded as such and not as a retraction. Three sources are not indexed in PubMed and are cited by what they have. Laboratory lineages are recorded, so the four papers from one group, the three from another and the two readings of a single applicant dossier cannot be counted as separate lines of support. Study-specific doses, units, populations and limitations retained; activity units are never converted between systems. Not publisher full text. · supports · Bacillus subtilis var. natto · source_derived_draft · unverified_draft

The deposited 1.36 A subtilisin NAT structure models four calcium ions across its two chains, and the 1.74 A native structure is a monomeric assembly of one 275-residue chain.

compartment_description

ER membrane

experimental_model

Recombinant human ITPR3; cryo-EM in ligand-bound gating states

limitations

Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

ITPR3 provides a route for calcium to leave the ER.

primary_references

[ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

research_relationship_category

transport

tissue_or_cell_type

Recombinant ITPR3

transport_effect

raises A calcium-release channel: the recorded direction is ER lumen to cytosol.

transport_or_reaction_direction

ER lumen to cytosol

transport_pool

cytosolic calcium A calcium-release channel: the recorded direction is ER lumen to cytosol.

Calcium: mechanism-first literature curation (2026-09-17) · lines 478–490

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft

### ca-itpr3-er-calcium-channel Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ITPR3 provides a route for calcium to leave the ER. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype. research_relationship_category: transport transport_or_reaction_direction: ER lumen to cytosol compartment_description: ER membrane [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2

compartment_description

Inner mitochondrial membrane

experimental_model

Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers

limitations

Pore and overexpression evidence; native uptake also depends on accessory subunits and membrane potential.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

MCU lets calcium enter the mitochondrial matrix.

primary_references

[ca-destefani2011] A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685888/ DOI: 10.1038/nature10230

research_relationship_category

transport

tissue_or_cell_type

HeLa cells and purified channel

transport_effect

raises Recorded as promoting agonist-evoked matrix calcium uptake.

transport_or_reaction_direction

Intermembrane space to mitochondrial matrix

transport_pool

mitochondrial matrix calcium Recorded as promoting agonist-evoked matrix calcium uptake.

Calcium: mechanism-first literature curation (2026-09-17) · lines 679–691

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers · source_derived_draft · unverified_draft

### ca-mcu-matrix-uptake MCU supplies the inner-mitochondrial-membrane calcium-conducting pore and promotes agonist-evoked matrix calcium uptake. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MCU lets calcium enter the mitochondrial matrix. organism: Homo sapiens tissue_or_cell_type: HeLa cells and purified channel experimental_model: Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers limitations: Pore and overexpression evidence; native uptake also depends on accessory subunits and membrane potential. research_relationship_category: transport transport_or_reaction_direction: Intermembrane space to mitochondrial matrix compartment_description: Inner mitochondrial membrane [ca-destefani2011] A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685888/ DOI: 10.1038/nature10230

compartment_description

Plasma membrane

experimental_model

Human cardiac NCX1; cryo-EM and functional exchange assays

limitations

Net direction depends on electrochemical gradients and voltage; NCX1 is not an ATP-hydrolyzing pump.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

NCX1 couples calcium movement to sodium moving the other way.

primary_references

[ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4

research_relationship_category

transport

tissue_or_cell_type

Cardiac NCX1 expression system

transport_effect

depends Reversible exchange: forward mode extrudes calcium and reverse mode admits it, which the record states.

transport_or_reaction_direction

Reversible Na+/Ca2+ exchange; forward calcium extrusion or reverse calcium entry

transport_pool

cytosolic calcium Reversible exchange: forward mode extrudes calcium and reverse mode admits it, which the record states.

Calcium: mechanism-first literature curation (2026-09-17) · lines 625–637

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cardiac NCX1; cryo-EM and functional exchange assays · source_derived_draft · unverified_draft

### ca-ncx1-calcium-sodium-exchange Human cardiac NCX1 exchanges calcium and sodium in opposing directions across the membrane. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: NCX1 couples calcium movement to sodium moving the other way. organism: Homo sapiens tissue_or_cell_type: Cardiac NCX1 expression system experimental_model: Human cardiac NCX1; cryo-EM and functional exchange assays limitations: Net direction depends on electrochemical gradients and voltage; NCX1 is not an ATP-hydrolyzing pump. research_relationship_category: transport transport_or_reaction_direction: Reversible Na+/Ca2+ exchange; forward calcium extrusion or reverse calcium entry compartment_description: Plasma membrane [ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4

compartment_description

Plasma membrane

experimental_model

Human ORAI1 mutagenesis and membrane-current/selectivity measurements

limitations

Pore evidence does not specify channel stoichiometry or all tissue contributions.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

ORAI1 forms the pore through which store-operated calcium enters.

primary_references

[ca-prakriya2006] Orai1 is an essential pore subunit of the CRAC channel (2006). https://www.nature.com/articles/nature05122 DOI: 10.1038/nature05122

research_relationship_category

transport

tissue_or_cell_type

Recombinant channel assays

transport_effect

raises The CRAC pore carries calcium from extracellular fluid to cytosol.

transport_or_reaction_direction

Extracellular fluid to cytosol

transport_pool

cytosolic calcium The CRAC pore carries calcium from extracellular fluid to cytosol.

Calcium: mechanism-first literature curation (2026-09-17) · lines 544–556

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human ORAI1 mutagenesis and membrane-current/selectivity measurements · source_derived_draft · unverified_draft

### ca-orai1-calcium-permeation ORAI1 supplies the calcium-selective CRAC pore; transmembrane substitutions alter calcium and monovalent-ion permeability. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ORAI1 forms the pore through which store-operated calcium enters. organism: Homo sapiens tissue_or_cell_type: Recombinant channel assays experimental_model: Human ORAI1 mutagenesis and membrane-current/selectivity measurements limitations: Pore evidence does not specify channel stoichiometry or all tissue contributions. research_relationship_category: transport transport_or_reaction_direction: Extracellular fluid to cytosol compartment_description: Plasma membrane [ca-prakriya2006] Orai1 is an essential pore subunit of the CRAC channel (2006). https://www.nature.com/articles/nature05122 DOI: 10.1038/nature05122

compartment_description

Plasma membrane

experimental_model

Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays

limitations

This study combines structure and ATPase assays; it does not quantify whole-tissue extrusion flux.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

PMCA1 uses ATP to clear calcium from the cytosol.

primary_references

[ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7

research_relationship_category

transport

tissue_or_cell_type

Purified recombinant pump

transport_effect

lowers Recorded as an ATP-driven plasma-membrane calcium extrusion pump.

transport_or_reaction_direction

Cytosol to extracellular fluid

transport_pool

cytosolic calcium Recorded as an ATP-driven plasma-membrane calcium extrusion pump.

Calcium: mechanism-first literature curation (2026-09-17) · lines 585–597

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays · source_derived_draft · unverified_draft

### ca-pmca1-extrusion Human PMCA1 is an ATP-driven plasma-membrane calcium extrusion pump characterized structurally with neuroplastin. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PMCA1 uses ATP to clear calcium from the cytosol. organism: Homo sapiens tissue_or_cell_type: Purified recombinant pump experimental_model: Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays limitations: This study combines structure and ATPase assays; it does not quantify whole-tissue extrusion flux. research_relationship_category: transport transport_or_reaction_direction: Cytosol to extracellular fluid compartment_description: Plasma membrane [ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7

compartment_description

Sarcoplasmic reticulum membrane

experimental_model

Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings

limitations

Reconstituted channel; the study does not reconstruct voltage-sensor coupling in an intact muscle.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Oryctolagus cuniculus

plain_language

RyR1 supplies the skeletal-muscle calcium-release pathway.

primary_references

[ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075

research_relationship_category

transport

tissue_or_cell_type

Skeletal muscle

transport_effect

raises An intracellular calcium-release channel: the recorded direction is SR lumen to cytosol.

transport_or_reaction_direction

SR lumen to cytosol

transport_pool

cytosolic calcium An intracellular calcium-release channel: the recorded direction is SR lumen to cytosol.

Calcium: mechanism-first literature curation (2026-09-17) · lines 652–664

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings · source_derived_draft · unverified_draft

### ca-ryr1-calcium-release Purified skeletal-muscle RyR1 forms an intracellular calcium-release channel with ligand-dependent open and closed states. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: RyR1 supplies the skeletal-muscle calcium-release pathway. organism: Oryctolagus cuniculus tissue_or_cell_type: Skeletal muscle experimental_model: Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings limitations: Reconstituted channel; the study does not reconstruct voltage-sensor coupling in an intact muscle. research_relationship_category: transport transport_or_reaction_direction: SR lumen to cytosol compartment_description: Sarcoplasmic reticulum membrane [ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075

compartment_description

ER membrane

experimental_model

Purified recombinant human SERCA2b; cryo-EM and ATPase characterization

limitations

Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

SERCA2b uses ATP to refill ER calcium stores.

primary_references

[ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147

research_relationship_category

transport

tissue_or_cell_type

Recombinant SERCA2b

transport_effect

lowers Recorded as sequestration of cytosolic calcium into the ER.

transport_or_reaction_direction

Cytosol to ER lumen

transport_pool

cytosolic calcium Recorded as sequestration of cytosolic calcium into the ER.

Calcium: mechanism-first literature curation (2026-09-17) · lines 571–583

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human SERCA2b; cryo-EM and ATPase characterization · source_derived_draft · unverified_draft

### ca-serca2b-er-uptake Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: SERCA2b uses ATP to refill ER calcium stores. organism: Homo sapiens tissue_or_cell_type: Recombinant SERCA2b experimental_model: Purified recombinant human SERCA2b; cryo-EM and ATPase characterization limitations: Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform. research_relationship_category: transport transport_or_reaction_direction: Cytosol to ER lumen compartment_description: ER membrane [ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147

compartment_description

ER lumen and ER-plasma-membrane junctions

experimental_model

Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis

limitations

Local store depletion is a cellular signal, not evidence of dietary calcium deficiency.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

STIM1 detects falling calcium inside the ER.

primary_references

[ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

research_relationship_category

regulation

tissue_or_cell_type

HeLa cells

Calcium: mechanism-first literature curation (2026-09-17) · lines 505–516

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis · source_derived_draft · unverified_draft

### ca-stim1-store-sensing ER-store depletion causes STIM1 to redistribute into peripheral puncta through a mechanism requiring its luminal calcium-sensing region. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: STIM1 detects falling calcium inside the ER. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis limitations: Local store depletion is a cellular signal, not evidence of dietary calcium deficiency. research_relationship_category: regulation compartment_description: ER lumen and ER-plasma-membrane junctions [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

experimental_model

Rabbit ECaC/TRPV5 cloning, epithelial localization and expression in Xenopus oocytes

limitations

Expression assay; epithelial localization supports an apical role but does not quantify all renal calcium transport.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Oryctolagus cuniculus channel in Xenopus laevis

plain_language

TRPV5 provides a calcium entry channel.

primary_references

[hoenderop1999] Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia (1999). https://pubmed.ncbi.nlm.nih.gov/10085067/ DOI: 10.1074/jbc.274.13.8375

tissue_or_cell_type

Plasma membrane; renal epithelial channel origin

transport_effect

raises Confers calcium influx when expressed.

transport_or_reaction_direction

inward

transport_pool

cytosolic calcium Confers calcium influx when expressed.

Calcium: mechanism-first literature curation (2026-09-17) · lines 375–385

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rabbit ECaC/TRPV5 cloning, epithelial localization and expression in Xenopus oocytes · source_derived_draft · unverified_draft

### trpv5-direct-calcium-permeation Cloned rabbit ECaC, now termed TRPV5, confers calcium influx when expressed in Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPV5 provides a calcium entry channel. organism: Oryctolagus cuniculus channel in Xenopus laevis tissue_or_cell_type: Plasma membrane; renal epithelial channel origin experimental_model: Rabbit ECaC/TRPV5 cloning, epithelial localization and expression in Xenopus oocytes limitations: Expression assay; epithelial localization supports an apical role but does not quantify all renal calcium transport. transport_or_reaction_direction: inward [hoenderop1999] Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia (1999). https://pubmed.ncbi.nlm.nih.gov/10085067/ DOI: 10.1074/jbc.274.13.8375

experimental_model

Rat duodenal CaT1/TRPV6 expression in Xenopus oocytes; uptake and electrophysiology

limitations

Heterologous uptake is not proof that every intestinal calcium ion uses this channel.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Rattus norvegicus channel in Xenopus laevis

plain_language

TRPV6 permits calcium entry across a membrane.

primary_references

[peng1999] Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption (1999). https://pubmed.ncbi.nlm.nih.gov/10428857/ DOI: 10.1074/jbc.274.32.22739

tissue_or_cell_type

Plasma membrane; duodenal channel origin

transport_effect

raises Mediates electrogenic calcium uptake when expressed.

transport_or_reaction_direction

inward

transport_pool

cytosolic calcium Mediates electrogenic calcium uptake when expressed.

Calcium: mechanism-first literature curation (2026-09-17) · lines 387–397

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat duodenal CaT1/TRPV6 expression in Xenopus oocytes; uptake and electrophysiology · source_derived_draft · unverified_draft

### trpv6-direct-calcium-permeation Rat CaT1, now termed TRPV6, mediates electrogenic calcium uptake when expressed in Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPV6 permits calcium entry across a membrane. organism: Rattus norvegicus channel in Xenopus laevis tissue_or_cell_type: Plasma membrane; duodenal channel origin experimental_model: Rat duodenal CaT1/TRPV6 expression in Xenopus oocytes; uptake and electrophysiology limitations: Heterologous uptake is not proof that every intestinal calcium ion uses this channel. transport_or_reaction_direction: inward [peng1999] Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption (1999). https://pubmed.ncbi.nlm.nih.gov/10428857/ DOI: 10.1074/jbc.274.32.22739

evidence_span

{"source_cache": "artifacts/pectin-research/celus2018.publisher-abstract.txt", "locator": "Primary publisher abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ac4b4f67d7dfb4d68a06455691f949be93304d25c3475bd8caf4d618d96f472", "start_char": 0, "end_char": 1681, "text_sha256": "2ac4b4f67d7dfb4d68a06455691f949be93304d25c3475bd8caf4d618d96f472"}

experimental_model

Adsorption isotherms and simulated digestion

exposure

Citrus pectin with varied methylesterification and blockiness

limitations

In-vitro accessibility is not human mineral status.

nutrient_topic

Pectin research collection; topical membership is not evidence of a direct dietary effect. · Pectin, structurally heterogeneous plant polysaccharides

organism

No organism; in-vitro food chemistry

plain_language

Calcium interacts with the polymer.

primary_references

[pectin-pcelus2018] Interactions between citrus pectin and Zn2+ or Ca2+ and associated in vitro Zn2+ bioaccessibility as affected by degree of methylesterification and blockiness (2018). https://doi.org/10.1016/j.foodhyd.2018.01.003 DOI: 10.1016/j.foodhyd.2018.01.003

tissue_or_cell_type

Pectin-mineral solutions

Pectin: metabolism, signaling and nutrient connections (2026-09-17) · lines 503–514

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adsorption isotherms and simulated digestion · source_derived_draft · unverified_draft

### pectin-calcium-binding Calcium binding also increased with the tested structural changes. Condition category: normal nutrient_topic: Pectin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium interacts with the polymer. organism: No organism; in-vitro food chemistry tissue_or_cell_type: Pectin-mineral solutions experimental_model: Adsorption isotherms and simulated digestion limitations: In-vitro accessibility is not human mineral status. exposure: Citrus pectin with varied methylesterification and blockiness evidence_span: {"source_cache": "artifacts/pectin-research/celus2018.publisher-abstract.txt", "locator": "Primary publisher abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2ac4b4f67d7dfb4d68a06455691f949be93304d25c3475bd8caf4d618d96f472", "start_char": 0, "end_char": 1681, "text_sha256": "2ac4b4f67d7dfb4d68a06455691f949be93304d25c3475bd8caf4d618d96f472"} [pectin-pcelus2018] Interactions between citrus pectin and Zn2+ or Ca2+ and associated in vitro Zn2+ bioaccessibility as affected by degree of methylesterification and blockiness (2018). https://doi.org/10.1016/j.foodhyd.2018.01.003 DOI: 10.1016/j.foodhyd.2018.01.003

cell_type

· T cell

evidence_scope

Source-derived draft; primary-source verification required

organism

· Human

Selenium in immune cells · lines 30–38

Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

5. TCR → LCK → ZAP70 → LAT → PLCγ1 → PIP₂ → IP₃ + DAG 6. IP₃ → IP3R → ER Ca²⁺ release → store depletion 7. STIM1 oligomerizes → ORAI1 → CRAC channel → sustained Ca²⁺ entry 8. Ca²⁺/calmodulin → CALCINEURIN (PP2B) → dephosphorylates NFAT 9. NFAT → nucleus → partners with AP-1 → IL2, IFNG, CD25 transcription

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

magnesium -> PTH -> calcium

experimental_model

Human hypomagnesemic hypocalcemia clinical study

limitations

Delay is indirect evidence for resistance and does not by itself identify a receptor or cyclase defect.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Restoring the hormone signal did not immediately restore calcium; this pattern suggested an additional target-organ response problem.

primary_references

[rude-1976-human-pth-resistance] Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency (1976). https://pubmed.ncbi.nlm.nih.gov/182417/ DOI: 10.1111/j.1365-2265.1976.tb01947.x

tissue_or_cell_type

Blood; parathyroid-kidney axis

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 325–335

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human hypomagnesemic hypocalcemia clinical study · source_derived_draft · unverified_draft

### calcium-recovery-can-lag-pth-after-mg During early Mg repletion, PTH recovered before serum calcium normalized in the serially studied patients. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring the hormone signal did not immediately restore calcium; this pattern suggested an additional target-organ response problem. organism: Homo sapiens tissue_or_cell_type: Blood; parathyroid-kidney axis experimental_model: Human hypomagnesemic hypocalcemia clinical study limitations: Delay is indirect evidence for resistance and does not by itself identify a receptor or cyclase defect. cross_nutrient: magnesium -> PTH -> calcium [rude-1976-human-pth-resistance] Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency (1976). https://pubmed.ncbi.nlm.nih.gov/182417/ DOI: 10.1111/j.1365-2265.1976.tb01947.x

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

The regulatory protein site connects intracellular magnesium with calcium-channel current.

evidence-system

EF-hand mutagenesis and patch clamp; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits

experimental_model

EF-hand mutagenesis and patch clamp; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits

exposure

Calculated intracellular free Mg was varied over 0.1-7.2 mM, with a 0.8 mM control; pipette MgATP was held at 5 mM. Ca2+ or Ba2+ served as the permeant ion in separate recordings.

limitations

Supports an EF-hand-associated regulatory mechanism; not direct structural observation of bound Mg.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Rabbit cardiac CaV1.2 protein expressed in human-derived tsA-201 cells

plain_language

Changing the channel regulatory site changed its response to intracellular magnesium.

primary_references

[brunet-2005-cav12] Modulation of CaV1.2 channels by Mg2+ acting at an EF-hand motif in the COOH-terminal domain (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC2266622/ DOI: 10.1085/jgp.200509333

tissue

tsA-201 cells

tissue_or_cell_type

tsA-201 cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1303–1316

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · EF-hand mutagenesis and patch clamp; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits · source_derived_draft · unverified_draft

### cav12-ef-hand-magnesium-sensitivity CaV1.2 EF-hand substitutions shifted Mg inhibition, with D1546K eliminating sensitivity across the tested range. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing the channel regulatory site changed its response to intracellular magnesium. organism: Rabbit cardiac CaV1.2 protein expressed in human-derived tsA-201 cells tissue_or_cell_type: tsA-201 cells experimental_model: EF-hand mutagenesis and patch clamp; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits limitations: Supports an EF-hand-associated regulatory mechanism; not direct structural observation of bound Mg. cross_nutrient: The regulatory protein site connects intracellular magnesium with calcium-channel current. exposure: Calculated intracellular free Mg was varied over 0.1-7.2 mM, with a 0.8 mM control; pipette MgATP was held at 5 mM. Ca2+ or Ba2+ served as the permeant ion in separate recordings. evidence-system: EF-hand mutagenesis and patch clamp; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits tissue: tsA-201 cells [brunet-2005-cav12] Modulation of CaV1.2 channels by Mg2+ acting at an EF-hand motif in the COOH-terminal domain (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC2266622/ DOI: 10.1085/jgp.200509333

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

TAL electrical selectivity participates in magnesium and calcium conservation; no dietary synergy is implied.

evidence-system

Renal RNAi and isolated TAL electrophysiology

experimental_model

Renal RNAi and isolated TAL electrophysiology

limitations

Selectivity evidence is not proof claudin-16 alone forms a specifically magnesium-selective pore.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mouse

plain_language

The junction lost part of its preference for positively charged ions, changing the conditions that support mineral recovery.

primary_references

[hou-2007-cldn16] Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium. (2007). https://pubmed.ncbi.nlm.nih.gov/17442678/ DOI: 10.1074/jbc.M700632200

tissue

Renal thick ascending limb

tissue_or_cell_type

Renal thick ascending limb

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1097–1109

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Renal RNAi and isolated TAL electrophysiology · source_derived_draft · unverified_draft

### cldn16-depletion-selectivity Claudin-16 RNAi reduced paracellular cation selectivity in isolated mouse thick ascending limbs. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The junction lost part of its preference for positively charged ions, changing the conditions that support mineral recovery. organism: Mouse tissue_or_cell_type: Renal thick ascending limb experimental_model: Renal RNAi and isolated TAL electrophysiology limitations: Selectivity evidence is not proof claudin-16 alone forms a specifically magnesium-selective pore. cross_nutrient: TAL electrical selectivity participates in magnesium and calcium conservation; no dietary synergy is implied. evidence-system: Renal RNAi and isolated TAL electrophysiology tissue: Renal thick ascending limb [hou-2007-cldn16] Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium. (2007). https://pubmed.ncbi.nlm.nih.gov/17442678/ DOI: 10.1074/jbc.M700632200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Calcium wasting accompanied magnesium loss after shared tight-junction impairment.

evidence-system

Transgenic Cldn16 RNAi with renal mineral phenotyping

experimental_model

Transgenic Cldn16 RNAi with renal mineral phenotyping

limitations

This organismal endpoint accompanies selectivity changes; the experiment does not isolate every intervening transport step.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mouse

plain_language

Reducing this tight-junction component made the kidneys lose magnesium.

primary_references

[hou-2007-cldn16] Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium. (2007). https://pubmed.ncbi.nlm.nih.gov/17442678/ DOI: 10.1074/jbc.M700632200

tissue

Kidney; urine

tissue_or_cell_type

Kidney; urine

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1111–1123

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transgenic Cldn16 RNAi with renal mineral phenotyping · source_derived_draft · unverified_draft

### cldn16-rnai-magnesium-loss Claudin-16 RNAi mice developed renal magnesium wasting. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing this tight-junction component made the kidneys lose magnesium. organism: Mouse tissue_or_cell_type: Kidney; urine experimental_model: Transgenic Cldn16 RNAi with renal mineral phenotyping limitations: This organismal endpoint accompanies selectivity changes; the experiment does not isolate every intervening transport step. cross_nutrient: Calcium wasting accompanied magnesium loss after shared tight-junction impairment. evidence-system: Transgenic Cldn16 RNAi with renal mineral phenotyping tissue: Kidney; urine [hou-2007-cldn16] Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium. (2007). https://pubmed.ncbi.nlm.nih.gov/17442678/ DOI: 10.1074/jbc.M700632200

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

The disorder also includes abnormal calcium handling; shared renal machinery is implicated rather than competition for dietary absorption.

curation_notes

Existing catalog claim fb9278a2-5be5-5e4b-92f3-e02f00f3cfc7 covers the same families with urinary-calcium-excretion endpoint. This magnesium endpoint is deliberately separate.

evidence-system

Human family genetics with trafficking and assembly support

experimental_model

Human family genetics with trafficking and assembly support

limitations

Associated retinal abnormalities are not assigned solely to low Mg.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Human

plain_language

Claudin-19 failure can make the kidneys lose magnesium.

primary_references

[konrad-2006-cldn19] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement (2006). https://pubmed.ncbi.nlm.nih.gov/17033971/ DOI: 10.1086/508617

tissue

Renal tubules

tissue_or_cell_type

Renal tubules

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1069–1082

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human family genetics with trafficking and assembly support · source_derived_draft · unverified_draft

### human-cldn19-magnesium-wasting Pathogenic CLDN19 variants were identified in families with renal magnesium loss and hypomagnesemia. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Claudin-19 failure can make the kidneys lose magnesium. organism: Human tissue_or_cell_type: Renal tubules experimental_model: Human family genetics with trafficking and assembly support limitations: Associated retinal abnormalities are not assigned solely to low Mg. cross_nutrient: The disorder also includes abnormal calcium handling; shared renal machinery is implicated rather than competition for dietary absorption. curation_notes: Existing catalog claim fb9278a2-5be5-5e4b-92f3-e02f00f3cfc7 covers the same families with urinary-calcium-excretion endpoint. This magnesium endpoint is deliberately separate. evidence-system: Human family genetics with trafficking and assembly support tissue: Renal tubules [konrad-2006-cldn19] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement (2006). https://pubmed.ncbi.nlm.nih.gov/17033971/ DOI: 10.1086/508617

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Calcium concentration also fell in the inherited Mg-handling disorder; this record does not specify the downstream endocrine mechanism.

evidence-system

Familial positional genetics

experimental_model

Familial positional genetics

limitations

Mapping alone does not apportion intestinal versus renal contributions or prove every downstream symptom is Mg-only.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Human

plain_language

Inherited failure of magnesium handling produced a recognizable low-magnesium disorder.

primary_references

[schlingmann-2002-trpm6] Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. (2002). https://pubmed.ncbi.nlm.nih.gov/12032568/ DOI: 10.1038/ng889

tissue

Intestine and kidney implicated; serum phenotype

tissue_or_cell_type

Intestine and kidney implicated; serum phenotype

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 909–921

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Familial positional genetics · source_derived_draft · unverified_draft

### human-trpm6-loss-low-magnesium Pathogenic biallelic TRPM6 variants were identified in families with hypomagnesemia and secondary hypocalcemia. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Inherited failure of magnesium handling produced a recognizable low-magnesium disorder. organism: Human tissue_or_cell_type: Intestine and kidney implicated; serum phenotype experimental_model: Familial positional genetics limitations: Mapping alone does not apportion intestinal versus renal contributions or prove every downstream symptom is Mg-only. cross_nutrient: Calcium concentration also fell in the inherited Mg-handling disorder; this record does not specify the downstream endocrine mechanism. evidence-system: Familial positional genetics tissue: Intestine and kidney implicated; serum phenotype [schlingmann-2002-trpm6] Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. (2002). https://pubmed.ncbi.nlm.nih.gov/12032568/ DOI: 10.1038/ng889

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

TRPM7 is shared machinery for magnesium and calcium handling in this developmental model; causal Mg-to-Ca nutritional dependence was not isolated.

evidence-system

Conditional knockout; postnatal mineral phenotyping

experimental_model

Conditional knockout; postnatal mineral phenotyping

limitations

Shared channel loss; does not prove low Mg intake causes calcium malabsorption.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Mouse

plain_language

The same epithelial channel machinery supports calcium as well as magnesium supply.

primary_references

[mittermeier-2019-trpm7] TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival (2019). https://pubmed.ncbi.nlm.nih.gov/30770447/ DOI: 10.1073/pnas.1810633116

tissue

Intestine; serum and bone

tissue_or_cell_type

Intestine; serum and bone

trigger_kind

machinery_impairment Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 988–1000

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Conditional knockout; postnatal mineral phenotyping · source_derived_draft · unverified_draft

### intestinal-trpm7-loss-calcium Intestinal Trpm7 deletion reduced serum and bone calcium in suckling mice. Condition category: machinery_impairment nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same epithelial channel machinery supports calcium as well as magnesium supply. organism: Mouse tissue_or_cell_type: Intestine; serum and bone experimental_model: Conditional knockout; postnatal mineral phenotyping limitations: Shared channel loss; does not prove low Mg intake causes calcium malabsorption. cross_nutrient: TRPM7 is shared machinery for magnesium and calcium handling in this developmental model; causal Mg-to-Ca nutritional dependence was not isolated. evidence-system: Conditional knockout; postnatal mineral phenotyping tissue: Intestine; serum and bone [mittermeier-2019-trpm7] TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival (2019). https://pubmed.ncbi.nlm.nih.gov/30770447/ DOI: 10.1073/pnas.1810633116

cross_nutrient

Mg availability directly modulated Ca-channel function in an expression assay, not intestinal calcium absorption.

evidence-system

Whole-cell recordings with intracellular free-Mg control; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits

experimental_model

Whole-cell recordings with intracellular free-Mg control; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits

exposure

Calculated intracellular free Mg was varied over 0.1-7.2 mM, with a 0.8 mM control; pipette MgATP was held at 5 mM. Ca2+ or Ba2+ served as the permeant ion in separate recordings.

limitations

Free Mg was experimentally controlled; no dietary intake, serum threshold or cardiac event was measured.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Rabbit cardiac CaV1.2 protein expressed in human-derived tsA-201 cells

plain_language

Free magnesium inside the cell can restrain current through a calcium-entry channel.

primary_references

[brunet-2005-cav12] Modulation of CaV1.2 channels by Mg2+ acting at an EF-hand motif in the COOH-terminal domain (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC2266622/ DOI: 10.1085/jgp.200509333

tissue

tsA-201 cells

tissue_or_cell_type

tsA-201 cells

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1288–1301

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Whole-cell recordings with intracellular free-Mg control; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits · source_derived_draft · unverified_draft

### intracellular-magnesium-reduces-cav12-current Increasing intracellular free Mg reduced Ca2+ and Ba2+ currents through recombinant CaV1.2. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Free magnesium inside the cell can restrain current through a calcium-entry channel. organism: Rabbit cardiac CaV1.2 protein expressed in human-derived tsA-201 cells tissue_or_cell_type: tsA-201 cells experimental_model: Whole-cell recordings with intracellular free-Mg control; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits limitations: Free Mg was experimentally controlled; no dietary intake, serum threshold or cardiac event was measured. cross_nutrient: Mg availability directly modulated Ca-channel function in an expression assay, not intestinal calcium absorption. exposure: Calculated intracellular free Mg was varied over 0.1-7.2 mM, with a 0.8 mM control; pipette MgATP was held at 5 mM. Ca2+ or Ba2+ served as the permeant ion in separate recordings. evidence-system: Whole-cell recordings with intracellular free-Mg control; rabbit cardiac CaV1.2 with beta1b and alpha2delta auxiliary subunits tissue: tsA-201 cells [brunet-2005-cav12] Modulation of CaV1.2 channels by Mg2+ acting at an EF-hand motif in the COOH-terminal domain (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC2266622/ DOI: 10.1085/jgp.200509333

cross_nutrient

magnesium -> PTH -> calcium

experimental_model

Graded extracellular cations in cultured bovine parathyroid slices

limitations

Potency depends on concentrations and preparation; no general human replacement ratio follows.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Bos taurus

plain_language

Both ions can signal the gland to release less PTH; calcium and magnesium are not interchangeable inputs.

primary_references

[habener-1976-pth-synthesis-secretion] Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vitro (1976). https://pubmed.ncbi.nlm.nih.gov/1248443/ DOI: 10.1210/endo-98-1-197

tissue_or_cell_type

Parathyroid gland

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 253–263

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Graded extracellular cations in cultured bovine parathyroid slices · source_derived_draft · unverified_draft

### mg-ca-differential-pth-secretory-potency In bovine parathyroid slices, extracellular Mg and Ca inhibited PTH release additively, but Mg was less potent on a molar basis. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both ions can signal the gland to release less PTH; calcium and magnesium are not interchangeable inputs. organism: Bos taurus tissue_or_cell_type: Parathyroid gland experimental_model: Graded extracellular cations in cultured bovine parathyroid slices limitations: Potency depends on concentrations and preparation; no general human replacement ratio follows. cross_nutrient: magnesium -> PTH -> calcium [habener-1976-pth-synthesis-secretion] Relative effectiveness of magnesium and calcium on the secretion and biosynthesis of parathyroid hormone in vitro (1976). https://pubmed.ncbi.nlm.nih.gov/1248443/ DOI: 10.1210/endo-98-1-197

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Magnesium -> calcium response; vitamin D normalization is not obligatory in this cohort.

experimental_model

Five to thirteen days of parenteral Mg.

limitations

Nonrandomized clinical response; calcium recovery does not prove that calcitriol rose.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Restoring magnesium did not automatically normalize every vitamin D result.

primary_references

[mg-rude1985] Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency (1985). https://pubmed.ncbi.nlm.nih.gov/3840173/ DOI: 10.1210/jcem-61-5-933

tissue_or_cell_type

Human serum; circulating mineral and vitamin D metabolites

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1358–1368

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five to thirteen days of parenteral Mg. · source_derived_draft · unverified_draft

### mg-calcium-recovery-precedes-calcitriol Magnesium treatment normalized mean serum calcium, while calcitriol rose into or above normal in only five of the 23 patients. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring magnesium did not automatically normalize every vitamin D result. organism: Homo sapiens tissue_or_cell_type: Human serum; circulating mineral and vitamin D metabolites experimental_model: Five to thirteen days of parenteral Mg. limitations: Nonrandomized clinical response; calcium recovery does not prove that calcitriol rose. cross_nutrient: Magnesium -> calcium response; vitamin D normalization is not obligatory in this cohort. [mg-rude1985] Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency (1985). https://pubmed.ncbi.nlm.nih.gov/3840173/ DOI: 10.1210/jcem-61-5-933

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Magnesium -> vitamin D/calcium regulation; direct CYP cofactor step not established.

experimental_model

Clinical metabolite measurements.

limitations

Association within an affected cohort; substrate supply, PTH and other illness can contribute.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Magnesium depletion can accompany low active vitamin D.

primary_references

[mg-rude1985] Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency (1985). https://pubmed.ncbi.nlm.nih.gov/3840173/ DOI: 10.1210/jcem-61-5-933

tissue_or_cell_type

Human serum; circulating mineral and vitamin D metabolites

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1346–1356

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical metabolite measurements. · source_derived_draft · unverified_draft

### mg-deficient-human-low-calcitriol Sixteen of 23 hypocalcemic magnesium-deficient patients had low circulating calcitriol. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium depletion can accompany low active vitamin D. organism: Homo sapiens tissue_or_cell_type: Human serum; circulating mineral and vitamin D metabolites experimental_model: Clinical metabolite measurements. limitations: Association within an affected cohort; substrate supply, PTH and other illness can contribute. cross_nutrient: Magnesium -> vitamin D/calcium regulation; direct CYP cofactor step not established. [mg-rude1985] Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency (1985). https://pubmed.ncbi.nlm.nih.gov/3840173/ DOI: 10.1210/jcem-61-5-933

cross_nutrient

magnesium -> calcium sensing

experimental_model

Six-hour ex-vivo gland incubation with receptor expression assays

limitations

Receptor abundance alone does not prove altered clinical calcium balance; VDR, FGFR1 and Klotho also rose in this experiment.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Rattus norvegicus

plain_language

Mg exposure can change the amount of the calcium-sensing receptor, adding a slower response to immediate ion sensing.

primary_references

[rodriguez-ortiz-2014-pth-context] Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration (2014). https://pubmed.ncbi.nlm.nih.gov/24103811/ DOI: 10.1093/ndt/gft400

tissue_or_cell_type

Parathyroid gland

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 289–299

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-hour ex-vivo gland incubation with receptor expression assays · source_derived_draft · unverified_draft

### mg-increases-parathyroid-casr-expression At 1.0 mM Ca, six-hour exposure to 2.0 versus 0.5 mM Mg increased CaSR mRNA and protein in intact rat glands. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mg exposure can change the amount of the calcium-sensing receptor, adding a slower response to immediate ion sensing. organism: Rattus norvegicus tissue_or_cell_type: Parathyroid gland experimental_model: Six-hour ex-vivo gland incubation with receptor expression assays limitations: Receptor abundance alone does not prove altered clinical calcium balance; VDR, FGFR1 and Klotho also rose in this experiment. cross_nutrient: magnesium -> calcium sensing [rodriguez-ortiz-2014-pth-context] Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration (2014). https://pubmed.ncbi.nlm.nih.gov/24103811/ DOI: 10.1093/ndt/gft400

cross_nutrient

Magnesium and thiamine-derived ThDP intersect at mitochondrial carbon metabolism; purified-enzyme responses do not measure whole-body energy supply.

experimental_model

Human OGDH cryo-EM structure; deposited coordinate model 7WGR.

limitations

Structure does not establish a clinical Mg threshold or metal replacement equivalence.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The human alpha-ketoglutarate-processing enzyme has distinct cofactor and calcium-regulatory architecture.

primary_references

[zhong-2022-ogdh] Structural basis for the activity and regulation of human α-ketoglutarate dehydrogenase revealed by Cryo-EM (2022). https://pubmed.ncbi.nlm.nih.gov/35272141/ DOI: 10.1016/j.bbrc.2022.02.093

structure_url

https://pdbj.org/mine/summary/7wgr

tissue_or_cell_type

Recombinant mitochondrial OGDH

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 662–673

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human OGDH cryo-EM structure; deposited coordinate model 7WGR. · source_derived_draft · unverified_draft

### mg-ogdh-human-cofactor-structure The human OGDH cryo-EM model 7WGR contains Mg and ThDP as well as a separate Ca-binding site. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The human alpha-ketoglutarate-processing enzyme has distinct cofactor and calcium-regulatory architecture. organism: Homo sapiens tissue_or_cell_type: Recombinant mitochondrial OGDH experimental_model: Human OGDH cryo-EM structure; deposited coordinate model 7WGR. limitations: Structure does not establish a clinical Mg threshold or metal replacement equivalence. cross_nutrient: Magnesium and thiamine-derived ThDP intersect at mitochondrial carbon metabolism; purified-enzyme responses do not measure whole-body energy supply. structure_url: https://pdbj.org/mine/summary/7wgr [zhong-2022-ogdh] Structural basis for the activity and regulation of human α-ketoglutarate dehydrogenase revealed by Cryo-EM (2022). https://pubmed.ncbi.nlm.nih.gov/35272141/ DOI: 10.1016/j.bbrc.2022.02.093

cross_nutrient

magnesium -> PTH -> calcium

experimental_model

Intact rat parathyroid glands in graded Ca/Mg media

limitations

An ex-vivo concentration response, not a human threshold; very high 5 mM Mg produced broader suppression.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Rattus norvegicus

plain_language

How much extra Mg reduces PTH depends on the calcium signal already reaching the gland.

primary_references

[rodriguez-ortiz-2014-pth-context] Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration (2014). https://pubmed.ncbi.nlm.nih.gov/24103811/ DOI: 10.1093/ndt/gft400

tissue_or_cell_type

Parathyroid gland

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 277–287

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact rat parathyroid glands in graded Ca/Mg media · source_derived_draft · unverified_draft

### mg-pth-inhibition-depends-on-calcium In intact rat glands, raising Mg from 0.5 to 2 mM suppressed PTH most clearly at moderately low Ca; suppression was small or absent at normal-high Ca and diminished again at very low Ca. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: How much extra Mg reduces PTH depends on the calcium signal already reaching the gland. organism: Rattus norvegicus tissue_or_cell_type: Parathyroid gland experimental_model: Intact rat parathyroid glands in graded Ca/Mg media limitations: An ex-vivo concentration response, not a human threshold; very high 5 mM Mg produced broader suppression. cross_nutrient: magnesium -> PTH -> calcium [rodriguez-ortiz-2014-pth-context] Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration (2014). https://pubmed.ncbi.nlm.nih.gov/24103811/ DOI: 10.1093/ndt/gft400

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

magnesium -> PTH -> calcium

experimental_model

Acute Mg administration across clinical groups

limitations

Biphasic/status-dependent response does not establish one serum Mg breakpoint applicable to all patients.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

Restoring missing Mg can release a suppressed PTH response, while adding Mg in another starting state can inhibit it.

primary_references

[rude-1978-status-dependent-pth] Parathyroid hormone secretion in magnesium deficiency (1978). https://pubmed.ncbi.nlm.nih.gov/263326/ DOI: 10.1210/jcem-47-4-800

tissue_or_cell_type

Blood; parathyroid axis

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 349–359

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute Mg administration across clinical groups · source_derived_draft · unverified_draft

### mg-pth-response-depends-on-prior-status Mg administration promptly raised PTH in hypomagnesemic patients, whereas normal and hyperparathyroid comparison groups showed a decrease or little change. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring missing Mg can release a suppressed PTH response, while adding Mg in another starting state can inhibit it. organism: Homo sapiens tissue_or_cell_type: Blood; parathyroid axis experimental_model: Acute Mg administration across clinical groups limitations: Biphasic/status-dependent response does not establish one serum Mg breakpoint applicable to all patients. cross_nutrient: magnesium -> PTH -> calcium [rude-1978-status-dependent-pth] Parathyroid hormone secretion in magnesium deficiency (1978). https://pubmed.ncbi.nlm.nih.gov/263326/ DOI: 10.1210/jcem-47-4-800

cross_nutrient

Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure.

experimental_model

Recombinant human TKT crystallography, kinetics and NMR.

limitations

Retention is preparation- and protocol-specific; this is not a measurement of in vivo Mg depletion.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

The enzyme can retain loaded cofactors; free-metal changes need not immediately strip them away.

primary_references

[mitschke-2010-tkt] The Crystal Structure of Human Transketolase and New Insights into Its Mode of Action (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC2951230/ DOI: 10.1074/jbc.M110.149955

tissue_or_cell_type

Purified recombinant TKT

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 601–611

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human TKT crystallography, kinetics and NMR. · source_derived_draft · unverified_draft

### mg-tkt-tight-cofactor-retention Recombinant human TKT retained ThDP and Ca2+ strongly under cofactor-removal conditions used in the study. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme can retain loaded cofactors; free-metal changes need not immediately strip them away. organism: Homo sapiens tissue_or_cell_type: Purified recombinant TKT experimental_model: Recombinant human TKT crystallography, kinetics and NMR. limitations: Retention is preparation- and protocol-specific; this is not a measurement of in vivo Mg depletion. cross_nutrient: Magnesium availability supports vitamin B1 activation or cofactor use in the specified preparation; this does not establish a dietary threshold or universal treatment failure. [mitschke-2010-tkt] The Crystal Structure of Human Transketolase and New Insights into Its Mode of Action (2010). https://pmc.ncbi.nlm.nih.gov/articles/PMC2951230/ DOI: 10.1074/jbc.M110.149955

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

magnesium -> PTH -> calcium

experimental_model

26 initially normal adults before/after three-week low-Mg diet

limitations

Before/after experiment; not a population diagnostic rule. Depletion was supported by serum Mg, retention, and red-cell free Mg changes.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

PTH compensation was impaired during an induced shortage, before a failed calcium-replacement attempt was needed to reveal it.

primary_references

[fatemi-1991-selective-depletion] Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. (1991). https://pubmed.ncbi.nlm.nih.gov/1939521/ DOI: 10.1210/jcem-73-5-1067

tissue_or_cell_type

Blood; parathyroid and renal mineral axis

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 361–371

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 26 initially normal adults before/after three-week low-Mg diet · source_derived_draft · unverified_draft

### selective-mg-depletion-impairs-pth-compensation After selective dietary Mg depletion, 20 of 26 adults showed unchanged or reduced PTH despite falling serum Mg and Ca. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PTH compensation was impaired during an induced shortage, before a failed calcium-replacement attempt was needed to reveal it. organism: Homo sapiens tissue_or_cell_type: Blood; parathyroid and renal mineral axis experimental_model: 26 initially normal adults before/after three-week low-Mg diet limitations: Before/after experiment; not a population diagnostic rule. Depletion was supported by serum Mg, retention, and red-cell free Mg changes. cross_nutrient: magnesium -> PTH -> calcium [fatemi-1991-selective-depletion] Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. (1991). https://pubmed.ncbi.nlm.nih.gov/1939521/ DOI: 10.1210/jcem-73-5-1067

evidence-system

Recombinant channel recordings and tissue localization

experimental_model

Recombinant channel recordings and tissue localization

limitations

Expression-system currents do not establish the stoichiometry of native channels; TRPM7 can contribute.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Human protein; mouse tissues

plain_language

TRPM6 is part of the route by which magnesium crosses an epithelial cell membrane.

primary_references

[voets-2004-trpm6] TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. (2004). https://pubmed.ncbi.nlm.nih.gov/14576148/ DOI: 10.1074/jbc.M311201200

tissue

HEK expression cells; intestine and distal renal tubule

tissue_or_cell_type

HEK expression cells; intestine and distal renal tubule

transport_direction

Extracellular or luminal compartment toward cytosol.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 869–881

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant channel recordings and tissue localization · source_derived_draft · unverified_draft

### trpm6-mg-entry Recombinant TRPM6 expression generated Mg2+-permeable currents, supporting its participation in apical epithelial Mg entry. Condition category: normal nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPM6 is part of the route by which magnesium crosses an epithelial cell membrane. organism: Human protein; mouse tissues tissue_or_cell_type: HEK expression cells; intestine and distal renal tubule experimental_model: Recombinant channel recordings and tissue localization limitations: Expression-system currents do not establish the stoichiometry of native channels; TRPM7 can contribute. transport_direction: Extracellular or luminal compartment toward cytosol. evidence-system: Recombinant channel recordings and tissue localization tissue: HEK expression cells; intestine and distal renal tubule [voets-2004-trpm6] TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. (2004). https://pubmed.ncbi.nlm.nih.gov/14576148/ DOI: 10.1074/jbc.M311201200

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

magnesium -> CaSR/PTH -> calcium

experimental_model

Dispersed human parathyroid cells from hyperparathyroid tissue

limitations

Experiment used hyperparathyroid tissue; culture concentrations are not clinical deficiency cutoffs.

nutrient_topic

Magnesium research collection; topical membership is not evidence of a direct dietary effect. · Magnesium

organism

Homo sapiens

plain_language

At very low Mg, the gland cells released less PTH even though simple loss of an inhibitory extracellular ion might predict more release.

primary_references

[quitterer-2001-magnesium-paradox] Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits (2001). https://pubmed.ncbi.nlm.nih.gov/11102444/ DOI: 10.1074/jbc.M007727200

tissue_or_cell_type

Parathyroid cells in vitro

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 409–419

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dispersed human parathyroid cells from hyperparathyroid tissue · source_derived_draft · unverified_draft

### very-low-mg-suppresses-pth-in-human-cells Lowering extracellular Mg to 0.1 mM suppressed PTH release from dispersed human parathyroid cells in the tested media. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: At very low Mg, the gland cells released less PTH even though simple loss of an inhibitory extracellular ion might predict more release. organism: Homo sapiens tissue_or_cell_type: Parathyroid cells in vitro experimental_model: Dispersed human parathyroid cells from hyperparathyroid tissue limitations: Experiment used hyperparathyroid tissue; culture concentrations are not clinical deficiency cutoffs. cross_nutrient: magnesium -> CaSR/PTH -> calcium [quitterer-2001-magnesium-paradox] Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits (2001). https://pubmed.ncbi.nlm.nih.gov/11102444/ DOI: 10.1074/jbc.M007727200

evidence_access

Primary abstract

experimental_model

Human Caco-2 calcium-switch model.

limitations

This does not show that dietary calcium or magnesium supplementation improves the response.

nutrient_topic

Butyrate collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Butyrate

plain_language

Calcium signaling helped connect butyrate to barrier repair.

primary_references

Sodium Butyrate Promotes Reassembly of Tight Junctions in Caco-2 Monolayers Involving Inhibition of MLCK/MLC2 Pathway and Phosphorylation of PKCβ2. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27735862/ · DOI 10.3390/ijms17101696

Butyrate: microbial production, fuel use, signaling and nutrient interactions (2026-09-19) · lines 270–276

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human Caco-2 calcium-switch model. · source_derived_draft · unverified_draft

## butyrate-calcium-soce Calcium signaling helped connect butyrate to barrier repair. Sodium butyrate promoted store-operated calcium entry and activated the CaMKK-beta/AMPK pathway during Caco-2 tight-junction reassembly, without the change being explained by ATP concentration. Model: Human Caco-2 calcium-switch model. Limitations: This does not show that dietary calcium or magnesium supplementation improves the response. Evidence access: Primary abstract Sodium Butyrate Promotes Reassembly of Tight Junctions in Caco-2 Monolayers Involving Inhibition of MLCK/MLC2 Pathway and Phosphorylation of PKCβ2. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27735862/ · DOI 10.3390/ijms17101696

evidence_access

Primary abstract

experimental_model

Human Caco-2 monolayers; calcium-switch and permeability assays.

limitations

Compound C is not uniquely specific for AMPK; this is a culture mechanism, not proven treatment of human intestinal permeability.

nutrient_topic

Butyrate collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Butyrate

plain_language

An energy-sensing pathway contributed to barrier assembly.

primary_references

Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19625695/ · DOI 10.3945/jn.109.104638

Butyrate: microbial production, fuel use, signaling and nutrient interactions (2026-09-19) · lines 262–268

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human Caco-2 monolayers; calcium-switch and permeability assays. · source_derived_draft · unverified_draft

## butyrate-tight-junction-ampk An energy-sensing pathway contributed to barrier assembly. Butyrate increased AMPK activity and accelerated tight-junction assembly in human Caco-2 monolayers; compound C abolished the improvement in electrical resistance. Model: Human Caco-2 monolayers; calcium-switch and permeability assays. Limitations: Compound C is not uniquely specific for AMPK; this is a culture mechanism, not proven treatment of human intestinal permeability. Evidence access: Primary abstract Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19625695/ · DOI 10.3945/jn.109.104638

evidence_access

Primary abstract

experimental_model

Rat clonal beta-cell chronic exposure and acute rechallenge.

limitations

Linked measurements do not prove which upstream molecular change caused desensitization.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

The weakened insulin response was accompanied by weaker electrical and calcium signals.

primary_references

Prolonged L-alanine exposure induces changes in metabolism, Ca(2+) handling and desensitization of insulin secretion in clonal pancreatic beta-cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18702613/ · DOI 10.1042/CS20080138

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 408–414

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat clonal beta-cell chronic exposure and acute rechallenge. · source_derived_draft · unverified_draft

## alanine-beta-chronic-calcium The weakened insulin response was accompanied by weaker electrical and calcium signals. Prior prolonged alanine culture attenuated subsequent alanine-evoked depolarization and intracellular calcium rise in BRIN-BD11 cells. Model: Rat clonal beta-cell chronic exposure and acute rechallenge. Limitations: Linked measurements do not prove which upstream molecular change caused desensitization. Evidence access: Primary abstract Prolonged L-alanine exposure induces changes in metabolism, Ca(2+) handling and desensitization of insulin secretion in clonal pancreatic beta-cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18702613/ · DOI 10.1042/CS20080138

evidence_access

Primary abstract

experimental_model

Normal rat islets; radiocalcium uptake.

limitations

This does not identify a unique sodium transporter or calcium-channel isoform.

nutrient_topic

L-Alanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Alanine

plain_language

Amino-acid exposure can affect the ion signal used for secretion.

primary_references

The stimulus-secretion coupling of amino acid-induced insulin release. Insulinotropic action of L-alanine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12383948/ · DOI 10.1016/s0304-4165(02)00337-9

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 384–390

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Normal rat islets; radiocalcium uptake. · source_derived_draft · unverified_draft

## alanine-islet-calcium Amino-acid exposure can affect the ion signal used for secretion. Alanine stimulated calcium-45 uptake in rat islets without another exogenous nutrient. Model: Normal rat islets; radiocalcium uptake. Limitations: This does not identify a unique sodium transporter or calcium-channel isoform. Evidence access: Primary abstract The stimulus-secretion coupling of amino acid-induced insulin release. Insulinotropic action of L-alanine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12383948/ · DOI 10.1016/s0304-4165(02)00337-9

evidence_span

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experimental_model

Acute-hypoxia cellular and mitochondrial experiments with ion imaging and respiratory/membrane assays

exposure

Acute hypoxia and inhibition of mitochondrial sodium/calcium exchange

limitations

Mechanistic research under hypoxia, including multiple preparations. Do not infer that dietary salt drives this chain, that every tissue responds identically, or that ROS here proves disease.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Human and mouse cells; additional rat vascular experiments in the paper

plain_language

Calcium stored in deposits became available as free calcium.

primary_references

[sodium-p32728214] Na+ controls hypoxic signalling by the mitochondrial respiratory chain. (2020). https://pubmed.ncbi.nlm.nih.gov/32728214/ DOI: 10.1038/s41586-020-2551-y

tissue_or_cell_type

Mitochondrial matrix and inner membrane

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 759–770

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute-hypoxia cellular and mitochondrial experiments with ion imaging and respiratory/membrane assays · source_derived_draft · unverified_draft

### sodium-matrix-calcium Matrix acidification released free calcium from mitochondrial calcium phosphate deposits. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium stored in deposits became available as free calcium. organism: Human and mouse cells; additional rat vascular experiments in the paper tissue_or_cell_type: Mitochondrial matrix and inner membrane experimental_model: Acute-hypoxia cellular and mitochondrial experiments with ion imaging and respiratory/membrane assays limitations: Mechanistic research under hypoxia, including multiple preparations. Do not infer that dietary salt drives this chain, that every tissue responds identically, or that ROS here proves disease. exposure: Acute hypoxia and inhibition of mitochondrial sodium/calcium exchange evidence_span: {"source_cache": "artifacts/sodium-research/32728214.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2780431aa362c99c816f986e923fd65ed0c0324e8c8674af8ff2a2f9367762c1", "start_char": 0, "end_char": 1533, "text_sha256": "2780431aa362c99c816f986e923fd65ed0c0324e8c8674af8ff2a2f9367762c1"} [sodium-p32728214] Na+ controls hypoxic signalling by the mitochondrial respiratory chain. (2020). https://pubmed.ncbi.nlm.nih.gov/32728214/ DOI: 10.1038/s41586-020-2551-y

evidence_span

{"source_cache": "artifacts/sodium-research/32728214.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2780431aa362c99c816f986e923fd65ed0c0324e8c8674af8ff2a2f9367762c1", "start_char": 0, "end_char": 1533, "text_sha256": "2780431aa362c99c816f986e923fd65ed0c0324e8c8674af8ff2a2f9367762c1"}

experimental_model

Acute-hypoxia cellular and mitochondrial experiments with ion imaging and respiratory/membrane assays

exposure

Acute hypoxia and inhibition of mitochondrial sodium/calcium exchange

limitations

Mechanistic research under hypoxia, including multiple preparations. Do not infer that dietary salt drives this chain, that every tissue responds identically, or that ROS here proves disease.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Human and mouse cells; additional rat vascular experiments in the paper

plain_language

Calcium handling can bring sodium into the mitochondrion.

primary_references

[sodium-p32728214] Na+ controls hypoxic signalling by the mitochondrial respiratory chain. (2020). https://pubmed.ncbi.nlm.nih.gov/32728214/ DOI: 10.1038/s41586-020-2551-y

tissue_or_cell_type

Mitochondrial matrix and inner membrane

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 772–783

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute-hypoxia cellular and mitochondrial experiments with ion imaging and respiratory/membrane assays · source_derived_draft · unverified_draft

### sodium-matrix-sodium Activation of mitochondrial sodium/calcium exchange promoted sodium import into the matrix during the hypoxic pathway. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium handling can bring sodium into the mitochondrion. organism: Human and mouse cells; additional rat vascular experiments in the paper tissue_or_cell_type: Mitochondrial matrix and inner membrane experimental_model: Acute-hypoxia cellular and mitochondrial experiments with ion imaging and respiratory/membrane assays limitations: Mechanistic research under hypoxia, including multiple preparations. Do not infer that dietary salt drives this chain, that every tissue responds identically, or that ROS here proves disease. exposure: Acute hypoxia and inhibition of mitochondrial sodium/calcium exchange evidence_span: {"source_cache": "artifacts/sodium-research/32728214.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2780431aa362c99c816f986e923fd65ed0c0324e8c8674af8ff2a2f9367762c1", "start_char": 0, "end_char": 1533, "text_sha256": "2780431aa362c99c816f986e923fd65ed0c0324e8c8674af8ff2a2f9367762c1"} [sodium-p32728214] Na+ controls hypoxic signalling by the mitochondrial respiratory chain. (2020). https://pubmed.ncbi.nlm.nih.gov/32728214/ DOI: 10.1038/s41586-020-2551-y

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/sodium-research/16358215.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "876374dd0624cf69b89f3f5b17e5be423d7d9a0358f135add88f2493314d2ceb", "start_char": 0, "end_char": 1515, "text_sha256": "876374dd0624cf69b89f3f5b17e5be423d7d9a0358f135add88f2493314d2ceb"}

experimental_model

Mapping and sequencing in families with hereditary hypophosphatemic rickets with hypercalciuria

exposure

SLC34A3 disease-associated mutations in five families

limitations

Genotype–phenotype evidence supports a primary renal defect; downstream calcitriol/calcium pattern is observed, not a dietary sodium intervention.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Human

plain_language

This phosphate disorder can also increase calcium loss into urine.

primary_references

[sodium-p16358215] Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. (2006). https://pubmed.ncbi.nlm.nih.gov/16358215/ DOI: 10.1086/499410

tissue_or_cell_type

Renal proximal tubule and systemic mineral phenotype

trigger_kind

machinery_impairment Imported condition classification; unverified.

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 694–705

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mapping and sequencing in families with hereditary hypophosphatemic rickets with hypercalciuria · source_derived_draft · unverified_draft

### sodium-napi2c-calcium The sodium/phosphate-transporter-associated HHRH phenotype included hypercalciuria. Condition category: machinery_impairment nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This phosphate disorder can also increase calcium loss into urine. organism: Human tissue_or_cell_type: Renal proximal tubule and systemic mineral phenotype experimental_model: Mapping and sequencing in families with hereditary hypophosphatemic rickets with hypercalciuria limitations: Genotype–phenotype evidence supports a primary renal defect; downstream calcitriol/calcium pattern is observed, not a dietary sodium intervention. exposure: SLC34A3 disease-associated mutations in five families evidence_span: {"source_cache": "artifacts/sodium-research/16358215.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "876374dd0624cf69b89f3f5b17e5be423d7d9a0358f135add88f2493314d2ceb", "start_char": 0, "end_char": 1515, "text_sha256": "876374dd0624cf69b89f3f5b17e5be423d7d9a0358f135add88f2493314d2ceb"} [sodium-p16358215] Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. (2006). https://pubmed.ncbi.nlm.nih.gov/16358215/ DOI: 10.1086/499410

evidence_span

{"source_cache": "artifacts/sodium-research/20018762.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8594465b44cbb04ed3a631d5dae19959e7c0494a86537d6a60d33d6db1821831", "start_char": 0, "end_char": 1085, "text_sha256": "8594465b44cbb04ed3a631d5dae19959e7c0494a86537d6a60d33d6db1821831"}

experimental_model

Overexpression, siRNA, rescue, mutant and fluorescent ion-imaging experiments

exposure

NCLX abundance, inactive mutant and ion substitutions

limitations

Supports molecular identification in these assays. Protein species and construct details must be taken from the original methods; not evidence for raising dietary sodium.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Mammalian cultured-cell preparations

plain_language

A mitochondrial exchanger connects sodium movement with calcium removal.

primary_references

[sodium-p20018762] NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. (2010). https://pubmed.ncbi.nlm.nih.gov/20018762/ DOI: 10.1073/pnas.0908099107

tissue_or_cell_type

Mitochondrial cristae

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 733–744

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Overexpression, siRNA, rescue, mutant and fluorescent ion-imaging experiments · source_derived_draft · unverified_draft

### sodium-nclx-efflux NCLX overexpression increased sodium-dependent mitochondrial calcium efflux; silencing reduced it and heterologous rescue restored it. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A mitochondrial exchanger connects sodium movement with calcium removal. organism: Mammalian cultured-cell preparations tissue_or_cell_type: Mitochondrial cristae experimental_model: Overexpression, siRNA, rescue, mutant and fluorescent ion-imaging experiments limitations: Supports molecular identification in these assays. Protein species and construct details must be taken from the original methods; not evidence for raising dietary sodium. exposure: NCLX abundance, inactive mutant and ion substitutions evidence_span: {"source_cache": "artifacts/sodium-research/20018762.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8594465b44cbb04ed3a631d5dae19959e7c0494a86537d6a60d33d6db1821831", "start_char": 0, "end_char": 1085, "text_sha256": "8594465b44cbb04ed3a631d5dae19959e7c0494a86537d6a60d33d6db1821831"} [sodium-p20018762] NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. (2010). https://pubmed.ncbi.nlm.nih.gov/20018762/ DOI: 10.1073/pnas.0908099107

evidence_span

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experimental_model

Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers

exposure

Four five-week calcium/salt diet combinations: 518 or 1284 mg calcium; 3.9 or 11.2 g salt daily

limitations

Small study; bone balance was modeled, fractures were not measured. Salt means sodium chloride, not elemental sodium.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Human postmenopausal women

plain_language

Calcium intake changed the context of the modeled salt effect; this was not a fracture trial.

primary_references

[sodium-p18410231] Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. (2008). https://pubmed.ncbi.nlm.nih.gov/18410231/ DOI: 10.1359/jbmr.080408

tissue_or_cell_type

Intestinal, renal and modeled skeletal calcium balance

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 1123–1134

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers · source_derived_draft · unverified_draft

### sodium-salt-bone-model Higher salt shifted modeled bone calcium balance from positive to negative on the higher-calcium diet; balance was negative at both salt levels on the lower-calcium diet. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium intake changed the context of the modeled salt effect; this was not a fracture trial. organism: Human postmenopausal women tissue_or_cell_type: Intestinal, renal and modeled skeletal calcium balance experimental_model: Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers limitations: Small study; bone balance was modeled, fractures were not measured. Salt means sodium chloride, not elemental sodium. exposure: Four five-week calcium/salt diet combinations: 518 or 1284 mg calcium; 3.9 or 11.2 g salt daily evidence_span: {"source_cache": "artifacts/sodium-research/18410231.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa", "start_char": 0, "end_char": 1558, "text_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa"} [sodium-p18410231] Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. (2008). https://pubmed.ncbi.nlm.nih.gov/18410231/ DOI: 10.1359/jbmr.080408

evidence_span

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experimental_model

Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers

exposure

Four five-week calcium/salt diet combinations: 518 or 1284 mg calcium; 3.9 or 11.2 g salt daily

limitations

Small study; bone balance was modeled, fractures were not measured. Salt means sodium chloride, not elemental sodium.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Human postmenopausal women

plain_language

The kidney calcium loss was not matched by a measured salt-driven increase in absorption.

primary_references

[sodium-p18410231] Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. (2008). https://pubmed.ncbi.nlm.nih.gov/18410231/ DOI: 10.1359/jbmr.080408

tissue_or_cell_type

Intestinal, renal and modeled skeletal calcium balance

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 1110–1121

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers · source_derived_draft · unverified_draft

### sodium-salt-calcium-absorption Fractional calcium absorption adapted to calcium intake but was not significantly altered by salt intake. Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The kidney calcium loss was not matched by a measured salt-driven increase in absorption. organism: Human postmenopausal women tissue_or_cell_type: Intestinal, renal and modeled skeletal calcium balance experimental_model: Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers limitations: Small study; bone balance was modeled, fractures were not measured. Salt means sodium chloride, not elemental sodium. exposure: Four five-week calcium/salt diet combinations: 518 or 1284 mg calcium; 3.9 or 11.2 g salt daily evidence_span: {"source_cache": "artifacts/sodium-research/18410231.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa", "start_char": 0, "end_char": 1558, "text_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa"} [sodium-p18410231] Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. (2008). https://pubmed.ncbi.nlm.nih.gov/18410231/ DOI: 10.1359/jbmr.080408

evidence_span

{"source_cache": "artifacts/sodium-research/18410231.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa", "start_char": 0, "end_char": 1558, "text_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa"}

experimental_model

Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers

exposure

Four five-week calcium/salt diet combinations: 518 or 1284 mg calcium; 3.9 or 11.2 g salt daily

limitations

Small study; bone balance was modeled, fractures were not measured. Salt means sodium chloride, not elemental sodium.

nutrient_topic

Sodium research collection; topical membership is not evidence of a direct dietary effect. · Sodium

organism

Human postmenopausal women

plain_language

More dietary salt increased measured urinary calcium loss in these women.

primary_references

[sodium-p18410231] Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. (2008). https://pubmed.ncbi.nlm.nih.gov/18410231/ DOI: 10.1359/jbmr.080408

tissue_or_cell_type

Intestinal, renal and modeled skeletal calcium balance

Sodium: gradients, nutrient transport, fluid regulation and loss states (2026-09-17) · lines 1097–1108

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers · source_derived_draft · unverified_draft

### sodium-salt-calciuria The higher-salt diet increased urinary calcium excretion in the crossover trial (P=0.0008). Condition category: normal nutrient_topic: Sodium research collection; topical membership is not evidence of a direct dietary effect. plain_language: More dietary salt increased measured urinary calcium loss in these women. organism: Human postmenopausal women tissue_or_cell_type: Intestinal, renal and modeled skeletal calcium balance experimental_model: Randomized crossover with stable-isotope calcium measures and compartmental modeling in 11 completers limitations: Small study; bone balance was modeled, fractures were not measured. Salt means sodium chloride, not elemental sodium. exposure: Four five-week calcium/salt diet combinations: 518 or 1284 mg calcium; 3.9 or 11.2 g salt daily evidence_span: {"source_cache": "artifacts/sodium-research/18410231.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa", "start_char": 0, "end_char": 1558, "text_sha256": "f831f038a6c4249510bbeeae68778a216f1c36aa440e33816072959d1a07fefa"} [sodium-p18410231] Sodium and bone health: impact of moderately high and low salt intakes on calcium metabolism in postmenopausal women. (2008). https://pubmed.ncbi.nlm.nih.gov/18410231/ DOI: 10.1359/jbmr.080408

evidence_access

Primary abstract

experimental_model

Human artery preparations in the translational blood-pressure study.

limitations

Do not infer that oral taurine directly binds TRPC3; the signaling pathway and clinical mediation are distinct.

nutrient_topic

Taurine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Taurine

plain_language

The mechanistic experiments implicated a calcium entry channel.

primary_references

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26781281/ · DOI 10.1161/HYPERTENSIONAHA.115.06624

Taurine: synthesis, transport, mitochondrial decoding and nutrient interactions (2026-09-19) · lines 497–503

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human artery preparations in the translational blood-pressure study. · source_derived_draft · unverified_draft

## taurine-human-trpc3 The mechanistic experiments implicated a calcium entry channel. Taurine treatment reduced agonist-induced vascular reactivity through inhibition of TRPC3-mediated calcium influx in human mesenteric artery experiments. Model: Human artery preparations in the translational blood-pressure study. Limitations: Do not infer that oral taurine directly binds TRPC3; the signaling pathway and clinical mediation are distinct. Evidence access: Primary abstract Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26781281/ · DOI 10.1161/HYPERTENSIONAHA.115.06624

evidence_access

Primary abstract

experimental_model

Mouse vascular experiments paired with the human study.

limitations

Mouse and human preparations are linked evidence, not identical biological records.

nutrient_topic

Taurine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Taurine

plain_language

The vascular mechanism was also examined in mouse arteries.

primary_references

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26781281/ · DOI 10.1161/HYPERTENSIONAHA.115.06624

Taurine: synthesis, transport, mitochondrial decoding and nutrient interactions (2026-09-19) · lines 505–511

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse vascular experiments paired with the human study. · source_derived_draft · unverified_draft

## taurine-mouse-trpc3 The vascular mechanism was also examined in mouse arteries. The same study reported reduced TRPC3-mediated calcium influx and vascular reactivity in mouse mesenteric artery experiments after taurine treatment. Model: Mouse vascular experiments paired with the human study. Limitations: Mouse and human preparations are linked evidence, not identical biological records. Evidence access: Primary abstract Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26781281/ · DOI 10.1161/HYPERTENSIONAHA.115.06624

evidence_access

Primary abstract

experimental_model

Same human skinned-fiber study.

limitations

Small preparation-specific effect; do not merge with rodent muscle or whole-person strength.

nutrient_topic

Taurine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Taurine

plain_language

The contractile response differed between muscle fiber types.

primary_references

Acute effects of taurine on sarcoplasmic reticulum Ca2+ accumulation and contractility in human type I and type II skeletal muscle fibers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25123198/ · DOI 10.1152/japplphysiol.00494.2014

Taurine: synthesis, transport, mitochondrial decoding and nutrient interactions (2026-09-19) · lines 457–463

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same human skinned-fiber study. · source_derived_draft · unverified_draft

## taurine-muscle-calcium-sensitivity The contractile response differed between muscle fiber types. Taurine slightly increased contractile calcium sensitivity in human type I fibers, but not type II fibers; maximum calcium-activated force was unchanged in both. Model: Same human skinned-fiber study. Limitations: Small preparation-specific effect; do not merge with rodent muscle or whole-person strength. Evidence access: Primary abstract Acute effects of taurine on sarcoplasmic reticulum Ca2+ accumulation and contractility in human type I and type II skeletal muscle fibers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25123198/ · DOI 10.1152/japplphysiol.00494.2014

evidence_access

Primary abstract

experimental_model

Mechanically skinned human vastus lateralis fibers.

limitations

Intracellular bath exposure bypasses absorption and transport; it does not prove oral performance benefits.

nutrient_topic

Taurine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Taurine

plain_language

Taurine affected how quickly muscle stored calcium.

primary_references

Acute effects of taurine on sarcoplasmic reticulum Ca2+ accumulation and contractility in human type I and type II skeletal muscle fibers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25123198/ · DOI 10.1152/japplphysiol.00494.2014

Taurine: synthesis, transport, mitochondrial decoding and nutrient interactions (2026-09-19) · lines 449–455

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mechanically skinned human vastus lateralis fibers. · source_derived_draft · unverified_draft

## taurine-muscle-calcium-uptake Taurine affected how quickly muscle stored calcium. Exposing skinned human type I and II muscle fibers to taurine for more than ten minutes increased the SR calcium accumulation rate; 10 and 20 mM produced similar rates, while 5 mM was slower. Model: Mechanically skinned human vastus lateralis fibers. Limitations: Intracellular bath exposure bypasses absorption and transport; it does not prove oral performance benefits. Evidence access: Primary abstract Acute effects of taurine on sarcoplasmic reticulum Ca2+ accumulation and contractility in human type I and type II skeletal muscle fibers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25123198/ · DOI 10.1152/japplphysiol.00494.2014

evidence_access

Primary abstract

experimental_model

Human skinned type I and II muscle fibers.

limitations

The proposed action inside the SR lumen was a hypothesis, not a demonstrated binding target.

nutrient_topic

Taurine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Taurine

plain_language

Faster calcium accumulation did not mean every calcium process increased.

primary_references

Acute effects of taurine on sarcoplasmic reticulum Ca2+ accumulation and contractility in human type I and type II skeletal muscle fibers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25123198/ · DOI 10.1152/japplphysiol.00494.2014

Taurine: synthesis, transport, mitochondrial decoding and nutrient interactions (2026-09-19) · lines 465–471

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human skinned type I and II muscle fibers. · source_derived_draft · unverified_draft

## taurine-muscle-release-null Faster calcium accumulation did not mean every calcium process increased. At 20 mM, taurine had no detectable effect on the responsiveness of SR calcium-release channels in either human fiber type. Model: Human skinned type I and II muscle fibers. Limitations: The proposed action inside the SR lumen was a hypothesis, not a demonstrated binding target. Evidence access: Primary abstract Acute effects of taurine on sarcoplasmic reticulum Ca2+ accumulation and contractility in human type I and type II skeletal muscle fibers. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25123198/ · DOI 10.1152/japplphysiol.00494.2014

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary Results, in-vitro analysis and Figure 4; clinical cohorts and Discussion.

experimental_model

Human candidate-gene study with supporting enzyme assays

exposure

First cohort received 500 IU/day; second cohort became symptomatic 2-3 weeks after intermittent high-dose prophylaxis.

limitations

Selected families do not estimate population risk. Genotype, dose and penetrance matter; this is not a universal safe/unsafe serum or dose threshold.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

Defective vitamin D breakdown can make infants unusually sensitive to supplementation.

primary_references

[schlingmann2011] Mutations in CYP24A1 and idiopathic infantile hypercalcemia. (2011). https://pubmed.ncbi.nlm.nih.gov/21675912/ DOI: 10.1056/NEJMoa1103864

tissue_or_cell_type

systemic calcium handling

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 602–615

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human candidate-gene study with supporting enzyme assays · source_derived_draft · unverified_draft

### vd-act-cyp24a1-hypercalcemia Recessive CYP24A1 variants were identified in infants with hypercalcemia, including a second group whose illness followed high-dose vitamin D prophylaxis. Condition category: machinery_impairment nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Defective vitamin D breakdown can make infants unusually sensitive to supplementation. organism: Homo sapiens tissue_or_cell_type: systemic calcium handling experimental_model: Human candidate-gene study with supporting enzyme assays limitations: Selected families do not estimate population risk. Genotype, dose and penetrance matter; this is not a universal safe/unsafe serum or dose threshold. exposure: First cohort received 500 IU/day; second cohort became symptomatic 2-3 weeks after intermittent high-dose prophylaxis. cross_nutrient: true evidence_location: Primary Results, in-vitro analysis and Figure 4; clinical cohorts and Discussion. nutrient: Vitamin D2 and D3 [schlingmann2011] Mutations in CYP24A1 and idiopathic infantile hypercalcemia. (2011). https://pubmed.ncbi.nlm.nih.gov/21675912/ DOI: 10.1056/NEJMoa1103864

cross_nutrient

true

experimental_model

311 healthy adults 55–70 randomized to daily 400, 4000, 10000 IU D3 for 3 years; 287 completed

exposure

D3 400, 4000 or 10000 IU/day for 3 years; calcium added for dietary intake<1200 mg/day.

limitations

Adults without osteoporosis, baseline 25(OH)D30–125 nmol/L; surrogate outcomes, not a deficiency-repletion trial or fracture endpoint.

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

More vitamin D did not produce denser bone at the forearm in this trial.

primary_references

[burt2019] Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. (2019). https://pubmed.ncbi.nlm.nih.gov/31454046/ DOI: 10.1001/jama.2019.11889

tissue_or_cell_type

Radius

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1600–1611

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 311 healthy adults 55–70 randomized to daily 400, 4000, 10000 IU D3 for 3 years; 287 completed · source_derived_draft · unverified_draft

### vd-burt-radius Relative to 400 IU/day, final radial volumetric BMD was lower by 3.9 mgHA/cm³ with 4000 IU (95% CI−6.5 to−1.3) and 7.5 mgHA/cm³ with 10000 IU (CI−10.1 to−5.0). Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: More vitamin D did not produce denser bone at the forearm in this trial. organism: Homo sapiens tissue_or_cell_type: Radius experimental_model: 311 healthy adults 55–70 randomized to daily 400, 4000, 10000 IU D3 for 3 years; 287 completed limitations: Adults without osteoporosis, baseline 25(OH)D30–125 nmol/L; surrogate outcomes, not a deficiency-repletion trial or fracture endpoint. exposure: D3 400, 4000 or 10000 IU/day for 3 years; calcium added for dietary intake<1200 mg/day. cross_nutrient: true [burt2019] Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. (2019). https://pubmed.ncbi.nlm.nih.gov/31454046/ DOI: 10.1001/jama.2019.11889

cross_nutrient

true

experimental_model

311 healthy adults 55–70 randomized to daily 400, 4000, 10000 IU D3 for 3 years; 287 completed

exposure

D3 400, 4000 or 10000 IU/day for 3 years; calcium added for dietary intake<1200 mg/day.

limitations

Adults without osteoporosis, baseline 25(OH)D30–125 nmol/L; surrogate outcomes, not a deficiency-repletion trial or fracture endpoint.

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

The tibial result depended on dose; the lower comparison included no difference.

primary_references

[burt2019] Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. (2019). https://pubmed.ncbi.nlm.nih.gov/31454046/ DOI: 10.1001/jama.2019.11889

tissue_or_cell_type

Tibia

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1613–1624

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 311 healthy adults 55–70 randomized to daily 400, 4000, 10000 IU D3 for 3 years; 287 completed · source_derived_draft · unverified_draft

### vd-burt-tibia Tibial BMD differences versus 400 IU/day were−1.8 mgHA/cm³ with 4000 IU (95% CI−3.7 to 0.1; not significant) and−4.1 mgHA/cm³ with 10000 IU (CI−6.0 to−2.2). Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tibial result depended on dose; the lower comparison included no difference. organism: Homo sapiens tissue_or_cell_type: Tibia experimental_model: 311 healthy adults 55–70 randomized to daily 400, 4000, 10000 IU D3 for 3 years; 287 completed limitations: Adults without osteoporosis, baseline 25(OH)D30–125 nmol/L; surrogate outcomes, not a deficiency-repletion trial or fracture endpoint. exposure: D3 400, 4000 or 10000 IU/day for 3 years; calcium added for dietary intake<1200 mg/day. cross_nutrient: true [burt2019] Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. (2019). https://pubmed.ncbi.nlm.nih.gov/31454046/ DOI: 10.1001/jama.2019.11889

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Six-week randomized comparison in 40 infants/toddlers with 25(OH)D<20 ng/mL; all prescribed calcium

exposure

D2 2000 IU/day, D2 50, 000 IU/week or D3 2000 IU/day for 6 weeks; all also 50 mg/kg/day elemental calcium.

limitations

Small pediatric trial; D and calcium effects cannot be separated; biochemical outcomes do not establish long-term comparative safety.

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

D2 could correct the low marker too in this short pediatric study.

primary_references

[gordon2008] Treatment of hypovitaminosis D in infants and toddlers. (2008). https://pubmed.ncbi.nlm.nih.gov/18413426/ DOI: 10.1210/jc.2007-2790

tissue_or_cell_type

Human circulating measurements

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1470–1481

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-week randomized comparison in 40 infants/toddlers with 25(OH)D<20 ng/mL; all prescribed calcium · source_derived_draft · unverified_draft

### vd-gordon-25-response All three regimens approximately tripled total 25(OH)D; daily D2 versus daily D3 differed by 7% with P=0.82. Condition category: biomarker_context nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: D2 could correct the low marker too in this short pediatric study. organism: Homo sapiens tissue_or_cell_type: Human circulating measurements experimental_model: Six-week randomized comparison in 40 infants/toddlers with 25(OH)D<20 ng/mL; all prescribed calcium limitations: Small pediatric trial; D and calcium effects cannot be separated; biochemical outcomes do not establish long-term comparative safety. exposure: D2 2000 IU/day, D2 50, 000 IU/week or D3 2000 IU/day for 6 weeks; all also 50 mg/kg/day elemental calcium. cross_nutrient: true [gordon2008] Treatment of hypovitaminosis D in infants and toddlers. (2008). https://pubmed.ncbi.nlm.nih.gov/18413426/ DOI: 10.1210/jc.2007-2790

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Six-week randomized comparison in 40 infants/toddlers with 25(OH)D<20 ng/mL; all prescribed calcium

exposure

D2 2000 IU/day, D2 50, 000 IU/week or D3 2000 IU/day for 6 weeks; all also 50 mg/kg/day elemental calcium.

limitations

Small pediatric trial; D and calcium effects cannot be separated; biochemical outcomes do not establish long-term comparative safety.

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

The hormone response was not detectably different between these treatment groups.

primary_references

[gordon2008] Treatment of hypovitaminosis D in infants and toddlers. (2008). https://pubmed.ncbi.nlm.nih.gov/18413426/ DOI: 10.1210/jc.2007-2790

tissue_or_cell_type

Human circulating measurements

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1483–1494

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-week randomized comparison in 40 infants/toddlers with 25(OH)D<20 ng/mL; all prescribed calcium · source_derived_draft · unverified_draft

### vd-gordon-pth PTH suppression did not differ significantly among the three vitamin D regimens given with calcium. Condition category: biomarker_context nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The hormone response was not detectably different between these treatment groups. organism: Homo sapiens tissue_or_cell_type: Human circulating measurements experimental_model: Six-week randomized comparison in 40 infants/toddlers with 25(OH)D<20 ng/mL; all prescribed calcium limitations: Small pediatric trial; D and calcium effects cannot be separated; biochemical outcomes do not establish long-term comparative safety. exposure: D2 2000 IU/day, D2 50, 000 IU/week or D3 2000 IU/day for 6 weeks; all also 50 mg/kg/day elemental calcium. cross_nutrient: true [gordon2008] Treatment of hypovitaminosis D in infants and toddlers. (2008). https://pubmed.ncbi.nlm.nih.gov/18413426/ DOI: 10.1210/jc.2007-2790

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Figure 6; Results: Increased circulating 1,25(OH)2D levels impair mineralization by upregulating mineralization inhibitors

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Differentiated primary Vdr-intact mouse osteoblasts; conditioned-medium pyrophosphate normalized to DNA

exposure

10^-8 M calcitriol for 4 days after osteogenic differentiation.

limitations

Direct culture result does not imply that usual dietary vitamin D damages bone; physiological outcome also depends on intestinal mineral delivery.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Mus musculus

plain_language

In this model, active vitamin D increased a molecule that restrains mineral deposition.

primary_references

[vdm-lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. (2012). https://pubmed.ncbi.nlm.nih.gov/22523068/ DOI: 10.1172/jci45890

tissue_or_cell_type

Osteoblast culture

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 809–823

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated primary Vdr-intact mouse osteoblasts; conditioned-medium pyrophosphate normalized to DNA · source_derived_draft · unverified_draft

### vdm-calcitriol-increases-extracellular-ppi Calcitriol treatment increased extracellular pyrophosphate in differentiated Vdr-intact mouse osteoblast cultures. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this model, active vitamin D increased a molecule that restrains mineral deposition. organism: Mus musculus tissue_or_cell_type: Osteoblast culture experimental_model: Differentiated primary Vdr-intact mouse osteoblasts; conditioned-medium pyrophosphate normalized to DNA limitations: Direct culture result does not imply that usual dietary vitamin D damages bone; physiological outcome also depends on intestinal mineral delivery. exposure: 10^-8 M calcitriol for 4 days after osteogenic differentiation. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Figure 6; Results: Increased circulating 1,25(OH)2D levels impair mineralization by upregulating mineralization inhibitors nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. (2012). https://pubmed.ncbi.nlm.nih.gov/22523068/ DOI: 10.1172/jci45890

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Primary abstract and Results/Discussion on calcitriol-induced claudin expression; cached web-primary-excerpts.json

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Human Caco-2 cells; RT-PCR, immunoblotting and junctional localization

exposure

Calcitriol-treated versus vehicle Caco-2 cultures; exact hormone dose/time not recovered in the primary passages used.

limitations

Cell-line expression response; the separately reused permeability experiments support function, but neither establishes a universal fraction of human dietary calcium absorption.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

Active vitamin D can increase a tight-junction protein involved in calcium movement between intestinal cells.

primary_references

[vdm-fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. (2008). https://pubmed.ncbi.nlm.nih.gov/18287530/ DOI: 10.1091/mbc.e07-09-0973

tissue_or_cell_type

Intestinal epithelial cell model

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 633–647

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human Caco-2 cells; RT-PCR, immunoblotting and junctional localization · source_derived_draft · unverified_draft

### vdm-calcitriol-induces-cldn12 Calcitriol increased Claudin-12 expression in human Caco-2 intestinal epithelial cells. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Active vitamin D can increase a tight-junction protein involved in calcium movement between intestinal cells. organism: Homo sapiens tissue_or_cell_type: Intestinal epithelial cell model experimental_model: Human Caco-2 cells; RT-PCR, immunoblotting and junctional localization limitations: Cell-line expression response; the separately reused permeability experiments support function, but neither establishes a universal fraction of human dietary calcium absorption. exposure: Calcitriol-treated versus vehicle Caco-2 cultures; exact hormone dose/time not recovered in the primary passages used. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Primary abstract and Results/Discussion on calcitriol-induced claudin expression; cached web-primary-excerpts.json nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. (2008). https://pubmed.ncbi.nlm.nih.gov/18287530/ DOI: 10.1091/mbc.e07-09-0973

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Primary abstract and Results/Discussion on calcitriol-induced claudin expression; cached web-primary-excerpts.json

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Human Caco-2 cells; RT-PCR, immunoblotting and junctional localization

exposure

Calcitriol-treated versus vehicle Caco-2 cultures; exact hormone dose/time not recovered in the primary passages used.

limitations

Cell-line expression response; the separately reused permeability experiments support function, but neither establishes a universal fraction of human dietary calcium absorption.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

Active vitamin D can increase a tight-junction protein involved in calcium movement between intestinal cells.

primary_references

[vdm-fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. (2008). https://pubmed.ncbi.nlm.nih.gov/18287530/ DOI: 10.1091/mbc.e07-09-0973

tissue_or_cell_type

Intestinal epithelial cell model

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 617–631

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human Caco-2 cells; RT-PCR, immunoblotting and junctional localization · source_derived_draft · unverified_draft

### vdm-calcitriol-induces-cldn2 Calcitriol increased Claudin-2 expression in human Caco-2 intestinal epithelial cells. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Active vitamin D can increase a tight-junction protein involved in calcium movement between intestinal cells. organism: Homo sapiens tissue_or_cell_type: Intestinal epithelial cell model experimental_model: Human Caco-2 cells; RT-PCR, immunoblotting and junctional localization limitations: Cell-line expression response; the separately reused permeability experiments support function, but neither establishes a universal fraction of human dietary calcium absorption. exposure: Calcitriol-treated versus vehicle Caco-2 cultures; exact hormone dose/time not recovered in the primary passages used. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Primary abstract and Results/Discussion on calcitriol-induced claudin expression; cached web-primary-excerpts.json nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. (2008). https://pubmed.ncbi.nlm.nih.gov/18287530/ DOI: 10.1091/mbc.e07-09-0973

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Abstract: reported experimental results

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Mouse osteoblastic cells; VDR/RXR ChIP-chip, reporter mutagenesis and transcriptional assays

exposure

Calcitriol-treated cell and reporter systems; dose and time vary by experiment and are not specified in the retrieved abstract.

limitations

Enhancer activation is distinct from a fracture outcome. The human and mouse regulatory landscapes are not asserted to be identical.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Mus musculus

plain_language

Active vitamin D can induce the osteoclast-development signal RANKL through distant DNA control regions.

primary_references

[vdm-meyer2006rankl] Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. (2006). https://pubmed.ncbi.nlm.nih.gov/16914732/ DOI: 10.1128/mcb.00353-06

tissue_or_cell_type

Osteoblastic cell chromatin

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 841–855

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse osteoblastic cells; VDR/RXR ChIP-chip, reporter mutagenesis and transcriptional assays · source_derived_draft · unverified_draft

### vdm-calcitriol-rankl-distal-enhancer Calcitriol activated mouse Rankl transcription through distal VDR/RXR-associated regulatory regions, including a functional element about 76 kb upstream. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Active vitamin D can induce the osteoclast-development signal RANKL through distant DNA control regions. organism: Mus musculus tissue_or_cell_type: Osteoblastic cell chromatin experimental_model: Mouse osteoblastic cells; VDR/RXR ChIP-chip, reporter mutagenesis and transcriptional assays limitations: Enhancer activation is distinct from a fracture outcome. The human and mouse regulatory landscapes are not asserted to be identical. exposure: Calcitriol-treated cell and reporter systems; dose and time vary by experiment and are not specified in the retrieved abstract. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Abstract: reported experimental results nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-meyer2006rankl] Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. (2006). https://pubmed.ncbi.nlm.nih.gov/16914732/ DOI: 10.1128/mcb.00353-06

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Abstract: reported experimental results

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Vitamin-D-deficient wild-type mice; everted duodenal gut-sac calcium transport

exposure

Diet-induced vitamin D deficiency followed by calcitriol administration; exact replacement dose/time not reported in the retrieved abstract.

limitations

Wild-type arm is separated from the knockout arms; this is active-hormone replacement, not a D2/D3 oral-dose equivalence test.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Mus musculus

plain_language

Providing the active hormone restored part of the intestinal calcium-transport response after vitamin D deprivation.

primary_references

[vdm-benn2008] Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. (2008). https://pubmed.ncbi.nlm.nih.gov/18325990/ DOI: 10.1210/en.2007-1655

tissue_or_cell_type

Duodenum

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 649–663

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Vitamin-D-deficient wild-type mice; everted duodenal gut-sac calcium transport · source_derived_draft · unverified_draft

### vdm-calcitriol-restores-transport-after-d-deficiency Calcitriol administration increased active duodenal calcium transport in vitamin-D-deficient wild-type mice in the Benn study. Condition category: nutrient_deficiency nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Providing the active hormone restored part of the intestinal calcium-transport response after vitamin D deprivation. organism: Mus musculus tissue_or_cell_type: Duodenum experimental_model: Vitamin-D-deficient wild-type mice; everted duodenal gut-sac calcium transport limitations: Wild-type arm is separated from the knockout arms; this is active-hormone replacement, not a D2/D3 oral-dose equivalence test. exposure: Diet-induced vitamin D deficiency followed by calcitriol administration; exact replacement dose/time not reported in the retrieved abstract. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Abstract: reported experimental results nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-benn2008] Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. (2008). https://pubmed.ncbi.nlm.nih.gov/18325990/ DOI: 10.1210/en.2007-1655

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Abstract: reported experimental results

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

VDR-ablated mice and control littermates receiving a mineral/lactose rescue diet

exposure

Combined mineral/lactose rescue diet; individual ingredient contributions and exact formulation are not resolved by the retrieved abstract.

limitations

This is a combined dietary rescue of receptor-deficient mice, not phosphate monotherapy, not a D2/D3 trial, and not evidence that VDR has no direct skeletal functions.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Mus musculus

plain_language

Improving mineral delivery protected the skeleton even when the vitamin D receptor was missing.

primary_references

[vdm-li1998] Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. (1998). https://pubmed.ncbi.nlm.nih.gov/9751523/ DOI: 10.1210/endo.139.10.6262

tissue_or_cell_type

Skeleton

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 761–775

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · VDR-ablated mice and control littermates receiving a mineral/lactose rescue diet · source_derived_draft · unverified_draft

### vdm-mineral-rescue-prevents-vdr-null-skeletal-defects The combined mineral/lactose rescue diet prevented rickets and osteomalacia in VDR-ablated mice. Condition category: machinery_impairment nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Improving mineral delivery protected the skeleton even when the vitamin D receptor was missing. organism: Mus musculus tissue_or_cell_type: Skeleton experimental_model: VDR-ablated mice and control littermates receiving a mineral/lactose rescue diet limitations: This is a combined dietary rescue of receptor-deficient mice, not phosphate monotherapy, not a D2/D3 trial, and not evidence that VDR has no direct skeletal functions. exposure: Combined mineral/lactose rescue diet; individual ingredient contributions and exact formulation are not resolved by the retrieved abstract. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Abstract: reported experimental results nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-li1998] Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. (1998). https://pubmed.ncbi.nlm.nih.gov/9751523/ DOI: 10.1210/endo.139.10.6262

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Results: biochemical parameters, growth-plate histology and TUNEL; primary text excerpts cached in web-assay-excerpts.json

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Wild-type mice fed high-calcium/low-phosphate diet; growth-plate histology and TUNEL assay

exposure

High-calcium/low-phosphate diet; biochemical comparisons at 24 days of age in Figure 2. Exact diet duration/formulation not resolved in retrieved passages.

limitations

The diet arm is separated from Vdr-null and Phex-mutant models. No single human serum threshold or claim that every rachitic disorder has one mechanism is inferred.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Mus musculus

plain_language

Low phosphate disrupted maturation of growth-plate cartilage even when calcium was high.

primary_references

[vdm-sabbagh2005] Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. (2005). https://pubmed.ncbi.nlm.nih.gov/15976027/ DOI: 10.1073/pnas.0502249102

tissue_or_cell_type

Growth-plate hypertrophic chondrocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 777–791

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Wild-type mice fed high-calcium/low-phosphate diet; growth-plate histology and TUNEL assay · source_derived_draft · unverified_draft

### vdm-phosphate-restriction-reduces-growth-plate-apoptosis Diet-induced hypophosphatemic mice had impaired late hypertrophic-chondrocyte apoptosis and rachitic growth-plate expansion despite hypercalcemia and suppressed PTH. Condition category: nutrient_deficiency nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low phosphate disrupted maturation of growth-plate cartilage even when calcium was high. organism: Mus musculus tissue_or_cell_type: Growth-plate hypertrophic chondrocytes experimental_model: Wild-type mice fed high-calcium/low-phosphate diet; growth-plate histology and TUNEL assay limitations: The diet arm is separated from Vdr-null and Phex-mutant models. No single human serum threshold or claim that every rachitic disorder has one mechanism is inferred. exposure: High-calcium/low-phosphate diet; biochemical comparisons at 24 days of age in Figure 2. Exact diet duration/formulation not resolved in retrieved passages. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Results: biochemical parameters, growth-plate histology and TUNEL; primary text excerpts cached in web-assay-excerpts.json nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-sabbagh2005] Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. (2005). https://pubmed.ncbi.nlm.nih.gov/15976027/ DOI: 10.1073/pnas.0502249102

cross_nutrient

Vitamin D–calcium–phosphate regulation.

evidence_locator

Figure 6 and adjacent Results: mineralization restored by TNAP

evidence_scope

D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison.

experimental_model

Differentiated primary mouse osteoblasts; Alizarin red mineralization and conditioned-medium pyrophosphate assays

exposure

10^-8 M calcitriol and 1 U/mL added TNAP for 4 days; companion cultures tested 5 x 10^-6 M pyrophosphate.

limitations

Enzyme-addition culture rescue supports pyrophosphate involvement; it does not quantify human bone outcomes or establish the contribution of each calcitriol-regulated gene.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Mus musculus

plain_language

Removing the pyrophosphate brake restored mineral deposition in the treated cultures.

primary_references

[vdm-lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. (2012). https://pubmed.ncbi.nlm.nih.gov/22523068/ DOI: 10.1172/jci45890

tissue_or_cell_type

Osteoblast extracellular matrix

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 825–839

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated primary mouse osteoblasts; Alizarin red mineralization and conditioned-medium pyrophosphate assays · source_derived_draft · unverified_draft

### vdm-tnap-rescues-calcitriol-culture-mineralization Added TNAP restored mineralization in calcitriol-treated differentiated mouse osteoblast cultures while lowering extracellular pyrophosphate. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing the pyrophosphate brake restored mineral deposition in the treated cultures. organism: Mus musculus tissue_or_cell_type: Osteoblast extracellular matrix experimental_model: Differentiated primary mouse osteoblasts; Alizarin red mineralization and conditioned-medium pyrophosphate assays limitations: Enzyme-addition culture rescue supports pyrophosphate involvement; it does not quantify human bone outcomes or establish the contribution of each calcitriol-regulated gene. exposure: 10^-8 M calcitriol and 1 U/mL added TNAP for 4 days; companion cultures tested 5 x 10^-6 M pyrophosphate. cross_nutrient: Vitamin D–calcium–phosphate regulation. evidence_locator: Figure 6 and adjacent Results: mineralization restored by TNAP nutrient: Vitamin D2 and D3 evidence_scope: D3 active metabolite or VDR machinery experiment; not a direct D2-versus-D3 comparison. [vdm-lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. (2012). https://pubmed.ncbi.nlm.nih.gov/22523068/ DOI: 10.1172/jci45890

evidence_access

Primary abstract

experimental_model

Paired receptor and human osteoclast experiments; cinacalcet behaved differently.

limitations

Distinct ligand and cell contexts; no claim that CaSR alone fully explains osteoclast effects.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A stronger receptor assay signal did not guarantee the same cell-level outcome.

primary_references

Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29714810/ · DOI 10.1111/bph.14344

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 262–268

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Paired receptor and human osteoclast experiments; cinacalcet behaved differently. · source_derived_draft · unverified_draft

## strontium-calcimimetic-dissociation A stronger receptor assay signal did not guarantee the same cell-level outcome. AC-265347 and BTU-compound 13 potentiated calcium/strontium CaSR signaling in HEK293 cells but neither replicated nor potentiated strontium inhibition of human osteoclast function. Model: Paired receptor and human osteoclast experiments; cinacalcet behaved differently. Limitations: Distinct ligand and cell contexts; no claim that CaSR alone fully explains osteoclast effects. Evidence access: Primary abstract Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29714810/ · DOI 10.1111/bph.14344

evidence_access

Primary abstract

experimental_model

Rat medullary thyroid carcinoma cell concentration-response assays.

limitations

Calcitonin is not T3/T4, and this does not establish the net human calcium response.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A calcium-like ion can affect a hormone involved in calcium regulation.

primary_references

Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22942242/ · DOI 10.1124/jpet.112.197210

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 350–356

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat medullary thyroid carcinoma cell concentration-response assays. · source_derived_draft · unverified_draft

## strontium-calcitonin-secretion A calcium-like ion can affect a hormone involved in calcium regulation. Strontium stimulated calcitonin secretion with higher potency than calcium in the rat 6-23 cell study despite differing signaling bias. Model: Rat medullary thyroid carcinoma cell concentration-response assays. Limitations: Calcitonin is not T3/T4, and this does not establish the net human calcium response. Evidence access: Primary abstract Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22942242/ · DOI 10.1124/jpet.112.197210

evidence_access

Primary abstract

experimental_model

Small before/after subgroup within the dual-tracer study.

limitations

Four patients, active hormone and renal impairment; not a universal effect of vitamin D3 supplementation.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Active vitamin D changed the two absorption responses by different amounts.

primary_references

Stable strontium absorption as a measure of intestinal calcium absorption: comparison with the double-radiotracer calcium absorption test. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7955914/ · DOI 10.1042/cs0870363

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 54–60

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small before/after subgroup within the dual-tracer study. · source_derived_draft · unverified_draft

## strontium-calcitriol-absorption Active vitamin D changed the two absorption responses by different amounts. In four renal-failure patients retested after calcitriol 1 microgram/day for ten days, six-hour strontium absorption increased 4.29-fold and calcium absorption 2.4-fold. Model: Small before/after subgroup within the dual-tracer study. Limitations: Four patients, active hormone and renal impairment; not a universal effect of vitamin D3 supplementation. Evidence access: Primary abstract Stable strontium absorption as a measure of intestinal calcium absorption: comparison with the double-radiotracer calcium absorption test. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7955914/ · DOI 10.1042/cs0870363

evidence_access

Primary abstract

experimental_model

Primary rabbit osteoclast combination experiment.

limitations

Greater combined effect is not proof of clinical synergy, an optimal ratio or a supplement recommendation.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A measured interaction between the two ions is preserved as its own finding.

primary_references

The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18927086/ · DOI 10.1074/jbc.M801668200

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 238–244

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary rabbit osteoclast combination experiment. · source_derived_draft · unverified_draft

## strontium-calcium-combination A measured interaction between the two ions is preserved as its own finding. Combining extracellular strontium and calcium produced greater apoptosis of mature rabbit osteoclasts than either ion alone. Model: Primary rabbit osteoclast combination experiment. Limitations: Greater combined effect is not proof of clinical synergy, an optimal ratio or a supplement recommendation. Evidence access: Primary abstract The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18927086/ · DOI 10.1074/jbc.M801668200

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Physical phantom experiments with 0–3.5 mol% strontium.

limitations

Mixture calibration is not a patient-specific correction; bone strontium content at the scanned site is required.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Strontium can make a scan read denser without an equivalent increase in calcium mineral.

primary_references

Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10677790/ · DOI 10.1016/s1094-6950(06)60402-2

trigger_kind

biomarker_context Imported condition classification; unverified.

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 310–316

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Physical phantom experiments with 0–3.5 mol% strontium. · source_derived_draft · unverified_draft

## strontium-dxa-physics Strontium can make a scan read denser without an equivalent increase in calcium mineral. In calcium/strontium hydroxyapatite mixtures, approximately 1 mol% strontium caused about 10% overestimation of DXA bone mineral density/content across the tested instruments. Model: Physical phantom experiments with 0–3.5 mol% strontium. Limitations: Mixture calibration is not a patient-specific correction; bone strontium content at the scanned site is required. Evidence access: Primary abstract Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10677790/ · DOI 10.1016/s1094-6950(06)60402-2

evidence_access

Primary abstract

experimental_model

Human receptor transfection and dose-response signaling assays.

limitations

Receptor signaling is not itself proof of stronger bone or a nutritional requirement.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Strontium can engage a receptor normally used to sense extracellular calcium.

primary_references

The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20560105/ · DOI 10.1055/s-0030-1255091

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 70–76

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human receptor transfection and dose-response signaling assays. · source_derived_draft · unverified_draft

## strontium-human-casr Strontium can engage a receptor normally used to sense extracellular calcium. Strontium chloride and the ranelate preparation stimulated ERK phosphorylation in HEK293 cells transfected with human CaSR. Model: Human receptor transfection and dose-response signaling assays. Limitations: Receptor signaling is not itself proof of stronger bone or a nutritional requirement. Evidence access: Primary abstract The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20560105/ · DOI 10.1055/s-0030-1255091

evidence_access

Primary full text

experimental_model

Small human oocyte study, largely in-vitro matured material, with mouse comparisons.

limitations

Limited fresh in-vivo-matured human oocytes and no human knockout; channel presence is not proof of strontium permeability.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

The mouse result did not transfer to these human eggs.

primary_references

Strontium fails to induce Ca2+ release and activation in human oocytes despite the presence of functional TRPV3 channels. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30895246/ · DOI 10.1093/hropen/hoy005

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 398–404

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small human oocyte study, largely in-vitro matured material, with mouse comparisons. · source_derived_draft · unverified_draft

## strontium-human-egg-null The mouse result did not transfer to these human eggs. At 10 mM, strontium did not produce calcium oscillations or activation in the tested human oocytes, although TRPV3 expression and responses to TRPV3 agonists were detected. Model: Small human oocyte study, largely in-vitro matured material, with mouse comparisons. Limitations: Limited fresh in-vivo-matured human oocytes and no human knockout; channel presence is not proof of strontium permeability. Evidence access: Primary full text Strontium fails to induce Ca2+ release and activation in human oocytes despite the presence of functional TRPV3 channels. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30895246/ · DOI 10.1093/hropen/hoy005

evidence_access

Primary abstract

experimental_model

Electron microscopy and morphology in human keratinocyte cultures.

limitations

This does not define whole-body calcium deficiency or a dermatologic therapy.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Supporting cell growth did not replace calcium’s differentiation function.

primary_references

Use of strontium to separate calcium-dependent pathways for proliferation and differentiation in human keratinocytes. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2439523/ · DOI 10.1002/jcp.1041320111

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 414–420

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Electron microscopy and morphology in human keratinocyte cultures. · source_derived_draft · unverified_draft

## strontium-keratinocyte-differentiation Supporting cell growth did not replace calcium’s differentiation function. Strontium-supported keratinocyte cultures lacked the stratification and desmosomes found with 1.8 mM calcium, despite increased cell yield. Model: Electron microscopy and morphology in human keratinocyte cultures. Limitations: This does not define whole-body calcium deficiency or a dermatologic therapy. Evidence access: Primary abstract Use of strontium to separate calcium-dependent pathways for proliferation and differentiation in human keratinocytes. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2439523/ · DOI 10.1002/jcp.1041320111

evidence_access

Primary abstract

experimental_model

Human keratinocytes with 0.03 mM basal calcium; dose-response culture study.

limitations

Cell yield is not skin healing or systemic nutritional benefit.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Strontium supported proliferation in a specialized skin-cell culture.

primary_references

Use of strontium to separate calcium-dependent pathways for proliferation and differentiation in human keratinocytes. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2439523/ · DOI 10.1002/jcp.1041320111

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 406–412

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human keratinocytes with 0.03 mM basal calcium; dose-response culture study. · source_derived_draft · unverified_draft

## strontium-keratinocyte-growth Strontium supported proliferation in a specialized skin-cell culture. In human keratinocytes grown in low-calcium serum-free medium, SrCl2 increased seven-day cell yield, with the reported optimum at 1.8 mM. Model: Human keratinocytes with 0.03 mM basal calcium; dose-response culture study. Limitations: Cell yield is not skin healing or systemic nutritional benefit. Evidence access: Primary abstract Use of strontium to separate calcium-dependent pathways for proliferation and differentiation in human keratinocytes. · 1987 · https://pubmed.ncbi.nlm.nih.gov/2439523/ · DOI 10.1002/jcp.1041320111

evidence_access

Primary full text

experimental_model

Same rat primary osteoblast cultures.

limitations

Does not establish that all bone effects are physicochemical, nor deny fracture outcomes in a clinical trial.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Making a scaffold and depositing calcium mineral are different steps.

primary_references

Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25048011/ · DOI 10.1007/s00198-014-2791-5

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 278–284

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same rat primary osteoblast cultures. · source_derived_draft · unverified_draft

## strontium-matrix-versus-mineral Making a scaffold and depositing calcium mineral are different steps. Strontium strongly inhibited mineral deposition while collagenous matrix structures remained apparent and osteoblast numbers were unchanged; ionized calcium remained in the medium. Model: Same rat primary osteoblast cultures. Limitations: Does not establish that all bone effects are physicochemical, nor deny fracture outcomes in a clinical trial. Evidence access: Primary full text Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25048011/ · DOI 10.1007/s00198-014-2791-5

evidence_access

Primary full text

experimental_model

Mouse egg electrophysiology and genetic experiments.

limitations

Laboratory artificial activation; no claim about dietary strontium or human fertility.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A calcium-permeable channel can also admit strontium in mouse eggs.

primary_references

TRPV3 channels mediate strontium-induced mouse-egg activation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24316078/ · DOI 10.1016/j.celrep.2013.11.007

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 382–388

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse egg electrophysiology and genetic experiments. · source_derived_draft · unverified_draft

## strontium-mouse-egg-entry A calcium-permeable channel can also admit strontium in mouse eggs. TRPV3 mediated strontium influx into mouse eggs in the reported channel and activation experiments. Model: Mouse egg electrophysiology and genetic experiments. Limitations: Laboratory artificial activation; no claim about dietary strontium or human fertility. Evidence access: Primary full text TRPV3 channels mediate strontium-induced mouse-egg activation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24316078/ · DOI 10.1016/j.celrep.2013.11.007

evidence_access

Primary abstract

experimental_model

Rabbit osteoclast pathway perturbations.

limitations

Absence of IP3 dependence here is not absence of calcium signaling in every strontium response.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Similar ions need not use identical intracellular messengers.

primary_references

The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18927086/ · DOI 10.1074/jbc.M801668200

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 230–236

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rabbit osteoclast pathway perturbations. · source_derived_draft · unverified_draft

## strontium-rabbit-ip3-difference Similar ions need not use identical intracellular messengers. Unlike calcium in the same experimental program, strontium-associated osteoclast apoptosis was independent of inositol 1,4,5-trisphosphate action. Model: Rabbit osteoclast pathway perturbations. Limitations: Absence of IP3 dependence here is not absence of calcium signaling in every strontium response. Evidence access: Primary abstract The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. · 2009 · https://pubmed.ncbi.nlm.nih.gov/18927086/ · DOI 10.1074/jbc.M801668200

evidence_access

Primary full text

experimental_model

Primary rat osteoblast cultures; quantified mineralized nodules.

limitations

Full-text results clarify these numbers are percent inhibition, despite ambiguous abstract wording. Species, culture conditions and soluble exposure require matched comparison.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

This study found less mineral deposition, directly challenging a general stimulatory claim.

primary_references

Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25048011/ · DOI 10.1007/s00198-014-2791-5

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 270–276

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary rat osteoblast cultures; quantified mineralized nodules. · source_derived_draft · unverified_draft

## strontium-rat-mineralization-negative This study found less mineral deposition, directly challenging a general stimulatory claim. Continuous strontium ranelate at 0.01, 0.1 and 1 mM caused 59%, 98% and 100% inhibition of mineralization in 14-day rat calvarial osteoblast cultures; strontium chloride also strongly inhibited it. Model: Primary rat osteoblast cultures; quantified mineralized nodules. Limitations: Full-text results clarify these numbers are percent inhibition, despite ambiguous abstract wording. Species, culture conditions and soluble exposure require matched comparison. Evidence access: Primary full text Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures. · 2014 · https://pubmed.ncbi.nlm.nih.gov/25048011/ · DOI 10.1007/s00198-014-2791-5

evidence_access

Primary full text

experimental_model

Renal-vesicle uptake kinetics.

limitations

Assay-specific apparent affinities; do not assign them to every calcium channel or human compartment.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Using the same pump does not mean being transported equally efficiently.

primary_references

A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 30–36

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Renal-vesicle uptake kinetics. · source_derived_draft · unverified_draft

## strontium-renal-affinity Using the same pump does not mean being transported equally efficiently. The reported uptake half-saturation concentrations were about 13.4 micromolar for Sr2+ and 0.28 micromolar for Ca2+, consistent with lower affinity for strontium. Model: Renal-vesicle uptake kinetics. Limitations: Assay-specific apparent affinities; do not assign them to every calcium channel or human compartment. Evidence access: Primary full text A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

evidence_access

Primary full text

experimental_model

Radiotracer uptake in isolated renal basolateral membranes.

limitations

Shared-site kinetics do not establish a dietary calcium-loss threshold or quantify whole-kidney excretion.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

The two ions compete for access to the same transport machinery.

primary_references

A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 22–28

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Radiotracer uptake in isolated renal basolateral membranes. · source_derived_draft · unverified_draft

## strontium-renal-competition The two ions compete for access to the same transport machinery. Calcium and strontium each competitively inhibited uptake of the other in the renal-vesicle assay, increasing apparent half-saturation concentration without changing maximum velocity. Model: Radiotracer uptake in isolated renal basolateral membranes. Limitations: Shared-site kinetics do not establish a dietary calcium-loss threshold or quantify whole-kidney excretion. Evidence access: Primary full text A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

evidence_access

Primary full text

experimental_model

Isolated renal membrane vesicles; 90Sr and 45Ca tracers; ATP/Mg uptake assays.

limitations

Accessed methods refer to a prior preparation protocol without resolving species or ATP2B isoform. The assay measures ion transport, not radiation injury or net human renal clearance.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A calcium-handling membrane preparation can also pump strontium.

primary_references

A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

transport_effect

depends Membrane vesicles accumulated strontium in the assay, while the basolateral pump's role in the intact cell is extrusion toward blood; the two pools move opposite ways.

transport_pool

the proximal-tubule cell interior Membrane vesicles accumulated strontium in the assay, while the basolateral pump's role in the intact cell is extrusion toward blood; the two pools move opposite ways.

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 14–20

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated renal membrane vesicles; 90Sr and 45Ca tracers; ATP/Mg uptake assays. · source_derived_draft · unverified_draft

## strontium-renal-uptake A calcium-handling membrane preparation can also pump strontium. Basolateral proximal-tubule membrane vesicles accumulated radiolabeled strontium in an ATP- and Mg2+-dependent transport assay. Model: Isolated renal membrane vesicles; 90Sr and 45Ca tracers; ATP/Mg uptake assays. Limitations: Accessed methods refer to a prior preparation protocol without resolving species or ATP2B isoform. The assay measures ion transport, not radiation injury or net human renal clearance. Evidence access: Primary full text A Comparison Between Calcium and Strontium Transport by the (Ca2+ + Mg2+)ATPase of the Basolateral Plasma Membrane of Renal Proximal Convoluted Tubules. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40277992/ · DOI 10.3390/membranes15040122

evidence_access

Primary abstract

experimental_model

Randomized placebo-controlled SOTI trial; both groups received calcium and vitamin D.

limitations

Specific drug, population and co-treatment; no equivalent efficacy established for dietary strontium or strontium citrate. Trial mechanisms are not identified by the fracture endpoint.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

A clinical trial measured fewer fractures, separately from density scans.

primary_references

The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. · 2004 · https://pubmed.ncbi.nlm.nih.gov/14749454/ · DOI 10.1056/NEJMoa022436

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 422–428

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized placebo-controlled SOTI trial; both groups received calcium and vitamin D. · source_derived_draft · unverified_draft

## strontium-soti-fractures A clinical trial measured fewer fractures, separately from density scans. In 1,649 postmenopausal women with osteoporosis and a prior vertebral fracture, 2 g/day ranelate reduced new vertebral-fracture risk over three years: relative risk 0.59, 95% CI 0.48–0.73. Model: Randomized placebo-controlled SOTI trial; both groups received calcium and vitamin D. Limitations: Specific drug, population and co-treatment; no equivalent efficacy established for dietary strontium or strontium citrate. Trial mechanisms are not identified by the fracture endpoint. Evidence access: Primary abstract The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. · 2004 · https://pubmed.ncbi.nlm.nih.gov/14749454/ · DOI 10.1056/NEJMoa022436

evidence_access

Primary abstract

experimental_model

Biochemical domain/phospholipid binding accompanying mouse neuronal experiments.

limitations

Accessed abstract does not identify the species of recombinant domain constructs; that identity remains unresolved.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Different domains of a calcium sensor discriminate between the ions.

primary_references

Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12526776/ · DOI 10.1016/s0896-6273(02)01145-5

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 358–364

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical domain/phospholipid binding accompanying mouse neuronal experiments. · source_derived_draft · unverified_draft

## strontium-syt-binding Different domains of a calcium sensor discriminate between the ions. In the synaptotagmin-1 domain assays, strontium supported C2B/phospholipid complexes but not C2A/phospholipid complexes, whereas calcium supported both. Model: Biochemical domain/phospholipid binding accompanying mouse neuronal experiments. Limitations: Accessed abstract does not identify the species of recombinant domain constructs; that identity remains unresolved. Evidence access: Primary abstract Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12526776/ · DOI 10.1016/s0896-6273(02)01145-5

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse synaptotagmin-1 knockout synaptic recordings.

limitations

Ion substitution in neuronal experiments is not evidence that oral strontium reaches or improves this pathway.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Fast release needs this sensor even when strontium replaces calcium experimentally.

primary_references

Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12526776/ · DOI 10.1016/s0896-6273(02)01145-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 374–380

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse synaptotagmin-1 knockout synaptic recordings. · source_derived_draft · unverified_draft

## strontium-syt-knockout Fast release needs this sensor even when strontium replaces calcium experimentally. Synaptotagmin-1 knockout selectively impaired the fast component of both calcium- and strontium-induced neurotransmitter release in mouse neurons. Model: Mouse synaptotagmin-1 knockout synaptic recordings. Limitations: Ion substitution in neuronal experiments is not evidence that oral strontium reaches or improves this pathway. Evidence access: Primary abstract Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12526776/ · DOI 10.1016/s0896-6273(02)01145-5

evidence_access

Primary abstract

experimental_model

Biochemical protein-binding assays.

limitations

Negative result is specific to the stimulated-binding assay, not absence of SNARE machinery from exocytosis.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

Triggering release did not require every interaction induced by calcium.

primary_references

Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12526776/ · DOI 10.1016/s0896-6273(02)01145-5

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 366–372

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical protein-binding assays. · source_derived_draft · unverified_draft

## strontium-syt-no-snare-stimulation Triggering release did not require every interaction induced by calcium. Unlike calcium, strontium did not stimulate synaptotagmin C2-domain binding to SNARE proteins even at high tested concentrations. Model: Biochemical protein-binding assays. Limitations: Negative result is specific to the stimulated-binding assay, not absence of SNARE machinery from exocytosis. Evidence access: Primary abstract Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12526776/ · DOI 10.1016/s0896-6273(02)01145-5

evidence_access

Primary abstract

experimental_model

Rat C-cell model; concentration-response measurements across six signaling outputs.

limitations

Biased agonism is model- and assay-dependent; not a direct human thyroid-hormone effect.

nutrient_topic

Strontium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Strontium

plain_language

The same receptor can send different relative signals depending on the ion.

primary_references

Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22942242/ · DOI 10.1124/jpet.112.197210

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 342–348

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat C-cell model; concentration-response measurements across six signaling outputs. · source_derived_draft · unverified_draft

## strontium-thyroid-bias The same receptor can send different relative signals depending on the ion. In rat medullary thyroid carcinoma 6-23 cells, strontium biased CaSR signaling toward ERK1/2 relative to Gq/11 and intracellular-calcium mobilization compared with calcium. Model: Rat C-cell model; concentration-response measurements across six signaling outputs. Limitations: Biased agonism is model- and assay-dependent; not a direct human thyroid-hormone effect. Evidence access: Primary abstract Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22942242/ · DOI 10.1124/jpet.112.197210

evidence_access

Primary abstract

experimental_model

Cultured bovine pulmonary artery endothelial cells.

limitations

Dose was not available in the accessed abstract; no dietary calcium-depletion claim is made.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

The compound can change the activating signal upstream of an enzyme.

primary_references

Agmatine activation of nitric oxide synthase in endothelial cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9010916/

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 244–250

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured bovine pulmonary artery endothelial cells. · source_derived_draft · unverified_draft

## agmatine-sulfate-endothelial-calcium The compound can change the activating signal upstream of an enzyme. Agmatine induced cytosolic calcium transients in bovine pulmonary artery endothelial cells; repeated exposure downregulated the response. Model: Cultured bovine pulmonary artery endothelial cells. Limitations: Dose was not available in the accessed abstract; no dietary calcium-depletion claim is made. Evidence access: Primary abstract Agmatine activation of nitric oxide synthase in endothelial cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9010916/

evidence_access

Primary abstract

experimental_model

Bovine endothelial culture; pharmacological antagonist comparison.

limitations

The imidazoline-associated mechanism is pharmacologically inferred; a specific receptor gene was not established.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

An intact-cell signaling effect can differ from direct enzyme inhibition.

primary_references

Agmatine activation of nitric oxide synthase in endothelial cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9010916/

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 252–258

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bovine endothelial culture; pharmacological antagonist comparison. · source_derived_draft · unverified_draft

## agmatine-sulfate-endothelial-no An intact-cell signaling effect can differ from direct enzyme inhibition. Agmatine increased nitrite production about threefold in bovine endothelial cells; idazoxan inhibited the effect whereas yohimbine did not. Model: Bovine endothelial culture; pharmacological antagonist comparison. Limitations: The imidazoline-associated mechanism is pharmacologically inferred; a specific receptor gene was not established. Evidence access: Primary abstract Agmatine activation of nitric oxide synthase in endothelial cells. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9010916/

evidence_access

Primary abstract

experimental_model

Same isolated rat mitochondrial study with inhibitor probes.

limitations

Outer-membrane permeabilization was proposed; it is not a demonstrated beneficial effect of supplementation.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

Less swelling did not mean that every cell-death-related endpoint was prevented.

primary_references

Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31654209/ · DOI 10.1007/s00726-019-02791-6

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 396–402

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same isolated rat mitochondrial study with inhibitor probes. · source_derived_draft · unverified_draft

## agmatine-sulfate-mitochondrial-release Less swelling did not mean that every cell-death-related endpoint was prevented. At conditions inhibiting swelling, agmatine still enhanced cytochrome-c and Smac/DIABLO release while preventing AIF release. Model: Same isolated rat mitochondrial study with inhibitor probes. Limitations: Outer-membrane permeabilization was proposed; it is not a demonstrated beneficial effect of supplementation. Evidence access: Primary abstract Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31654209/ · DOI 10.1007/s00726-019-02791-6

evidence_access

Primary abstract

experimental_model

Isolated rat liver mitochondria; swelling and protein-release assays.

limitations

Numerical concentration ranges are not provided in the accessed abstract; no human protective threshold is inferred.

nutrient_topic

Agmatine Sulfate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Agmatine Sulfate

plain_language

A compound can change direction across concentrations and assay endpoints.

primary_references

Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31654209/ · DOI 10.1007/s00726-019-02791-6

Agmatine Sulfate: transport, guanidino metabolism, ion channels and cross-nutrient mechanisms (2026-09-20) · lines 388–394

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated rat liver mitochondria; swelling and protein-release assays. · source_derived_draft · unverified_draft

## agmatine-sulfate-mitochondrial-state A compound can change direction across concentrations and assay endpoints. Agmatine induced permeability transition at lower tested concentrations but inhibited calcium/phosphate-associated swelling at higher concentrations in isolated rat liver mitochondria. Model: Isolated rat liver mitochondria; swelling and protein-release assays. Limitations: Numerical concentration ranges are not provided in the accessed abstract; no human protective threshold is inferred. Evidence access: Primary abstract Involvement of the biogenic active amine agmatine in mitochondrial membrane permeabilization and release of pro-apoptotic factors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31654209/ · DOI 10.1007/s00726-019-02791-6

evidence_access

Primary abstract

experimental_model

Human CD38 enzyme assay with docking.

limitations

Docking does not prove a binding pose; no human NAD increase or longevity effect established.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

One experimentally inhibited target consumes NAD-related substrates.

primary_references

Flavonoids as inhibitors of human CD38. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21641214/ · DOI 10.1016/j.bmcl.2011.05.022

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 276–282

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human CD38 enzyme assay with docking. · source_derived_draft · unverified_draft

## luteolin-cd38-inhibition One experimentally inhibited target consumes NAD-related substrates. Luteolin inhibited human CD38 at an IC50 below 10 micromolar in vitro. Model: Human CD38 enzyme assay with docking. Limitations: Docking does not prove a binding pose; no human NAD increase or longevity effect established. Evidence access: Primary abstract Flavonoids as inhibitors of human CD38. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21641214/ · DOI 10.1016/j.bmcl.2011.05.022

evidence_access

Primary full text

experimental_model

Washed human platelets, 2.5–25 micromolar range in activation assays.

limitations

Not systemic calcium depletion or evidence of human bleeding safety.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

Calcium signaling connects receptor activation to platelet release.

primary_references

Luteolin inhibits GPVI-mediated platelet activation, oxidative stress, and thrombosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/38026984/ · DOI 10.3389/fphar.2023.1255069

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 436–442

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Washed human platelets, 2.5–25 micromolar range in activation assays. · source_derived_draft · unverified_draft

## luteolin-platelet-calcium Calcium signaling connects receptor activation to platelet release. Luteolin reduced collagen/convulxin-induced calcium responses and secretion in washed human platelets. Model: Washed human platelets, 2.5–25 micromolar range in activation assays. Limitations: Not systemic calcium depletion or evidence of human bleeding safety. Evidence access: Primary full text Luteolin inhibits GPVI-mediated platelet activation, oxidative stress, and thrombosis. · 2023 · https://pubmed.ncbi.nlm.nih.gov/38026984/ · DOI 10.3389/fphar.2023.1255069

evidence_access

Primary abstract

experimental_model

Human NSCLC cells; mouse tumor experiments provide a separate translational level.

limitations

Do not merge all tumor-cell death into one obligatory linear chain.

nutrient_topic

Cucurbitacins collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Cucurbitacins

plain_language

Inflammatory membrane rupture is separate from ferroptotic lipid damage.

primary_references

Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34217831/ · DOI 10.1016/j.phrs.2021.105748

Cucurbitacins: thiol chemistry, cytoskeleton, metabolic dependencies and signaling (2026-09-20) · lines 300–306

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human NSCLC cells; mouse tumor experiments provide a separate translational level. · source_derived_draft · unverified_draft

## cucurbitacin-b-pyroptosis-route Inflammatory membrane rupture is separate from ferroptotic lipid damage. Cucurbitacin B exposure was associated with the TLR4/mitochondrial-ROS/NLRP3 route and gasdermin D cleavage in the NSCLC pyroptosis experiments. Model: Human NSCLC cells; mouse tumor experiments provide a separate translational level. Limitations: Do not merge all tumor-cell death into one obligatory linear chain. Evidence access: Primary abstract Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34217831/ · DOI 10.1016/j.phrs.2021.105748

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human NSCLC loss-of-function experiments.

limitations

The accessed abstract does not establish the calcium store or channel; oral calcium depletion is not implied.

nutrient_topic

Cucurbitacins collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Cucurbitacins

plain_language

Removing the receptor weakened the tested death pathway.

primary_references

Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34217831/ · DOI 10.1016/j.phrs.2021.105748

trigger_kind

machinery_impairment Imported condition classification; unverified.

Cucurbitacins: thiol chemistry, cytoskeleton, metabolic dependencies and signaling (2026-09-20) · lines 292–298

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human NSCLC loss-of-function experiments. · source_derived_draft · unverified_draft

## cucurbitacin-b-tlr4-loss Removing the receptor weakened the tested death pathway. TLR4 silencing reduced cucurbitacin B-induced pyroptosis and associated mitochondrial ROS and calcium signals in human NSCLC cells. Model: Human NSCLC loss-of-function experiments. Limitations: The accessed abstract does not establish the calcium store or channel; oral calcium depletion is not implied. Evidence access: Primary abstract Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34217831/ · DOI 10.1016/j.phrs.2021.105748

dose

Eugenol around the effective 2-micromolar range

duration

Acute

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Washed human platelets

limitations

Pathway suppression does not identify one direct binding target and must not be generalized to every platelet agonist.

nutrient_topic

Eugenol chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Eugenol

organism

Washed human platelets

plain_language

Eugenol suppressed collagen-induced PLC-gamma2/PKC, PI3K/Akt/GSK3beta, MAPK and cPLA2/thromboxane-A2 signaling in human platelets.

primary_references

Eugenol Suppresses Platelet Activation and Mitigates Pulmonary Thromboembolism in Humans and Murine Models. (2024). https://pubmed.ncbi.nlm.nih.gov/38396774/ DOI: 10.3390/ijms25042098

route

In vitro

tissue

Signal phosphorylation, ATP release, P-selectin and calcium

Eugenol: mechanism of action and interactions (2026-09-20) · lines 22–31

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Washed human platelets · source_derived_draft · unverified_draft

## eugenol-platelet-pathways Eugenol suppressed collagen-induced PLC-gamma2/PKC, PI3K/Akt/GSK3beta, MAPK and cPLA2/thromboxane-A2 signaling in human platelets. Model/species: Washed human platelets Tissue/system: Signal phosphorylation, ATP release, P-selectin and calcium Exposure: Eugenol around the effective 2-micromolar range Route: In vitro Duration: Acute Limits: Pathway suppression does not identify one direct binding target and must not be generalized to every platelet agonist. Primary reference: Eugenol Suppresses Platelet Activation and Mitigates Pulmonary Thromboembolism in Humans and Murine Models. (2024). https://pubmed.ncbi.nlm.nih.gov/38396774/ DOI: 10.3390/ijms25042098 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_access

Primary abstract

experimental_model

Rodent osteoblast-like cell cultures; 2.5–100 micromolar vanadate.

limitations

Mixed cell models are named explicitly; NO is a proposed mediator, not proven sole cause of growth effects.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

A growth-related exposure can engage nitrosative signaling at higher concentrations.

primary_references

Vanadate-induced nitric oxide production: role in osteoblast growth and differentiation. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10988345/ · DOI 10.1016/s0014-2999(00)00356-3

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 326–332

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rodent osteoblast-like cell cultures; 2.5–100 micromolar vanadate. · source_derived_draft · unverified_draft

## vanadium-bone-no A growth-related exposure can engage nitrosative signaling at higher concentrations. Vanadate increased NO release above 50 micromolar in the tested rat UMR106 and mouse MC3T3-E1 osteoblast-like cultures, with a biphasic concentration response. Model: Rodent osteoblast-like cell cultures; 2.5–100 micromolar vanadate. Limitations: Mixed cell models are named explicitly; NO is a proposed mediator, not proven sole cause of growth effects. Evidence access: Primary abstract Vanadate-induced nitric oxide production: role in osteoblast growth and differentiation. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10988345/ · DOI 10.1016/s0014-2999(00)00356-3

evidence_access

Primary abstract

experimental_model

Fura-2 imaging in neonatal rat cardiomyocytes.

limitations

Association does not identify whether SERCA, other transporters or secondary cell injury caused the calcium rise.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

Ion regulation changed alongside mitochondrial injury.

primary_references

Vanadate induces necrotic death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18251508/ · DOI 10.1021/tx700204r

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 302–308

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fura-2 imaging in neonatal rat cardiomyocytes. · source_derived_draft · unverified_draft

## vanadium-cardiac-calcium Ion regulation changed alongside mitochondrial injury. Vanadate-treated rat cardiomyocytes showed sustained elevation of cytosolic calcium after 24 hours near the viability-loss concentrations. Model: Fura-2 imaging in neonatal rat cardiomyocytes. Limitations: Association does not identify whether SERCA, other transporters or secondary cell injury caused the calcium rise. Evidence access: Primary abstract Vanadate induces necrotic death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18251508/ · DOI 10.1021/tx700204r

evidence_access

Primary full text

experimental_model

Duck liver ultrastructure and MAM proteomics/co-association measurements.

limitations

No genetic or inhibitor rescue establishing this chain was extracted. Human orthologues are not substituted for duck measurements.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

A change at organelle contacts may link calcium handling, metabolism and injury.

primary_references

Dual-pathway mechanism of vanadium-induced hepatotoxicity in ducks: Synergistic crosstalk between glucose homeostasis disruption and NADH/FSP1/COQ10 axis-driven ferroptosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41362732/ · DOI 10.7150/ijbs.123482

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 366–372

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Duck liver ultrastructure and MAM proteomics/co-association measurements. · source_derived_draft · unverified_draft

## vanadium-duck-mam A change at organelle contacts may link calcium handling, metabolism and injury. Vanadium-exposed duck livers showed wider ER–mitochondrial gaps and altered abundance/association of the IP3R–GRP75–VDAC1 contact complex. Model: Duck liver ultrastructure and MAM proteomics/co-association measurements. Limitations: No genetic or inhibitor rescue establishing this chain was extracted. Human orthologues are not substituted for duck measurements. Evidence access: Primary full text Dual-pathway mechanism of vanadium-induced hepatotoxicity in ducks: Synergistic crosstalk between glucose homeostasis disruption and NADH/FSP1/COQ10 axis-driven ferroptosis. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41362732/ · DOI 10.7150/ijbs.123482

evidence_access

Primary abstract and RCSB PDB 5A3Q author deposition

experimental_model

Rabbit SERCA structure, deposition 5A3Q; primary abstract plus author-deposited structure identity.

limitations

Structure used nucleotide analogues and thapsigargin; not a measured human intracellular calcium effect.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

A phosphate analogue can trap a calcium pump in a catalytic state.

primary_references

Crystal Structure of the Vanadate-Inhibited Ca(2+)-ATPase. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27050689/ · DOI 10.1016/j.str.2016.02.018

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 254–260

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rabbit SERCA structure, deposition 5A3Q; primary abstract plus author-deposited structure identity. · source_derived_draft · unverified_draft

## vanadium-serca-transition A phosphate analogue can trap a calcium pump in a catalytic state. Vanadate occupied the catalytic site of calcium-free SERCA as planar VO3 with water and magnesium in a dephosphorylation-transition-like conformation. Model: Rabbit SERCA structure, deposition 5A3Q; primary abstract plus author-deposited structure identity. Limitations: Structure used nucleotide analogues and thapsigargin; not a measured human intracellular calcium effect. Evidence access: Primary abstract and RCSB PDB 5A3Q author deposition Crystal Structure of the Vanadate-Inhibited Ca(2+)-ATPase. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27050689/ · DOI 10.1016/j.str.2016.02.018

evidence_access

Primary abstract

experimental_model

Human lysosomal sulfatase crystallography.

limitations

Structural inhibition is not evidence that oral vanadium causes mucopolysaccharidosis.

nutrient_topic

Vanadium collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Vanadium

plain_language

Vanadium’s targets extend beyond insulin signaling and ATPases.

primary_references

Structure of a human lysosomal sulfatase. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9032078/ · DOI 10.1016/s0969-2126(97)00185-8

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 270–276

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human lysosomal sulfatase crystallography. · source_derived_draft · unverified_draft

## vanadium-sulfatase-binding Vanadium’s targets extend beyond insulin signaling and ATPases. In the vanadate-inhibited human ARSB structure, vanadate replaced sulfate at the active site and was covalently linked to the modified catalytic residue. Model: Human lysosomal sulfatase crystallography. Limitations: Structural inhibition is not evidence that oral vanadium causes mucopolysaccharidosis. Evidence access: Primary abstract Structure of a human lysosomal sulfatase. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9032078/ · DOI 10.1016/s0969-2126(97)00185-8

evidence_access

Primary abstract

experimental_model

Same 12-month calcium/D3-background trial.

limitations

Post-hoc subgroup findings are exploratory; not independent replication.

nutrient_topic

Silica collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Silica and soluble silicon

plain_language

A matrix marker and bone-density outcome did not provide equivalent evidence.

primary_references

Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18547426/ · DOI 10.1186/1471-2474-9-85

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 384–390

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same 12-month calcium/D3-background trial. · source_derived_draft · unverified_draft

## silica-human-bmd-null A matrix marker and bone-density outcome did not provide equivalent evidence. Lumbar spine BMD did not significantly change; a femoral-neck signal arose in a post-hoc subgroup. Model: Same 12-month calcium/D3-background trial. Limitations: Post-hoc subgroup findings are exploratory; not independent replication. Evidence access: Primary abstract Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18547426/ · DOI 10.1186/1471-2474-9-85

evidence_access

Primary abstract

experimental_model

184 women randomized; 136 completed; all received 1,000 mg calcium and 20 micrograms D3 daily.

limitations

Marker result is not fracture prevention; attrition and multiple endpoints matter.

nutrient_topic

Silica collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Silica and soluble silicon

plain_language

A collagen-formation marker changed on top of calcium and vitamin D.

primary_references

Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18547426/ · DOI 10.1186/1471-2474-9-85

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 376–382

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 184 women randomized; 136 completed; all received 1,000 mg calcium and 20 micrograms D3 daily. · source_derived_draft · unverified_draft

## silica-human-pinp A collagen-formation marker changed on top of calcium and vitamin D. PINP differed from placebo at 12 months in the 6- and 12-mg Si groups without a clear dose response. Model: 184 women randomized; 136 completed; all received 1,000 mg calcium and 20 micrograms D3 daily. Limitations: Marker result is not fracture prevention; attrition and multiple endpoints matter. Evidence access: Primary abstract Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18547426/ · DOI 10.1186/1471-2474-9-85

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Rat glucose challenges and isolated intestinal/islet experiments

exposure

Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes

limitations

Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Rat

plain_language

Buffering intracellular calcium weakened the response; this is not the same as low calcium intake.

primary_references

[ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

tissue_or_cell_type

Intestine and pancreatic islets

trigger_kind

machinery_impairment Imported condition classification; unverified.

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 441–452

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat glucose challenges and isolated intestinal/islet experiments · source_derived_draft · unverified_draft

### ceylon-calcium-chelation BAPTA-AM at 50 micromolar reduced cinnamaldehyde-induced islet calcium influx by approximately 27%. Condition category: machinery_impairment nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: Buffering intracellular calcium weakened the response; this is not the same as low calcium intake. organism: Rat tissue_or_cell_type: Intestine and pancreatic islets experimental_model: Rat glucose challenges and isolated intestinal/islet experiments limitations: Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy. exposure: Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes evidence_span: {"source_cache": "artifacts/ceylon-research/37631083.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "81c61f935e3b9e0e16acb5e76bd56be59ca99bea4e3da001710e6d994abb92e7", "start_char": 15149, "end_char": 21214, "text_sha256": "472b3baeedfb72dc1405349207bce32da9e04cb33d20a481f90ef39269fe0c75"} [ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

evidence_span

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experimental_model

Human TRPA1 expression, calcium fluorescence and patch clamp

exposure

Cinnamaldehyde concentration response; 300 micromolar challenge; triple cysteine-to-serine construct

limitations

Channel expression and high cell-assay concentrations do not establish dietary exposure or a human calcium-deficiency effect.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Human TRPA1 in HEK293 cells

plain_language

Cinnamaldehyde can open a cellular sensor channel that lets a calcium signal develop.

primary_references

[ceylon-p24516781] Ligand determinants of fatty acid activation of the pronociceptive ion channel TRPA1. (2014). https://pubmed.ncbi.nlm.nih.gov/24516781/ DOI: 10.7717/peerj.248

tissue_or_cell_type

Engineered cultured cells

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 337–348

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human TRPA1 expression, calcium fluorescence and patch clamp · source_derived_draft · unverified_draft

### ceylon-human-trpa1 Cinnamaldehyde activated human TRPA1, with calcium-fluorescence EC50 approximately 11 micromolar in the expression assay. Condition category: normal nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cinnamaldehyde can open a cellular sensor channel that lets a calcium signal develop. organism: Human TRPA1 in HEK293 cells tissue_or_cell_type: Engineered cultured cells experimental_model: Human TRPA1 expression, calcium fluorescence and patch clamp limitations: Channel expression and high cell-assay concentrations do not establish dietary exposure or a human calcium-deficiency effect. exposure: Cinnamaldehyde concentration response; 300 micromolar challenge; triple cysteine-to-serine construct evidence_span: {"source_cache": "artifacts/ceylon-research/24516781.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5605569464035286614b12021fc60adbaf6c8a003a6b634d03fc5b544ce59d27", "start_char": 0, "end_char": 1685, "text_sha256": "5605569464035286614b12021fc60adbaf6c8a003a6b634d03fc5b544ce59d27"} [ceylon-p24516781] Ligand determinants of fatty acid activation of the pronociceptive ion channel TRPA1. (2014). https://pubmed.ncbi.nlm.nih.gov/24516781/ DOI: 10.7717/peerj.248

evidence_span

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experimental_model

Rat glucose challenges and isolated intestinal/islet experiments

exposure

Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes

limitations

Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Rat

plain_language

Calcium movement connected the chemical stimulus to the insulin-secreting machinery.

primary_references

[ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

tissue_or_cell_type

Intestine and pancreatic islets

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 415–426

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat glucose challenges and isolated intestinal/islet experiments · source_derived_draft · unverified_draft

### ceylon-islet-calcium Cinnamaldehyde increased calcium influx into isolated rat pancreatic islets. Condition category: normal nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium movement connected the chemical stimulus to the insulin-secreting machinery. organism: Rat tissue_or_cell_type: Intestine and pancreatic islets experimental_model: Rat glucose challenges and isolated intestinal/islet experiments limitations: Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy. exposure: Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes evidence_span: {"source_cache": "artifacts/ceylon-research/37631083.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6e5158a53c14ee90391ae2756078dd5511e2caeaa1c078940b3e2f8c34775226", "start_char": 0, "end_char": 1437, "text_sha256": "6e5158a53c14ee90391ae2756078dd5511e2caeaa1c078940b3e2f8c34775226"} [ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Rat glucose challenges and isolated intestinal/islet experiments

exposure

Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes

limitations

Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Rat

plain_language

Blocking TRPA1 removed the measured calcium response.

primary_references

[ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

tissue_or_cell_type

Intestine and pancreatic islets

trigger_kind

machinery_impairment Imported condition classification; unverified.

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 428–439

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat glucose challenges and isolated intestinal/islet experiments · source_derived_draft · unverified_draft

### ceylon-trpa1-block HC-030031 at 100 micromolar abolished the cinnamaldehyde-induced calcium influx in isolated rat islets. Condition category: machinery_impairment nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking TRPA1 removed the measured calcium response. organism: Rat tissue_or_cell_type: Intestine and pancreatic islets experimental_model: Rat glucose challenges and isolated intestinal/islet experiments limitations: Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy. exposure: Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes evidence_span: {"source_cache": "artifacts/ceylon-research/37631083.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "81c61f935e3b9e0e16acb5e76bd56be59ca99bea4e3da001710e6d994abb92e7", "start_char": 14083, "end_char": 20148, "text_sha256": "c4c3a9bf3331afd13074d335e0130614002673a177990f17495f0c9d893af7c4"} [ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ceylon-research/37631083.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "81c61f935e3b9e0e16acb5e76bd56be59ca99bea4e3da001710e6d994abb92e7", "start_char": 15149, "end_char": 21214, "text_sha256": "472b3baeedfb72dc1405349207bce32da9e04cb33d20a481f90ef39269fe0c75"}

experimental_model

Rat glucose challenges and isolated intestinal/islet experiments

exposure

Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes

limitations

Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Rat

plain_language

Blocking voltage-dependent calcium channels removed part of the response.

primary_references

[ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

tissue_or_cell_type

Intestine and pancreatic islets

trigger_kind

machinery_impairment Imported condition classification; unverified.

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 454–465

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat glucose challenges and isolated intestinal/islet experiments · source_derived_draft · unverified_draft

### ceylon-vdcc-block Nifedipine at 1 micromolar reduced cinnamaldehyde-induced islet calcium influx by approximately 26%. Condition category: machinery_impairment nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking voltage-dependent calcium channels removed part of the response. organism: Rat tissue_or_cell_type: Intestine and pancreatic islets experimental_model: Rat glucose challenges and isolated intestinal/islet experiments limitations: Injection is not spice ingestion. Antagonists and calcium chelation probe machinery, not dietary mineral inadequacy. exposure: Cinnamaldehyde 5–20 mg/kg intraperitoneal in vivo; islet calcium experiment 100 micromolar for 10 minutes evidence_span: {"source_cache": "artifacts/ceylon-research/37631083.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "81c61f935e3b9e0e16acb5e76bd56be59ca99bea4e3da001710e6d994abb92e7", "start_char": 15149, "end_char": 21214, "text_sha256": "472b3baeedfb72dc1405349207bce32da9e04cb33d20a481f90ef39269fe0c75"} [ceylon-p37631083] Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. (2023). https://pubmed.ncbi.nlm.nih.gov/37631083/ DOI: 10.3390/ph16081167

evidence_access

Primary abstract

experimental_model

Biochemical kinase assays with cardiomyocyte and mouse experiments; exact purified construct species not resolved here.

limitations

Initial calcium/calmodulin exposure and sustained autonomous activity are distinct; not a dietary methionine effect.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

Oxidation can leave a signaling protein switched on.

primary_references

A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18455987/ · DOI 10.1016/j.cell.2008.02.048

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 332–338

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical kinase assays with cardiomyocyte and mouse experiments; exact purified construct species not resolved here. · source_derived_draft · unverified_draft

## methionine-camkii-oxidation Oxidation can leave a signaling protein switched on. Oxidation of paired CaMKII regulatory methionines sustained kinase activity after calcium/calmodulin was removed. Model: Biochemical kinase assays with cardiomyocyte and mouse experiments; exact purified construct species not resolved here. Limitations: Initial calcium/calmodulin exposure and sustained autonomous activity are distinct; not a dietary methionine effect. Evidence access: Primary abstract A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18455987/ · DOI 10.1016/j.cell.2008.02.048

compartment_description

Bone extracellular matrix

experimental_model

Microscopy, diffraction and elemental analysis

limitations

Biological apatite is substituted and nonstoichiometric; the ideal hydroxyapatite formula is not an exact tissue composition.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Danio rerio

plain_language

Bone contains calcium in a solid mineral phase, distinct from dissolved calcium ions.

primary_references

[mahamid2008] Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: Indications for an amorphous precursor phase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2529085/ DOI: 10.1073/pnas.0803354105

tissue_or_cell_type

Fin-ray bone

Calcium: mechanism-first literature curation (2026-09-17) · lines 862–872

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Microscopy, diffraction and elemental analysis · source_derived_draft · unverified_draft

### bone-calcium-in-solid-apatite Mature zebrafish fin-ray bone contains crystalline carbonated apatite platelets embedded in an organized collagen matrix. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bone contains calcium in a solid mineral phase, distinct from dissolved calcium ions. organism: Danio rerio tissue_or_cell_type: Fin-ray bone experimental_model: Microscopy, diffraction and elemental analysis limitations: Biological apatite is substituted and nonstoichiometric; the ideal hydroxyapatite formula is not an exact tissue composition. compartment_description: Bone extracellular matrix [mahamid2008] Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: Indications for an amorphous precursor phase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2529085/ DOI: 10.1073/pnas.0803354105

compartment_description

Cytosol and nucleus

experimental_model

Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays

limitations

NFAT1-specific evidence; do not assign this calcium response to all NFAT proteins or NFAT5.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Calcineurin connects calcium signaling to NFAT1 activation.

primary_references

[ca-loh1996] Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity (1996). https://pubmed.ncbi.nlm.nih.gov/8631904/ DOI: 10.1074/jbc.271.18.10884

research_relationship_category

regulation

tissue_or_cell_type

T lymphocytes

Calcium: mechanism-first literature curation (2026-09-17) · lines 425–436

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays · source_derived_draft · unverified_draft

### ca-calcineurin-nfat1-regulation Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcineurin connects calcium signaling to NFAT1 activation. organism: Mus musculus tissue_or_cell_type: T lymphocytes experimental_model: Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays limitations: NFAT1-specific evidence; do not assign this calcium response to all NFAT proteins or NFAT5. research_relationship_category: regulation compartment_description: Cytosol and nucleus [ca-loh1996] Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity (1996). https://pubmed.ncbi.nlm.nih.gov/8631904/ DOI: 10.1074/jbc.271.18.10884

compartment_description

Cytosol

experimental_model

Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry

limitations

Fragment and biochemical data support a regulatory mechanism; not tissue-level output.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Calcium-bound calmodulin helps switch on calcineurin.

primary_references

[ca-rumimasante2012] Structural basis for activation of calcineurin by calmodulin (2012). https://pubmed.ncbi.nlm.nih.gov/22100452/ DOI: 10.1016/j.jmb.2011.11.008

research_relationship_category

regulation

tissue_or_cell_type

Recombinant signaling proteins

Calcium: mechanism-first literature curation (2026-09-17) · lines 412–423

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry · source_derived_draft · unverified_draft

### ca-calmodulin-calcineurin-activation Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-bound calmodulin helps switch on calcineurin. organism: Homo sapiens tissue_or_cell_type: Recombinant signaling proteins experimental_model: Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry limitations: Fragment and biochemical data support a regulatory mechanism; not tissue-level output. research_relationship_category: regulation compartment_description: Cytosol [ca-rumimasante2012] Structural basis for activation of calcineurin by calmodulin (2012). https://pubmed.ncbi.nlm.nih.gov/22100452/ DOI: 10.1016/j.jmb.2011.11.008

compartment_description

Plasma membrane

experimental_model

Human erythrocyte membrane ghosts with purified human or bovine calmodulin

limitations

Membrane ghosts with controlled additions; pump isoforms were not resolved and this is not an intact-cell dose response.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Calmodulin makes the red-cell calcium pump respond more strongly to calcium.

primary_references

[ca-roufogalis1980] Regulation by calmodulin of the calcium affinity of the calcium-transport ATPase in human erythrocytes (1980). https://pubmed.ncbi.nlm.nih.gov/6109558/ DOI: 10.1139/o80-126

research_relationship_category

regulation

tissue_or_cell_type

Erythrocyte membranes

Calcium: mechanism-first literature curation (2026-09-17) · lines 612–623

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocyte membrane ghosts with purified human or bovine calmodulin · source_derived_draft · unverified_draft

### ca-calmodulin-pmca-affinity Calmodulin increases apparent calcium affinity and ATPase activity of the erythrocyte calcium pump. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calmodulin makes the red-cell calcium pump respond more strongly to calcium. organism: Homo sapiens tissue_or_cell_type: Erythrocyte membranes experimental_model: Human erythrocyte membrane ghosts with purified human or bovine calmodulin limitations: Membrane ghosts with controlled additions; pump isoforms were not resolved and this is not an intact-cell dose response. research_relationship_category: regulation compartment_description: Plasma membrane [ca-roufogalis1980] Regulation by calmodulin of the calcium affinity of the calcium-transport ATPase in human erythrocytes (1980). https://pubmed.ncbi.nlm.nih.gov/6109558/ DOI: 10.1139/o80-126

compartment_description

Cytosolic kinase complex

experimental_model

Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays

limitations

Brain holoenzyme assay; does not identify every isoform or phosphorylation site.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

Calcium-bound calmodulin starts CaMKII self-phosphorylation.

primary_references

[ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5

research_relationship_category

regulation

tissue_or_cell_type

Brain enzyme preparation

Calcium: mechanism-first literature curation (2026-09-17) · lines 438–449

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays · source_derived_draft · unverified_draft

### ca-camkii-calmodulin-activation Calcium/calmodulin stimulates autophosphorylation of purified brain CaMKII. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-bound calmodulin starts CaMKII self-phosphorylation. organism: Mammalia tissue_or_cell_type: Brain enzyme preparation experimental_model: Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays limitations: Brain holoenzyme assay; does not identify every isoform or phosphorylation site. research_relationship_category: regulation compartment_description: Cytosolic kinase complex [ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5

compartment_description

SR to local cytosol

experimental_model

Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations

limitations

Imaging and ryanodine sensitivity establish localized release; the historical single-channel estimate is not encoded as settled channel stoichiometry.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Rattus norvegicus

plain_language

Heart cells release small local bursts of stored calcium.

primary_references

[ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594

research_relationship_category

mechanism

tissue_or_cell_type

Cardiac myocytes

transport_or_reaction_direction

SR lumen to cytosol

Calcium: mechanism-first literature curation (2026-09-17) · lines 809–821

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations · source_derived_draft · unverified_draft

### ca-cardiac-sr-sparks Localized sarcoplasmic-reticulum calcium release generates brief calcium sparks in rat cardiac myocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Heart cells release small local bursts of stored calcium. organism: Rattus norvegicus tissue_or_cell_type: Cardiac myocytes experimental_model: Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations limitations: Imaging and ryanodine sensitivity establish localized release; the historical single-channel estimate is not encoded as settled channel stoichiometry. research_relationship_category: mechanism transport_or_reaction_direction: SR lumen to cytosol compartment_description: SR to local cytosol [ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594

compartment_description

Nonmitochondrial intracellular store to cytosol

experimental_model

Permeabilized rat pancreatic acinar cells

limitations

Permeabilized-cell application; receptor isoform and dietary status were not established.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Rattus norvegicus

plain_language

IP3 releases stored calcium inside acinar cells.

primary_references

[ca-streb1983] Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate (1983). https://pubmed.ncbi.nlm.nih.gov/6605482/ DOI: 10.1038/306067a0

research_relationship_category

mechanism

tissue_or_cell_type

Pancreatic acinar cells

transport_or_reaction_direction

Intracellular store to cytosol

Calcium: mechanism-first literature curation (2026-09-17) · lines 464–476

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Permeabilized rat pancreatic acinar cells · source_derived_draft · unverified_draft

### ca-ip3-mobilizes-store Applied IP3 releases calcium from a nonmitochondrial intracellular store in permeabilized pancreatic acinar cells. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: IP3 releases stored calcium inside acinar cells. organism: Rattus norvegicus tissue_or_cell_type: Pancreatic acinar cells experimental_model: Permeabilized rat pancreatic acinar cells limitations: Permeabilized-cell application; receptor isoform and dietary status were not established. research_relationship_category: mechanism transport_or_reaction_direction: Intracellular store to cytosol compartment_description: Nonmitochondrial intracellular store to cytosol [ca-streb1983] Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate (1983). https://pubmed.ncbi.nlm.nih.gov/6605482/ DOI: 10.1038/306067a0

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

Inner mitochondrial membrane

experimental_model

Cultured mammalian cells and in vivo mouse-liver MCU silencing

limitations

No inference of universal respiratory failure or dietary calcium deficiency.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens and Mus musculus

plain_language

Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion.

primary_references

[ca-baughman2011] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685886/ DOI: 10.1038/nature10234

research_relationship_category

loss_of_function

tissue_or_cell_type

Cultured cells and mouse liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 693–704

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured mammalian cells and in vivo mouse-liver MCU silencing · source_derived_draft · unverified_draft

### ca-mcu-loss-matrix-uptake MCU silencing sharply reduces mitochondrial calcium uptake while membrane potential and respiration remain intact in the tested preparations. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion. organism: Homo sapiens and Mus musculus tissue_or_cell_type: Cultured cells and mouse liver experimental_model: Cultured mammalian cells and in vivo mouse-liver MCU silencing limitations: No inference of universal respiratory failure or dietary calcium deficiency. research_relationship_category: loss_of_function compartment_description: Inner mitochondrial membrane [ca-baughman2011] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685886/ DOI: 10.1038/nature10234

compartment_description

Inner mitochondrial membrane

experimental_model

Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp

limitations

Contested interpretation; mitoplast preparation and subunit abundance are challenged by Tsai 2023. Not a settled universal edge.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

One electrophysiological study proposes that MICU proteins increase channel opening during calcium signals.

primary_references

[ca-garg2021] The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter (2021). https://pubmed.ncbi.nlm.nih.gov/34463251/ DOI: 10.7554/eLife.69312

tissue_or_cell_type

Isolated mitochondria and mitoplasts

Calcium: mechanism-first literature curation (2026-09-17) · lines 745–755

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp · source_derived_draft · unverified_draft

### ca-micu-potentiation-model Garg and colleagues interpret mitochondrial currents as MICU-dependent enhancement of uniporter opening at elevated external calcium, without pore occlusion. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: One electrophysiological study proposes that MICU proteins increase channel opening during calcium signals. organism: Mammalia tissue_or_cell_type: Isolated mitochondria and mitoplasts experimental_model: Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp limitations: Contested interpretation; mitoplast preparation and subunit abundance are challenged by Tsai 2023. Not a settled universal edge. compartment_description: Inner mitochondrial membrane [ca-garg2021] The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter (2021). https://pubmed.ncbi.nlm.nih.gov/34463251/ DOI: 10.7554/eLife.69312

compartment_description

Mitochondrial uniporter regulatory machinery

experimental_model

HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays

limitations

Threshold and molecular explanation are assay-dependent; see the separate MICU1 gating conflict.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

MICU1 helps prevent unnecessary calcium accumulation in resting mitochondria.

primary_references

[ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011

research_relationship_category

regulation

tissue_or_cell_type

HeLa, HEK293 and endothelial cells

Calcium: mechanism-first literature curation (2026-09-17) · lines 706–717

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays · source_derived_draft · unverified_draft

### ca-micu1-basal-uptake-restraint MICU1 limits MCU-dependent calcium uptake at low external calcium in the examined cell preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MICU1 helps prevent unnecessary calcium accumulation in resting mitochondria. organism: Homo sapiens tissue_or_cell_type: HeLa, HEK293 and endothelial cells experimental_model: HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays limitations: Threshold and molecular explanation are assay-dependent; see the separate MICU1 gating conflict. research_relationship_category: regulation compartment_description: Mitochondrial uniporter regulatory machinery [ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

Mitochondrial matrix

experimental_model

HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays

limitations

Cell-specific knockdown response; does not imply high dietary calcium or all MICU1 variants behave identically.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Loss of MICU1 can let mitochondria accumulate too much calcium at rest.

primary_references

[ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011

research_relationship_category

loss_of_function

tissue_or_cell_type

HeLa and endothelial cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 719–730

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays · source_derived_draft · unverified_draft

### ca-micu1-loss-overload MICU1 knockdown elevates basal matrix calcium through MCU-dependent uptake in the tested cells. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of MICU1 can let mitochondria accumulate too much calcium at rest. organism: Homo sapiens tissue_or_cell_type: HeLa and endothelial cells experimental_model: HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays limitations: Cell-specific knockdown response; does not imply high dietary calcium or all MICU1 variants behave identically. research_relationship_category: loss_of_function compartment_description: Mitochondrial matrix [ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011

compartment_description

Intermembrane-space face of inner mitochondrial membrane

experimental_model

Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays

limitations

Supports pore occlusion in these assays; competing potentiation evidence remains linked rather than discarded.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mammalia

plain_language

A later study directly observes MICU1 inhibiting the uniporter.

primary_references

[ca-tsai2023] Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex (2023). https://pubmed.ncbi.nlm.nih.gov/37036971/ DOI: 10.1073/pnas.2217665120

research_relationship_category

mechanistic_evidence

tissue_or_cell_type

Reconstituted protein and mitochondrial preparations

Calcium: mechanism-first literature curation (2026-09-17) · lines 757–768

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays · source_derived_draft · unverified_draft

### ca-micu1-occlusion-evidence Purified MICU1 suppresses MCU-complex currents in patch-clamp experiments, and disruption of its MCU-interacting K126 residue abolishes this suppression. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A later study directly observes MICU1 inhibiting the uniporter. organism: Mammalia tissue_or_cell_type: Reconstituted protein and mitochondrial preparations experimental_model: Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays limitations: Supports pore occlusion in these assays; competing potentiation evidence remains linked rather than discarded. research_relationship_category: mechanistic_evidence compartment_description: Intermembrane-space face of inner mitochondrial membrane [ca-tsai2023] Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex (2023). https://pubmed.ncbi.nlm.nih.gov/37036971/ DOI: 10.1073/pnas.2217665120

compartment_description

Plasma membrane protein complex

experimental_model

Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays

limitations

Purified PMCA1 complex; subunit availability and other PMCA isoforms require separate evidence.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Neuroplastin helps PMCA1 function.

primary_references

[ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7

research_relationship_category

regulation

tissue_or_cell_type

Purified recombinant proteins

Calcium: mechanism-first literature curation (2026-09-17) · lines 599–610

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays · source_derived_draft · unverified_draft

### ca-neuroplastin-pmca1-support Neuroplastin binds the transmembrane region of human PMCA1 and supports pump ATPase activity. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Neuroplastin helps PMCA1 function. organism: Homo sapiens tissue_or_cell_type: Purified recombinant proteins experimental_model: Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays limitations: Purified PMCA1 complex; subunit availability and other PMCA isoforms require separate evidence. research_relationship_category: regulation compartment_description: Plasma membrane protein complex [ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

Plasma membrane

experimental_model

Human inherited immune deficiency, patient T-cell rescue and functional channel assays

limitations

A rare channelopathy, not nutritional calcium deficiency; the evidence concerns the studied variant.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

This inherited channel defect interrupts calcium entry into T cells.

primary_references

[ca-feske2006] A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function (2006). https://pubmed.ncbi.nlm.nih.gov/16582901/ DOI: 10.1038/nature04702

research_relationship_category

loss_of_function

tissue_or_cell_type

Patient T lymphocytes

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 558–569

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human inherited immune deficiency, patient T-cell rescue and functional channel assays · source_derived_draft · unverified_draft

### ca-orai1-inherited-loss-influx Homozygous ORAI1 R91W loss of function abolishes CRAC activity in patient T cells; wild-type ORAI1 restores influx. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This inherited channel defect interrupts calcium entry into T cells. organism: Homo sapiens tissue_or_cell_type: Patient T lymphocytes experimental_model: Human inherited immune deficiency, patient T-cell rescue and functional channel assays limitations: A rare channelopathy, not nutritional calcium deficiency; the evidence concerns the studied variant. research_relationship_category: loss_of_function compartment_description: Plasma membrane [ca-feske2006] A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function (2006). https://pubmed.ncbi.nlm.nih.gov/16582901/ DOI: 10.1038/nature04702

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

Mitochondrial permeability-transition pathway

experimental_model

Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts

limitations

Protection does not extend to all classical apoptotic stimuli; calcium nutrition was not manipulated.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Removing cyclophilin D protects these cells against calcium-overload injury.

primary_references

[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434

research_relationship_category

loss_of_function

tissue_or_cell_type

Primary hepatocytes and fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 849–860

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft

### ca-ppif-loss-calcium-death-resistance Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing cyclophilin D protects these cells against calcium-overload injury. organism: Mus musculus tissue_or_cell_type: Primary hepatocytes and fibroblasts experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Protection does not extend to all classical apoptotic stimuli; calcium nutrition was not manipulated. research_relationship_category: loss_of_function compartment_description: Mitochondrial permeability-transition pathway [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434

compartment_description

ER-plasma-membrane junctions

experimental_model

Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays

limitations

Domain-expression experiments isolate coupling; physiological amplitude depends on cellular context.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

STIM1 directly opens the ORAI1 calcium-entry pathway.

primary_references

[ca-park2009] STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 (2009). https://pubmed.ncbi.nlm.nih.gov/19249086/ DOI: 10.1016/j.cell.2009.02.014

research_relationship_category

regulation

tissue_or_cell_type

HEK293 expression system and purified proteins

Calcium: mechanism-first literature curation (2026-09-17) · lines 531–542

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays · source_derived_draft · unverified_draft

### ca-stim1-direct-orai1-gating The cytosolic CRAC-activation domain of STIM1 binds ORAI1 directly and activates its calcium current. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: STIM1 directly opens the ORAI1 calcium-entry pathway. organism: Homo sapiens tissue_or_cell_type: HEK293 expression system and purified proteins experimental_model: Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays limitations: Domain-expression experiments isolate coupling; physiological amplitude depends on cellular context. research_relationship_category: regulation compartment_description: ER-plasma-membrane junctions [ca-park2009] STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 (2009). https://pubmed.ncbi.nlm.nih.gov/19249086/ DOI: 10.1016/j.cell.2009.02.014

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

ER-plasma-membrane signaling junction

experimental_model

Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis

limitations

RNA interference perturbs signaling machinery; it does not model low calcium intake.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Reducing STIM1 weakens calcium entry after stores empty.

primary_references

[ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

research_relationship_category

loss_of_function

tissue_or_cell_type

HeLa cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 518–529

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis · source_derived_draft · unverified_draft

### ca-stim1-knockdown-influx STIM1 knockdown suppresses store-depletion-triggered calcium influx in HeLa cells. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing STIM1 weakens calcium entry after stores empty. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis limitations: RNA interference perturbs signaling machinery; it does not model low calcium intake. research_relationship_category: loss_of_function compartment_description: ER-plasma-membrane signaling junction [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055

availability_state

machinery_impairment Imported condition classification; unverified.

compartment_description

Presynaptic terminal

experimental_model

Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements

limitations

Readily releasable pool size and spontaneous release were unchanged; this is a sensor mutation, not calcium deprivation.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Changing the calcium sensor changes the calcium needed to trigger release.

primary_references

[ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004

research_relationship_category

loss_of_function

tissue_or_cell_type

Cultured neurons

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 796–807

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements · source_derived_draft · unverified_draft

### ca-synaptotagmin-mutant-sensitivity A synaptotagmin-1 knock-in mutation reducing calcium affinity also reduces the calcium sensitivity of evoked neurotransmitter release. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing the calcium sensor changes the calcium needed to trigger release. organism: Mus musculus tissue_or_cell_type: Cultured neurons experimental_model: Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements limitations: Readily releasable pool size and spontaneous release were unchanged; this is a sensor mutation, not calcium deprivation. research_relationship_category: loss_of_function compartment_description: Presynaptic terminal [ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004

experimental_model

Same short crossover experiment.

limitations

A saturation-related proxy is not an observed kidney-stone event or a universal prediction.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

The urinary crystallization proxy depended on timing.

primary_references

[cal-clin-domrong2004] Schedule of taking calcium supplement and the risk of nephrolithiasis (2004). https://pubmed.ncbi.nlm.nih.gov/15086924/ DOI: 10.1111/j.1523-1755.2004.00587.x

tissue_or_cell_type

Human clinical or absorption endpoint

Calcium: mechanism-first literature curation (2026-09-17) · lines 1270–1279

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same short crossover experiment. · source_derived_draft · unverified_draft

### cal-bedtime-activity-product Urinary calcium-oxalate activity product increased after bedtime calcium carbonate but not after meal dosing. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The urinary crystallization proxy depended on timing. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Same short crossover experiment. limitations: A saturation-related proxy is not an observed kidney-stone event or a universal prediction. [cal-clin-domrong2004] Schedule of taking calcium supplement and the risk of nephrolithiasis (2004). https://pubmed.ncbi.nlm.nih.gov/15086924/ DOI: 10.1111/j.1523-1755.2004.00587.x

experimental_model

11 achlorhydric patients and nine controls; 250 mg calcium isotope tests.

exposure

Fasting achlorhydric mean fractions: carbonate 0.042, citrate 0.452; normal subjects showed no significant formulation difference.

limitations

Not evidence that carbonate always fails or citrate always outperforms it.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Low stomach acid can change how a calcium preparation is absorbed.

primary_references

[cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202

tissue_or_cell_type

Human clinical or absorption endpoint

Calcium: mechanism-first literature curation (2026-09-17) · lines 1164–1174

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 11 achlorhydric patients and nine controls; 250 mg calcium isotope tests. · source_derived_draft · unverified_draft

### cal-carbonate-fasting-achlorhydria Fasting achlorhydric participants absorbed substantially less calcium from carbonate than from citrate. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low stomach acid can change how a calcium preparation is absorbed. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 11 achlorhydric patients and nine controls; 250 mg calcium isotope tests. limitations: Not evidence that carbonate always fails or citrate always outperforms it. exposure: Fasting achlorhydric mean fractions: carbonate 0.042, citrate 0.452; normal subjects showed no significant formulation difference. [cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202

experimental_model

Meal comparison in the achlorhydria absorption study.

limitations

Small study; the meal experiment did not isolate a molecular rescue mechanism.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

The meal changed the result seen during fasting.

primary_references

[cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202

tissue_or_cell_type

Human clinical or absorption endpoint

Calcium: mechanism-first literature curation (2026-09-17) · lines 1176–1185

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Meal comparison in the achlorhydria absorption study. · source_derived_draft · unverified_draft

### cal-carbonate-meal-achlorhydria Calcium carbonate given with a normal breakfast showed normal absorption in the achlorhydric participants. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The meal changed the result seen during fasting. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Meal comparison in the achlorhydria absorption study. limitations: Small study; the meal experiment did not isolate a molecular rescue mechanism. [cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202

experimental_model

13-adult crossover; 200 mg calcium per test meal, double-isotope measurement.

exposure

Mean fractional absorption: spinach 5.1%, milk 27.6%; oxalate slightly exceeded calcium stoichiometrically in tested spinach.

limitations

Food-matrix comparison; oxalate binding was inferred from composition, not isolated experimentally. Not a comparison of every plant food.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Equal calcium on a food label need not mean equal absorption.

primary_references

[cal-clin-heaney1988] Calcium absorbability from spinach (1988). https://pubmed.ncbi.nlm.nih.gov/3354496/ DOI: 10.1093/ajcn/47.4.707

tissue_or_cell_type

Human clinical or absorption endpoint

Calcium: mechanism-first literature curation (2026-09-17) · lines 1152–1162

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 13-adult crossover; 200 mg calcium per test meal, double-isotope measurement. · source_derived_draft · unverified_draft

### cal-food-spinach-absorption Calcium absorption from the tested spinach meal was lower than from milk at equal calcium load. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Equal calcium on a food label need not mean equal absorption. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 13-adult crossover; 200 mg calcium per test meal, double-isotope measurement. limitations: Food-matrix comparison; oxalate binding was inferred from composition, not isolated experimentally. Not a comparison of every plant food. exposure: Mean fractional absorption: spinach 5.1%, milk 27.6%; oxalate slightly exceeded calcium stoichiometrically in tested spinach. [cal-clin-heaney1988] Calcium absorbability from spinach (1988). https://pubmed.ncbi.nlm.nih.gov/3354496/ DOI: 10.1093/ajcn/47.4.707

compartment_description

Phospholipid surface

experimental_model

Kinetic reconstitution with defined phospholipids

limitations

Low residual Xa activity exists without the complete complex; this establishes biochemical assistance, not that extra dietary calcium accelerates clotting.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Bos taurus

plain_language

Calcium helps the membrane-associated clotting machinery generate thrombin.

primary_references

[rosing1980] The role of phospholipids and factor Va in the prothrombinase complex (1980). https://pubmed.ncbi.nlm.nih.gov/7350159/ DOI: 10.1016/S0021-9258(19)86294-4

tissue_or_cell_type

Purified blood proteins

Calcium: mechanism-first literature curation (2026-09-17) · lines 1116–1126

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic reconstitution with defined phospholipids · source_derived_draft · unverified_draft

### calcium-phospholipid-prothrombinase Factor Xa activated bovine prothrombin efficiently when factor Va, Ca2+ and phosphatidylserine-containing phospholipids assembled the complete prothrombinase system. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps the membrane-associated clotting machinery generate thrombin. organism: Bos taurus tissue_or_cell_type: Purified blood proteins experimental_model: Kinetic reconstitution with defined phospholipids limitations: Low residual Xa activity exists without the complete complex; this establishes biochemical assistance, not that extra dietary calcium accelerates clotting. compartment_description: Phospholipid surface [rosing1980] The role of phospholipids and factor Va in the prothrombinase complex (1980). https://pubmed.ncbi.nlm.nih.gov/7350159/ DOI: 10.1016/S0021-9258(19)86294-4

experimental_model

Bovine parathyroid cells and human CaSR-expressing HEK293 cells

limitations

Pharmacological cell experiment; potentiation required extracellular calcium.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Bos taurus

plain_language

Greater calcium-sensor activation reduces hormone release.

primary_references

[nemeth1998] Calcimimetics with potent and selective activity on the parathyroid calcium receptor (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19959/ DOI: 10.1073/pnas.95.7.4040

tissue_or_cell_type

Parathyroid cells

Calcium: mechanism-first literature curation (2026-09-17) · lines 25–34

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine parathyroid cells and human CaSR-expressing HEK293 cells · source_derived_draft · unverified_draft

### casr-calcium-pth-suppression CaSR potentiation by NPS R-568 strengthens extracellular-calcium-mediated inhibition of PTH secretion in bovine parathyroid cells. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Greater calcium-sensor activation reduces hormone release. organism: Bos taurus tissue_or_cell_type: Parathyroid cells experimental_model: Bovine parathyroid cells and human CaSR-expressing HEK293 cells limitations: Pharmacological cell experiment; potentiation required extracellular calcium. [nemeth1998] Calcimimetics with potent and selective activity on the parathyroid calcium receptor (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19959/ DOI: 10.1073/pnas.95.7.4040

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human family; E128A CaSR expressed in Xenopus oocytes

limitations

One family and oocyte assays; not dietary calcium deficiency.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

An oversensitive sensor can lower blood calcium.

primary_references

[pollak1994] Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation (1994). https://pubmed.ncbi.nlm.nih.gov/7874174/ DOI: 10.1038/ng1194-303

tissue_or_cell_type

Systemic calcium regulation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 47–56

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human family; E128A CaSR expressed in Xenopus oocytes · source_derived_draft · unverified_draft

### casr-gain-hypocalcemia The CaSR E128A variant increases receptor responsiveness and causes dominant hypocalcemia in the studied family. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An oversensitive sensor can lower blood calcium. organism: Homo sapiens tissue_or_cell_type: Systemic calcium regulation experimental_model: Human family; E128A CaSR expressed in Xenopus oocytes limitations: One family and oocyte assays; not dietary calcium deficiency. [pollak1994] Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation (1994). https://pubmed.ncbi.nlm.nih.gov/7874174/ DOI: 10.1038/ng1194-303

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human pedigrees and mutant-receptor expression in Xenopus oocytes

limitations

Mutation-specific inherited disease; not evidence of dietary calcium excess.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

A faulty sensor can raise blood calcium.

primary_references

[pollak1993] Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (1993). https://pubmed.ncbi.nlm.nih.gov/7916660/ DOI: 10.1016/0092-8674(93)90617-y

tissue_or_cell_type

Parathyroid/kidney calcium regulation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 36–45

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human pedigrees and mutant-receptor expression in Xenopus oocytes · source_derived_draft · unverified_draft

### casr-loss-hypercalcemia Inactivating CASR variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A faulty sensor can raise blood calcium. organism: Homo sapiens tissue_or_cell_type: Parathyroid/kidney calcium regulation experimental_model: Human pedigrees and mutant-receptor expression in Xenopus oocytes limitations: Mutation-specific inherited disease; not evidence of dietary calcium excess. [pollak1993] Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (1993). https://pubmed.ncbi.nlm.nih.gov/7916660/ DOI: 10.1016/0092-8674(93)90617-y

experimental_model

Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression

limitations

Assay context matters; this does not prove a mandatory claudin-2/12 complex.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens cell line

plain_language

Claudin-12 contributes another between-cell route.

primary_references

[fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973

tissue_or_cell_type

Caco-2 epithelial tight junctions

Calcium: mechanism-first literature curation (2026-09-17) · lines 203–212

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression · source_derived_draft · unverified_draft

### cldn12-calcium-permeability Claudin-12 knockdown/overexpression alters calcium permeability in Caco-2 monolayers. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Claudin-12 contributes another between-cell route. organism: Homo sapiens cell line tissue_or_cell_type: Caco-2 epithelial tight junctions experimental_model: Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression limitations: Assay context matters; this does not prove a mandatory claudin-2/12 complex. [fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human affected families; linkage, sequencing and claudin trafficking/assembly assays

limitations

Multimineral genetic disorder; ocular and renal manifestations vary.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Inherited junction defects can waste calcium.

primary_references

[konrad2006] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement (2006). https://pmc.ncbi.nlm.nih.gov/articles/PMC1698561/ DOI: 10.1086/508617

tissue_or_cell_type

Kidney tubules

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 269–278

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human affected families; linkage, sequencing and claudin trafficking/assembly assays · source_derived_draft · unverified_draft

### cldn19-variants-renal-calcium-wasting Biallelic CLDN19 variants were identified in families with renal magnesium wasting, hypercalciuria and nephrocalcinosis. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Inherited junction defects can waste calcium. organism: Homo sapiens tissue_or_cell_type: Kidney tubules experimental_model: Human affected families; linkage, sequencing and claudin trafficking/assembly assays limitations: Multimineral genetic disorder; ocular and renal manifestations vary. [konrad2006] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement (2006). https://pmc.ncbi.nlm.nih.gov/articles/PMC1698561/ DOI: 10.1086/508617

experimental_model

Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression

limitations

Cell-line permeability; not an obligatory route in every intestinal segment.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens cell line

plain_language

Claudin-2 supports calcium movement between cells.

primary_references

[fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973

tissue_or_cell_type

Caco-2 epithelial tight junctions

Calcium: mechanism-first literature curation (2026-09-17) · lines 192–201

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression · source_derived_draft · unverified_draft

### cldn2-calcium-permeability Claudin-2 manipulation changes calcium permeability across Caco-2 epithelial monolayers. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Claudin-2 supports calcium movement between cells. organism: Homo sapiens cell line tissue_or_cell_type: Caco-2 epithelial tight junctions experimental_model: Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression limitations: Cell-line permeability; not an obligatory route in every intestinal segment. [fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models

limitations

Global deletion also affects intestinal handling.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

The two claudins provide complementary renal retention.

primary_references

[beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118

tissue_or_cell_type

Kidney; proximal-tubule localization

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 225–234

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models · source_derived_draft · unverified_draft

### cldn2-cldn12-double-loss-calciuria Cldn2/Cldn12 double-null mice lose more urinary calcium than Cldn2-null mice. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two claudins provide complementary renal retention. organism: Mus musculus tissue_or_cell_type: Kidney; proximal-tubule localization experimental_model: Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models limitations: Global deletion also affects intestinal handling. [beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models

limitations

Global double knockout; single proteins are partly redundant.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

The measured defect was segment specific.

primary_references

[beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118

tissue_or_cell_type

Colon

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 214–223

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models · source_derived_draft · unverified_draft

### cldn2-cldn12-double-loss-colon Cldn2/Cldn12 double deletion lowers colonic calcium permeability; small-intestinal permeability was unchanged. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured defect was segment specific. organism: Mus musculus tissue_or_cell_type: Colon experimental_model: Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models limitations: Global double knockout; single proteins are partly redundant. [beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118

experimental_model

Atomic-scale imaging and correlative spectroscopy

limitations

A structural tissue study; it does not test dietary calcium intake or enamel regeneration.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

Tooth enamel is built from chemically varied calcium phosphate crystals.

primary_references

[derocher2020] Chemical gradients in human enamel crystallites (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC8290891/ DOI: 10.1038/s41586-020-2433-3

tissue_or_cell_type

Dental enamel

Calcium: mechanism-first literature curation (2026-09-17) · lines 886–895

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Atomic-scale imaging and correlative spectroscopy · source_derived_draft · unverified_draft

### enamel-calcium-in-substituted-apatite Human enamel crystallites have an apatite lattice containing calcium and phosphate, with heterogeneous magnesium, sodium, fluoride and carbonate substitutions. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Tooth enamel is built from chemically varied calcium phosphate crystals. organism: Homo sapiens tissue_or_cell_type: Dental enamel experimental_model: Atomic-scale imaging and correlative spectroscopy limitations: A structural tissue study; it does not test dietary calcium intake or enamel regeneration. [derocher2020] Chemical gradients in human enamel crystallites (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC8290891/ DOI: 10.1038/s41586-020-2433-3

experimental_model

Mouse Fgf23/Klotho/Vdr genetic models, recombinant FGF23, isolated tubules and kidney slices

limitations

Mouse genetic/pharmacological models; no claim of equivalent human effect magnitude.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

FGF23 can help kidneys retain calcium.

primary_references

[andrukhova2014] FGF23 promotes renal calcium reabsorption through the TRPV5 channel (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3983685/ DOI: 10.1002/embj.201284188

tissue_or_cell_type

Renal distal tubules

Calcium: mechanism-first literature curation (2026-09-17) · lines 124–133

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Fgf23/Klotho/Vdr genetic models, recombinant FGF23, isolated tubules and kidney slices · source_derived_draft · unverified_draft

### fgf23-increases-trpv5-membrane-abundance FGF23 increases renal distal-tubular TRPV5 membrane abundance through FGFR/alpha-Klotho signaling involving ERK1/2, SGK1 and WNK4. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: FGF23 can help kidneys retain calcium. organism: Mus musculus tissue_or_cell_type: Renal distal tubules experimental_model: Mouse Fgf23/Klotho/Vdr genetic models, recombinant FGF23, isolated tubules and kidney slices limitations: Mouse genetic/pharmacological models; no claim of equivalent human effect magnitude. [andrukhova2014] FGF23 promotes renal calcium reabsorption through the TRPV5 channel (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3983685/ DOI: 10.1002/embj.201284188

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Villin-Cre intestine-specific Atp2b1 deletion in mice

limitations

Conditional deletion and administered calcitriol; basal absorption was not shown to be zero.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

A calcium pump is needed for this hormone response.

primary_references

[ryan2015] Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3 (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4772868/ DOI: 10.1016/j.bbrc.2015.09.087

tissue_or_cell_type

Intestinal absorptive cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 280–289

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Villin-Cre intestine-specific Atp2b1 deletion in mice · source_derived_draft · unverified_draft

### intestinal-pmca1-loss-calcitriol-response Intestinal Atp2b1 deletion prevented the active-calcium-transport increase elicited by calcitriol in control mice. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium pump is needed for this hormone response. organism: Mus musculus tissue_or_cell_type: Intestinal absorptive cells experimental_model: Villin-Cre intestine-specific Atp2b1 deletion in mice limitations: Conditional deletion and administered calcitriol; basal absorption was not shown to be zero. [ryan2015] Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3 (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4772868/ DOI: 10.1016/j.bbrc.2015.09.087

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention

limitations

Retention indexes absorption; greater fraction does not guarantee adequate absolute uptake.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Homo sapiens

plain_language

The retained fraction adapts to low intake.

primary_references

[dawsonhughes1988] Effect of lowering dietary calcium intake on fractional whole body calcium retention (1988). https://pubmed.ncbi.nlm.nih.gov/3132484/ DOI: 10.1210/jcem-67-1-62

tissue_or_cell_type

Whole body

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 302–311

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention · source_derived_draft · unverified_draft

### low-calcium-intake-fractional-retention The same diet reduction increased fractional oral 47Ca retention within one week. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The retained fraction adapts to low intake. organism: Homo sapiens tissue_or_cell_type: Whole body experimental_model: Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention limitations: Retention indexes absorption; greater fraction does not guarantee adequate absolute uptake. [dawsonhughes1988] Effect of lowering dietary calcium intake on fractional whole body calcium retention (1988). https://pubmed.ncbi.nlm.nih.gov/3132484/ DOI: 10.1210/jcem-67-1-62

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Intestinal and osteoblast Vdr deletion, low-calcium diets, and skeletal assays in growing mice

limitations

Growing-mouse genetic model; not a validated human dietary diagnostic.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Normal blood calcium can coexist with inadequate skeletal supply.

primary_references

[lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3336970/ DOI: 10.1172/JCI45890

research_relationship_category

biomarker

tissue_or_cell_type

Blood, intestine and skeleton

trigger_kind

biomarker_context Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 337–347

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intestinal and osteoblast Vdr deletion, low-calcium diets, and skeletal assays in growing mice · source_derived_draft · unverified_draft

### normal-serum-calcium-does-not-establish-sufficiency Mice with intestinal Vdr deletion maintained serum calcium despite calcium malabsorption and impaired skeletal mineral storage. Condition category: biomarker_context nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Normal blood calcium can coexist with inadequate skeletal supply. organism: Mus musculus tissue_or_cell_type: Blood, intestine and skeleton experimental_model: Intestinal and osteoblast Vdr deletion, low-calcium diets, and skeletal assays in growing mice limitations: Growing-mouse genetic model; not a validated human dietary diagnostic. research_relationship_category: biomarker [lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3336970/ DOI: 10.1172/JCI45890

experimental_model

HEK293 expression, calcium uptake, FRET, patch clamp and TRPV5 mutagenesis

limitations

Response required strong intracellular calcium buffering; cultured-cell mechanism.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Heterologous HEK293 expression system

plain_language

PTH can increase calcium entry through TRPV5.

primary_references

[degroot2009] Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2723979/ DOI: 10.1681/ASN.2008080873

tissue_or_cell_type

Plasma membrane; distal-nephron mechanism

Calcium: mechanism-first literature curation (2026-09-17) · lines 58–67

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293 expression, calcium uptake, FRET, patch clamp and TRPV5 mutagenesis · source_derived_draft · unverified_draft

### pth-activates-trpv5 PTH increases TRPV5 activity through cAMP-PKA-dependent phosphorylation at T709 in receptor/channel expression assays. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PTH can increase calcium entry through TRPV5. organism: Heterologous HEK293 expression system tissue_or_cell_type: Plasma membrane; distal-nephron mechanism experimental_model: HEK293 expression, calcium uptake, FRET, patch clamp and TRPV5 mutagenesis limitations: Response required strong intracellular calcium buffering; cultured-cell mechanism. [degroot2009] Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2723979/ DOI: 10.1681/ASN.2008080873

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays

limitations

Compensation accompanies renal loss; not direct intestinal TRPV5 transport.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Gut uptake compensates for kidney losses.

primary_references

[hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826

tissue_or_cell_type

Intestine

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 247–256

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays · source_derived_draft · unverified_draft

### trpv5-loss-compensatory-intestinal-absorption Trpv5-null mice show increased intestinal absorption of orally administered calcium tracer. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gut uptake compensates for kidney losses. organism: Mus musculus tissue_or_cell_type: Intestine experimental_model: Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays limitations: Compensation accompanies renal loss; not direct intestinal TRPV5 transport. [hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays

limitations

Mouse knockout with micropuncture localization.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Hormonal compensation cannot replace the missing channel.

primary_references

[hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826

tissue_or_cell_type

Early distal convolution

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 236–245

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays · source_derived_draft · unverified_draft

### trpv5-loss-renal-reabsorption Trpv5-null mice have impaired distal calcium reabsorption and severe hypercalciuria despite increased vitamin D levels. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Hormonal compensation cannot replace the missing channel. organism: Mus musculus tissue_or_cell_type: Early distal convolution experimental_model: Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays limitations: Mouse knockout with micropuncture localization. [hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Trpv6 and calbindin-D9k single/double knockout mice; duodenal transport assays

limitations

Residual transport does not establish dispensability under every diet or life stage.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Other routes can support active calcium absorption.

primary_references

[benn2008] Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2408805/ DOI: 10.1210/en.2007-1655

reported_effect

retained

tissue_or_cell_type

Duodenum

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 169–179

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Trpv6 and calbindin-D9k single/double knockout mice; duodenal transport assays · source_derived_draft · unverified_draft

### trpv6-calbindin-independent-active-transport Significant active duodenal calcium transport persists in Trpv6/calbindin-D9k double-null mice under the tested stimulation conditions. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Other routes can support active calcium absorption. organism: Mus musculus tissue_or_cell_type: Duodenum experimental_model: Trpv6 and calbindin-D9k single/double knockout mice; duodenal transport assays limitations: Residual transport does not establish dispensability under every diet or life stage. reported_effect: retained [benn2008] Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2408805/ DOI: 10.1210/en.2007-1655

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Whole-body Trpv6 knockout mice under regular and low-calcium diets

limitations

Whole-body deletion; diet and assay matter; residual absorption remained.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

TRPV6 materially supports calcium uptake in this model.

primary_references

[bianco2007] Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene (2007). https://pubmed.ncbi.nlm.nih.gov/17129178/ DOI: 10.1359/jbmr.061110

tissue_or_cell_type

Intestine

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 158–167

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Whole-body Trpv6 knockout mice under regular and low-calcium diets · source_derived_draft · unverified_draft

### trpv6-loss-reduces-absorption Trpv6 deletion reduced intestinal calcium absorption by about 60% in the Bianco mouse model. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPV6 materially supports calcium uptake in this model. organism: Mus musculus tissue_or_cell_type: Intestine experimental_model: Whole-body Trpv6 knockout mice under regular and low-calcium diets limitations: Whole-body deletion; diet and assay matter; residual absorption remained. [bianco2007] Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene (2007). https://pubmed.ncbi.nlm.nih.gov/17129178/ DOI: 10.1359/jbmr.061110

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Mice with targeted disruption of the VDR DNA-binding domain

limitations

Global receptor deletion; not isolated dietary calcium shortage.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Vitamin D receptor failure disrupts calcium regulation.

primary_references

[li1997] Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia (1997). https://pmc.ncbi.nlm.nih.gov/articles/PMC23277/ DOI: 10.1073/pnas.94.18.9831

tissue_or_cell_type

Systemic mineral metabolism

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 135–144

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice with targeted disruption of the VDR DNA-binding domain · source_derived_draft · unverified_draft

### vdr-loss-hypocalcemia VDR-ablated mice develop hypocalcemia around postnatal day 21 with rising PTH. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin D receptor failure disrupts calcium regulation. organism: Mus musculus tissue_or_cell_type: Systemic mineral metabolism experimental_model: Mice with targeted disruption of the VDR DNA-binding domain limitations: Global receptor deletion; not isolated dietary calcium shortage. [li1997] Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia (1997). https://pmc.ncbi.nlm.nih.gov/articles/PMC23277/ DOI: 10.1073/pnas.94.18.9831

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

VDR-ablated mice and controls fed a mineral/lactose rescue diet

limitations

Combined dietary intervention; cannot attribute rescue to calcium alone.

nutrient_topic

Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium

organism

Mus musculus

plain_language

Dietary mineral delivery can bypass part of receptor failure.

primary_references

[li1998] Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice (1998). https://pubmed.ncbi.nlm.nih.gov/9751523/ DOI: 10.1210/endo.139.10.6262

reported_effect

normalizing

tissue_or_cell_type

Intestine and blood

trigger_kind

machinery_impairment Imported condition classification; unverified.

Calcium: mechanism-first literature curation (2026-09-17) · lines 146–156

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · VDR-ablated mice and controls fed a mineral/lactose rescue diet · source_derived_draft · unverified_draft

### vdr-null-mineral-diet-rescue A mineral/lactose rescue diet normalizes ionized calcium in VDR-ablated mice. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Dietary mineral delivery can bypass part of receptor failure. organism: Mus musculus tissue_or_cell_type: Intestine and blood experimental_model: VDR-ablated mice and controls fed a mineral/lactose rescue diet limitations: Combined dietary intervention; cannot attribute rescue to calcium alone. reported_effect: normalizing [li1998] Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice (1998). https://pubmed.ncbi.nlm.nih.gov/9751523/ DOI: 10.1210/endo.139.10.6262

evidence_span

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experimental_model

Rat pretreatment and isolated mitochondrial calcium challenge

exposure

40 mg/kg mangiferin pretreatment; isolated mitochondria exposed to calcium

limitations

Mitochondrial challenge does not establish harm from usual oral intake; proposed quinone-thiol adduct mechanism was not fully proven.

nutrient_topic

Mangiferin research collection; topical membership is not evidence of a direct dietary effect. · Mangiferin

organism

Rattus norvegicus

plain_language

The calcium challenge changed the redox consequences.

primary_references

[mangiferin-p15979560] Mangiferin, a natural occurring glucosyl xanthone, increases susceptibility of rat liver mitochondria to calcium-induced permeability transition. (2005). https://pubmed.ncbi.nlm.nih.gov/15979560/ DOI: 10.1016/j.abb.2005.05.015

tissue_or_cell_type

Liver mitochondria

Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 718–729

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat pretreatment and isolated mitochondrial calcium challenge · source_derived_draft · unverified_draft

### mangiferin-calcium-gsh Calcium-challenged mitochondria from treated rats showed glutathione depletion. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The calcium challenge changed the redox consequences. organism: Rattus norvegicus tissue_or_cell_type: Liver mitochondria experimental_model: Rat pretreatment and isolated mitochondrial calcium challenge limitations: Mitochondrial challenge does not establish harm from usual oral intake; proposed quinone-thiol adduct mechanism was not fully proven. exposure: 40 mg/kg mangiferin pretreatment; isolated mitochondria exposed to calcium evidence_span: {"source_cache": "artifacts/mangiferin-research/15979560.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3de89f65f9561fd94c5f07121e8150f116c59277658d7e611a399dc2d963ec1f", "start_char": 0, "end_char": 2234, "text_sha256": "3de89f65f9561fd94c5f07121e8150f116c59277658d7e611a399dc2d963ec1f"} [mangiferin-p15979560] Mangiferin, a natural occurring glucosyl xanthone, increases susceptibility of rat liver mitochondria to calcium-induced permeability transition. (2005). https://pubmed.ncbi.nlm.nih.gov/15979560/ DOI: 10.1016/j.abb.2005.05.015

evidence_span

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experimental_model

Rat pretreatment and isolated mitochondrial calcium challenge

exposure

40 mg/kg mangiferin pretreatment; isolated mitochondria exposed to calcium

limitations

Mitochondrial challenge does not establish harm from usual oral intake; proposed quinone-thiol adduct mechanism was not fully proven.

nutrient_topic

Mangiferin research collection; topical membership is not evidence of a direct dietary effect. · Mangiferin

organism

Rattus norvegicus

plain_language

Lower oxidative readouts do not necessarily mean preserved membrane function.

primary_references

[mangiferin-p15979560] Mangiferin, a natural occurring glucosyl xanthone, increases susceptibility of rat liver mitochondria to calcium-induced permeability transition. (2005). https://pubmed.ncbi.nlm.nih.gov/15979560/ DOI: 10.1016/j.abb.2005.05.015

tissue_or_cell_type

Liver mitochondria

Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 705–716

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat pretreatment and isolated mitochondrial calcium challenge · source_derived_draft · unverified_draft

### mangiferin-calcium-mpt Mangiferin exposure increased susceptibility to calcium-induced mitochondrial permeability transition. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower oxidative readouts do not necessarily mean preserved membrane function. organism: Rattus norvegicus tissue_or_cell_type: Liver mitochondria experimental_model: Rat pretreatment and isolated mitochondrial calcium challenge limitations: Mitochondrial challenge does not establish harm from usual oral intake; proposed quinone-thiol adduct mechanism was not fully proven. exposure: 40 mg/kg mangiferin pretreatment; isolated mitochondria exposed to calcium evidence_span: {"source_cache": "artifacts/mangiferin-research/15979560.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3de89f65f9561fd94c5f07121e8150f116c59277658d7e611a399dc2d963ec1f", "start_char": 0, "end_char": 2234, "text_sha256": "3de89f65f9561fd94c5f07121e8150f116c59277658d7e611a399dc2d963ec1f"} [mangiferin-p15979560] Mangiferin, a natural occurring glucosyl xanthone, increases susceptibility of rat liver mitochondria to calcium-induced permeability transition. (2005). https://pubmed.ncbi.nlm.nih.gov/15979560/ DOI: 10.1016/j.abb.2005.05.015

evidence_span

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experimental_model

Iron-coordination spectroscopy and mitochondrial challenge

exposure

Assay-defined ferric iron-mangiferin complex

limitations

Defined chemical form and calcium context explain the different response; no clinical iron/mangiferin co-dosing recommendation.

nutrient_topic

Mangiferin research collection; topical membership is not evidence of a direct dietary effect. · Mangiferin

organism

Rattus norvegicus and cell-free chemistry

plain_language

Changing chemical form changed the membrane response.

primary_references

[mangiferin-p17068204] Fe(III) shifts the mitochondria permeability transition-eliciting capacity of mangiferin to protection of organelle. (2007). https://pubmed.ncbi.nlm.nih.gov/17068204/ DOI: 10.1124/jpet.106.112003

tissue_or_cell_type

Isolated mitochondria

Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 744–755

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Iron-coordination spectroscopy and mitochondrial challenge · source_derived_draft · unverified_draft

### mangiferin-complex-mpt The ferric complex did not elicit permeability transition and protected against its induction in the assay. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing chemical form changed the membrane response. organism: Rattus norvegicus and cell-free chemistry tissue_or_cell_type: Isolated mitochondria experimental_model: Iron-coordination spectroscopy and mitochondrial challenge limitations: Defined chemical form and calcium context explain the different response; no clinical iron/mangiferin co-dosing recommendation. exposure: Assay-defined ferric iron-mangiferin complex evidence_span: {"source_cache": "artifacts/mangiferin-research/17068204.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1d0b364cee6629228fe7bc41446a0e2ddfe62b9274d77d4781ca7439aedfbb64", "start_char": 0, "end_char": 1172, "text_sha256": "1d0b364cee6629228fe7bc41446a0e2ddfe62b9274d77d4781ca7439aedfbb64"} [mangiferin-p17068204] Fe(III) shifts the mitochondria permeability transition-eliciting capacity of mangiferin to protection of organelle. (2007). https://pubmed.ncbi.nlm.nih.gov/17068204/ DOI: 10.1124/jpet.106.112003

dose

Repeated capsaicin; calcineurin inhibitor, forskolin and point mutants

duration

Acute repeated activation

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

TRPV1-transfected HEK293T or HeLa cells

limitations

Kinase and phosphatase manipulations identify regulatory machinery in engineered cells, not a dietary calcium threshold.

nutrient_topic

Capsaicin chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Capsaicin

organism

TRPV1-transfected HEK293T or HeLa cells

plain_language

Repeated capsaicin activation caused calcium-dependent TRPV1 desensitization regulated in part by calcineurin and PKA at Thr370.

primary_references

Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. (2005). https://pubmed.ncbi.nlm.nih.gov/15691846/ DOI: 10.1074/jbc.M410917200

route

In vitro

tissue

Whole-cell capsaicin currents

Capsaicin: mechanism of action and interactions (2026-09-20) · lines 33–42

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · TRPV1-transfected HEK293T or HeLa cells · source_derived_draft · unverified_draft

## capsaicin-calcineurin-desensitization Repeated capsaicin activation caused calcium-dependent TRPV1 desensitization regulated in part by calcineurin and PKA at Thr370. Model/species: TRPV1-transfected HEK293T or HeLa cells Tissue/system: Whole-cell capsaicin currents Exposure: Repeated capsaicin; calcineurin inhibitor, forskolin and point mutants Route: In vitro Duration: Acute repeated activation Limits: Kinase and phosphatase manipulations identify regulatory machinery in engineered cells, not a dietary calcium threshold. Primary reference: Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. (2005). https://pubmed.ncbi.nlm.nih.gov/15691846/ DOI: 10.1074/jbc.M410917200 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

dose

Capsaicin or piperine concentration-response; second exposure; SB366791 control

duration

Acute sequential exposure

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Human PC-3 cells expressing TRPV1

limitations

Comparable assay behavior does not establish equivalent potency, oral exposure, or benefit in humans.

nutrient_topic

Capsaicin chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Capsaicin

organism

Human PC-3 cells expressing TRPV1

plain_language

Piperine and capsaicin both stimulated TRPV1-dependent calcium responses in human PC-3 cells and both showed reduced responses on second exposure.

primary_references

Pharmacodynamics of TRPV1 agonists in a bioassay using human PC-3 cells. (2014). https://pubmed.ncbi.nlm.nih.gov/24688365/ DOI: 10.1155/2014/184526

route

In vitro

tissue

Fluo-4 calcium-response bioassay

Capsaicin: mechanism of action and interactions (2026-09-20) · lines 110–119

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Human PC-3 cells expressing TRPV1 · source_derived_draft · unverified_draft

## capsaicin-piperine-shared-trpv1 Piperine and capsaicin both stimulated TRPV1-dependent calcium responses in human PC-3 cells and both showed reduced responses on second exposure. Model/species: Human PC-3 cells expressing TRPV1 Tissue/system: Fluo-4 calcium-response bioassay Exposure: Capsaicin or piperine concentration-response; second exposure; SB366791 control Route: In vitro Duration: Acute sequential exposure Limits: Comparable assay behavior does not establish equivalent potency, oral exposure, or benefit in humans. Primary reference: Pharmacodynamics of TRPV1 agonists in a bioassay using human PC-3 cells. (2014). https://pubmed.ncbi.nlm.nih.gov/24688365/ DOI: 10.1155/2014/184526 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

dose

Capsaicin followed by mustard oil/TRPA1 stimulation

duration

Acute sequential exposure

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Sensory neurons and heterologous channel expression

limitations

The mechanism differed from mustard-oil homologous desensitization and was not regulated by calcineurin in this study.

nutrient_topic

Capsaicin chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Capsaicin

organism

Sensory neurons and heterologous channel expression

plain_language

Capsaicin cross-desensitized TRPA1 through a calcium-dependent route associated with PLC activation and PIP2 depletion.

primary_references

Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. (2007). https://pubmed.ncbi.nlm.nih.gov/17584831/ DOI: 10.1113/jphysiol.2007.133231

route

In vitro

tissue

TRPA1 responses after TRPV1 agonism

Capsaicin: mechanism of action and interactions (2026-09-20) · lines 55–64

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Sensory neurons and heterologous channel expression · source_derived_draft · unverified_draft

## capsaicin-trpa1-cross-desensitization Capsaicin cross-desensitized TRPA1 through a calcium-dependent route associated with PLC activation and PIP2 depletion. Model/species: Sensory neurons and heterologous channel expression Tissue/system: TRPA1 responses after TRPV1 agonism Exposure: Capsaicin followed by mustard oil/TRPA1 stimulation Route: In vitro Duration: Acute sequential exposure Limits: The mechanism differed from mustard-oil homologous desensitization and was not regulated by calcineurin in this study. Primary reference: Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. (2007). https://pubmed.ncbi.nlm.nih.gov/17584831/ DOI: 10.1113/jphysiol.2007.133231 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

dose

Capsaicin concentration-response and noxious-range temperature

duration

Acute

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Cloned capsaicin receptor expressed from sensory-neuron cDNA

limitations

The cloned receptor experiment establishes channel gating, not the whole organism response to chili foods.

nutrient_topic

Capsaicin chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Capsaicin

organism

Cloned capsaicin receptor expressed from sensory-neuron cDNA

plain_language

Capsaicin activates TRPV1, a nonselective cation channel that is also activated by noxious heat.

primary_references

The capsaicin receptor: a heat-activated ion channel in the pain pathway. (1997). https://pubmed.ncbi.nlm.nih.gov/9349813/ DOI: 10.1038/39807

route

In vitro

tissue

Calcium influx and heat activation

Capsaicin: mechanism of action and interactions (2026-09-20) · lines 11–20

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Cloned capsaicin receptor expressed from sensory-neuron cDNA · source_derived_draft · unverified_draft

## capsaicin-trpv1-gating Capsaicin activates TRPV1, a nonselective cation channel that is also activated by noxious heat. Model/species: Cloned capsaicin receptor expressed from sensory-neuron cDNA Tissue/system: Calcium influx and heat activation Exposure: Capsaicin concentration-response and noxious-range temperature Route: In vitro Duration: Acute Limits: The cloned receptor experiment establishes channel gating, not the whole organism response to chili foods. Primary reference: The capsaicin receptor: a heat-activated ion channel in the pain pathway. (1997). https://pubmed.ncbi.nlm.nih.gov/9349813/ DOI: 10.1038/39807 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Clcn7 knockout and human mutation identification

exposure

ClC-7 loss

limitations

Historical title calls ClC-7 a channel; current exchanger classification does not change the reported knockout phenotype. Not a dietary chloride study.

nutrient_topic

Chloride research collection; topical membership is not evidence of a direct dietary effect. · Chloride

organism

Mouse; human infantile osteopetrosis patient

plain_language

Having bone-resorbing cells is insufficient when their transport machinery fails.

primary_references

[chloride-p11207362] Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. (2001). https://pubmed.ncbi.nlm.nih.gov/11207362/ DOI: 10.1016/s0092-8674(01)00206-9

tissue_or_cell_type

Osteoclast ruffled border

trigger_kind

machinery_impairment Imported condition classification; unverified.

Chloride: transport, acid-base balance, nutrient interactions and loss states (2026-09-17) · lines 783–794

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clcn7 knockout and human mutation identification · source_derived_draft · unverified_draft

### chloride-clc7-bone Clcn7-null mice had severe osteopetrosis despite normal osteoclast numbers. Condition category: machinery_impairment nutrient_topic: Chloride research collection; topical membership is not evidence of a direct dietary effect. plain_language: Having bone-resorbing cells is insufficient when their transport machinery fails. organism: Mouse; human infantile osteopetrosis patient tissue_or_cell_type: Osteoclast ruffled border experimental_model: Clcn7 knockout and human mutation identification limitations: Historical title calls ClC-7 a channel; current exchanger classification does not change the reported knockout phenotype. Not a dietary chloride study. exposure: ClC-7 loss evidence_span: {"source_cache": "artifacts/chloride-research/11207362.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5e10ae61257fa402ab9e10d55af44013139462a9d85236b75f5b52bdea0c7b5a", "start_char": 0, "end_char": 821, "text_sha256": "5e10ae61257fa402ab9e10d55af44013139462a9d85236b75f5b52bdea0c7b5a"} [chloride-p11207362] Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. (2001). https://pubmed.ncbi.nlm.nih.gov/11207362/ DOI: 10.1016/s0092-8674(01)00206-9

evidence_span

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experimental_model

Protein adsorption to model phospholipid monolayers

exposure

Phosphatidylserine-containing monolayers

limitations

Model membrane binding, not whole-blood thrombosis. Species remain distinct.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Purified human and bovine proteins

plain_language

Carboxylation supports a protein surface that interacts with calcium and membranes.

primary_references

[k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

tissue_or_cell_type

Calcium-dependent Gla-domain membrane contact

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 942–953

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein adsorption to model phospholipid monolayers · source_derived_draft · unverified_draft

### k2-membrane-bovine-f2 The tested bovine-f2 Gla-domain protein showed calcium-specific contact with negatively charged phospholipid monolayers. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Carboxylation supports a protein surface that interacts with calcium and membranes. organism: Purified human and bovine proteins tissue_or_cell_type: Calcium-dependent Gla-domain membrane contact experimental_model: Protein adsorption to model phospholipid monolayers limitations: Model membrane binding, not whole-blood thrombosis. Species remain distinct. exposure: Phosphatidylserine-containing monolayers evidence_span: {"source_cache": "artifacts/k2-research/9609692.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd", "start_char": 0, "end_char": 2064, "text_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd"} [k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

evidence_span

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experimental_model

Protein adsorption to model phospholipid monolayers

exposure

Phosphatidylserine-containing monolayers

limitations

Model membrane binding, not whole-blood thrombosis. Species remain distinct.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Purified human and bovine proteins

plain_language

Carboxylation supports a protein surface that interacts with calcium and membranes.

primary_references

[k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

tissue_or_cell_type

Calcium-dependent Gla-domain membrane contact

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 981–992

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein adsorption to model phospholipid monolayers · source_derived_draft · unverified_draft

### k2-membrane-bovine-proc The tested bovine-proc Gla-domain protein showed calcium-specific contact with negatively charged phospholipid monolayers. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Carboxylation supports a protein surface that interacts with calcium and membranes. organism: Purified human and bovine proteins tissue_or_cell_type: Calcium-dependent Gla-domain membrane contact experimental_model: Protein adsorption to model phospholipid monolayers limitations: Model membrane binding, not whole-blood thrombosis. Species remain distinct. exposure: Phosphatidylserine-containing monolayers evidence_span: {"source_cache": "artifacts/k2-research/9609692.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd", "start_char": 0, "end_char": 2064, "text_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd"} [k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

evidence_span

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experimental_model

Protein adsorption to model phospholipid monolayers

exposure

Phosphatidylserine-containing monolayers

limitations

Model membrane binding, not whole-blood thrombosis. Species remain distinct.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Purified human and bovine proteins

plain_language

Carboxylation supports a protein surface that interacts with calcium and membranes.

primary_references

[k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

tissue_or_cell_type

Calcium-dependent Gla-domain membrane contact

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 955–966

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein adsorption to model phospholipid monolayers · source_derived_draft · unverified_draft

### k2-membrane-f9 The tested f9 Gla-domain protein showed calcium-specific contact with negatively charged phospholipid monolayers. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Carboxylation supports a protein surface that interacts with calcium and membranes. organism: Purified human and bovine proteins tissue_or_cell_type: Calcium-dependent Gla-domain membrane contact experimental_model: Protein adsorption to model phospholipid monolayers limitations: Model membrane binding, not whole-blood thrombosis. Species remain distinct. exposure: Phosphatidylserine-containing monolayers evidence_span: {"source_cache": "artifacts/k2-research/9609692.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd", "start_char": 0, "end_char": 2064, "text_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd"} [k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

evidence_span

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experimental_model

Protein adsorption to model phospholipid monolayers

exposure

Phosphatidylserine-containing monolayers

limitations

Model membrane binding, not whole-blood thrombosis. Species remain distinct.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Purified human and bovine proteins

plain_language

Carboxylation supports a protein surface that interacts with calcium and membranes.

primary_references

[k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

tissue_or_cell_type

Calcium-dependent Gla-domain membrane contact

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 994–1005

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein adsorption to model phospholipid monolayers · source_derived_draft · unverified_draft

### k2-membrane-proc The tested proc Gla-domain protein showed calcium-specific contact with negatively charged phospholipid monolayers. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Carboxylation supports a protein surface that interacts with calcium and membranes. organism: Purified human and bovine proteins tissue_or_cell_type: Calcium-dependent Gla-domain membrane contact experimental_model: Protein adsorption to model phospholipid monolayers limitations: Model membrane binding, not whole-blood thrombosis. Species remain distinct. exposure: Phosphatidylserine-containing monolayers evidence_span: {"source_cache": "artifacts/k2-research/9609692.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd", "start_char": 0, "end_char": 2064, "text_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd"} [k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

evidence_span

{"source_cache": "artifacts/k2-research/9609692.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd", "start_char": 0, "end_char": 2064, "text_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd"}

experimental_model

Protein adsorption to model phospholipid monolayers

exposure

Phosphatidylserine-containing monolayers

limitations

Model membrane binding, not whole-blood thrombosis. Species remain distinct.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Purified human and bovine proteins

plain_language

Carboxylation supports a protein surface that interacts with calcium and membranes.

primary_references

[k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

tissue_or_cell_type

Calcium-dependent Gla-domain membrane contact

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 968–979

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein adsorption to model phospholipid monolayers · source_derived_draft · unverified_draft

### k2-membrane-pros1 The tested pros1 Gla-domain protein showed calcium-specific contact with negatively charged phospholipid monolayers. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Carboxylation supports a protein surface that interacts with calcium and membranes. organism: Purified human and bovine proteins tissue_or_cell_type: Calcium-dependent Gla-domain membrane contact experimental_model: Protein adsorption to model phospholipid monolayers limitations: Model membrane binding, not whole-blood thrombosis. Species remain distinct. exposure: Phosphatidylserine-containing monolayers evidence_span: {"source_cache": "artifacts/k2-research/9609692.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd", "start_char": 0, "end_char": 2064, "text_sha256": "d29ed548c28e5a8015742351c50aa94c8853d0f1846794964b67a73324c879bd"} [k2-p9609692] Adsorption of vitamin K-dependent blood coagulation proteins to spread phospholipid monolayers as determined from combined measurements of the surface pressure and surface protein concentration. (1998). https://pubmed.ncbi.nlm.nih.gov/9609692/ DOI: 10.1021/bi973118+

evidence_span

{"source_cache": "artifacts/k2-research/18369157.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "34c7571f9f3a564647e458dc072113e807c277eaf5f542d6f3ab2e45f71ea5a4", "start_char": 0, "end_char": 1696, "text_sha256": "34c7571f9f3a564647e458dc072113e807c277eaf5f542d6f3ab2e45f71ea5a4"}

experimental_model

Site-directed mutants, calcium assays and BMP reporters

exposure

Gla and Pro64 alterations, calcium chelation and warfarin

limitations

Binding and calcification in experimental systems; systemic calcium should not be equated with a single binding-site measurement.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

MGP expression systems and calcifying vascular cells

plain_language

A calcium-binding protein also controls a signal that can change cell behavior.

primary_references

[k2-p18369157] Proline and gamma-carboxylated glutamate residues in matrix Gla protein are critical for binding of bone morphogenetic protein-4. (2008). https://pubmed.ncbi.nlm.nih.gov/18369157/ DOI: 10.1161/circresaha.107.166124

tissue_or_cell_type

Calcium/BMP binding and differentiation

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 552–563

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutants, calcium assays and BMP reporters · source_derived_draft · unverified_draft

### k2-mgp-bmp4 MGP Gla residues and Pro64 contributed to BMP4 binding and inhibition; only BMP4-binding-competent variants prevented osteogenic differentiation and calcification. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium-binding protein also controls a signal that can change cell behavior. organism: MGP expression systems and calcifying vascular cells tissue_or_cell_type: Calcium/BMP binding and differentiation experimental_model: Site-directed mutants, calcium assays and BMP reporters limitations: Binding and calcification in experimental systems; systemic calcium should not be equated with a single binding-site measurement. exposure: Gla and Pro64 alterations, calcium chelation and warfarin evidence_span: {"source_cache": "artifacts/k2-research/18369157.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "34c7571f9f3a564647e458dc072113e807c277eaf5f542d6f3ab2e45f71ea5a4", "start_char": 0, "end_char": 1696, "text_sha256": "34c7571f9f3a564647e458dc072113e807c277eaf5f542d6f3ab2e45f71ea5a4"} [k2-p18369157] Proline and gamma-carboxylated glutamate residues in matrix Gla protein are critical for binding of bone morphogenetic protein-4. (2008). https://pubmed.ncbi.nlm.nih.gov/18369157/ DOI: 10.1161/circresaha.107.166124

evidence_span

{"source_cache": "artifacts/k2-research/17848178.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2d79c43cc8142d6dc8f1eab4ac99b05ceb01e50e5afb41f5ca75aec732cba27", "start_char": 0, "end_char": 1745, "text_sha256": "d2d79c43cc8142d6dc8f1eab4ac99b05ceb01e50e5afb41f5ca75aec732cba27"}

experimental_model

Human vascular-cell calcification and synthetic-peptide assays

exposure

Elevated calcium, warfarin, K1 and modified MGP peptides

limitations

Vitamin K1 intervention in cells; K2-specific efficacy and human arterial reversal were not tested.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Human vascular smooth muscle cells

plain_language

One vitamin K-dependent protein modification contributes to local control of mineral deposition.

primary_references

[k2-p17848178] Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. (2007). https://pubmed.ncbi.nlm.nih.gov/17848178/ DOI: 10.1111/j.1538-7836.2007.02758.x

tissue_or_cell_type

Extracellular matrix and vesicle-like surfaces

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 513–524

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human vascular-cell calcification and synthetic-peptide assays · source_derived_draft · unverified_draft

### k2-mgp-gla Full-length MGP and its gamma-carboxylated domain inhibited calcium deposition in the tested vascular-cell model. Condition category: normal nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: One vitamin K-dependent protein modification contributes to local control of mineral deposition. organism: Human vascular smooth muscle cells tissue_or_cell_type: Extracellular matrix and vesicle-like surfaces experimental_model: Human vascular-cell calcification and synthetic-peptide assays limitations: Vitamin K1 intervention in cells; K2-specific efficacy and human arterial reversal were not tested. exposure: Elevated calcium, warfarin, K1 and modified MGP peptides evidence_span: {"source_cache": "artifacts/k2-research/17848178.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d2d79c43cc8142d6dc8f1eab4ac99b05ceb01e50e5afb41f5ca75aec732cba27", "start_char": 0, "end_char": 1745, "text_sha256": "d2d79c43cc8142d6dc8f1eab4ac99b05ceb01e50e5afb41f5ca75aec732cba27"} [k2-p17848178] Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. (2007). https://pubmed.ncbi.nlm.nih.gov/17848178/ DOI: 10.1111/j.1538-7836.2007.02758.x

evidence_access

Primary abstract

experimental_model

Rat Kupffer-cell culture with glycine, LPS and receptor pharmacology.

limitations

High in-vitro exposure; not a demonstrated systemic anti-inflammatory effect in humans.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

Glycine changed a calcium signal in liver immune cells.

primary_references

Kupffer cells contain a glycine-gated chloride channel. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9227496/ · DOI 10.1152/ajpgi.1997.272.6.G1581

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 330–336

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat Kupffer-cell culture with glycine, LPS and receptor pharmacology. · source_derived_draft · unverified_draft

## glycine-kupffer-calcium Glycine changed a calcium signal in liver immune cells. Glycine at 1 mM nearly prevented the calcium rise elicited by 10 micrograms/mL LPS in cultured rat Kupffer cells. Model: Rat Kupffer-cell culture with glycine, LPS and receptor pharmacology. Limitations: High in-vitro exposure; not a demonstrated systemic anti-inflammatory effect in humans. Evidence access: Primary abstract Kupffer cells contain a glycine-gated chloride channel. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9227496/ · DOI 10.1152/ajpgi.1997.272.6.G1581

evidence_access

Primary abstract

experimental_model

Rat immune-cell ion substitution and antagonist experiments.

limitations

Pharmacology does not uniquely identify a receptor-subunit combination; high-dose strychnine behaved differently.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

The ionic environment was required for the observed response.

primary_references

Kupffer cells contain a glycine-gated chloride channel. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9227496/ · DOI 10.1152/ajpgi.1997.272.6.G1581

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 338–344

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat immune-cell ion substitution and antagonist experiments. · source_derived_draft · unverified_draft

## glycine-kupffer-chloride-dependence The ionic environment was required for the observed response. Chloride-free buffer abolished the reported glycine effect, and 1 micromolar strychnine reversed it; glycine hyperpolarized the tested Kupffer cells. Model: Rat immune-cell ion substitution and antagonist experiments. Limitations: Pharmacology does not uniquely identify a receptor-subunit combination; high-dose strychnine behaved differently. Evidence access: Primary abstract Kupffer cells contain a glycine-gated chloride channel. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9227496/ · DOI 10.1152/ajpgi.1997.272.6.G1581

cross_nutrient

Bicarbonate coadministration modifies the calcium response attributed to potassium salts.

endpoint

The bicarbonate-containing arms reduced calcium excretion relative to non-bicarbonate arms in the older-adult trial; a potassium main effect was not significant.

experimental-exposure

171 adults aged at least 50 randomized to placebo, KHCO3, NaHCO3, or KCl at 67.5 mmol/day for three months; 162 analyzed; all received calcium and vitamin D.

experimental_model

171 adults aged at least 50 randomized to placebo, KHCO3, NaHCO3, or KCl at 67.5 mmol/day for three months; 162 analyzed; all received calcium and vitamin D.

limitations

Pooled factorial comparison, calcium/vitamin D co-supplementation, three-month surrogate endpoint; not evidence of fracture prevention or universal potassium neutrality.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Homo sapiens

plain_language

The calcium-loss effect tracked the alkali component rather than the presence of potassium in the salt.

primary_references

[dawson-hughes-2009-bicarbonate] Treatment with Potassium Bicarbonate Lowers Calcium Excretion and Bone Resorption in Older Men and Women (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2630872/ DOI: 10.1210/jc.2008-1662

tissue_or_cell_type

kidney and urine

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1260–1272

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 171 adults aged at least 50 randomized to placebo, KHCO3, NaHCO3, or KCl at 67.5 mmol/day for three months; 162 analyzed; all received calcium and vitamin D. · source_derived_draft · unverified_draft

### bicarbonate-component-lowers-calciuria The bicarbonate-containing arms reduced calcium excretion relative to non-bicarbonate arms in the older-adult trial; a potassium main effect was not significant. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The calcium-loss effect tracked the alkali component rather than the presence of potassium in the salt. organism: Homo sapiens tissue_or_cell_type: kidney and urine experimental_model: 171 adults aged at least 50 randomized to placebo, KHCO3, NaHCO3, or KCl at 67.5 mmol/day for three months; 162 analyzed; all received calcium and vitamin D. limitations: Pooled factorial comparison, calcium/vitamin D co-supplementation, three-month surrogate endpoint; not evidence of fracture prevention or universal potassium neutrality. cross_nutrient: Bicarbonate coadministration modifies the calcium response attributed to potassium salts. experimental-exposure: 171 adults aged at least 50 randomized to placebo, KHCO3, NaHCO3, or KCl at 67.5 mmol/day for three months; 162 analyzed; all received calcium and vitamin D. endpoint: The bicarbonate-containing arms reduced calcium excretion relative to non-bicarbonate arms in the older-adult trial; a potassium main effect was not significant. [dawson-hughes-2009-bicarbonate] Treatment with Potassium Bicarbonate Lowers Calcium Excretion and Bone Resorption in Older Men and Women (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2630872/ DOI: 10.1210/jc.2008-1662

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium deprivation increases renal calcium loss in a controlled human dietary model.

endpoint

Five-day dietary potassium withdrawal increased fasting and daily urinary calcium excretion whether the withdrawn salt was KCl or KHCO3.

experimental-exposure

Healthy adults on controlled diets; salt loading in ten participants and five-day potassium deprivation with recovery in two groups of four.

experimental_model

Healthy adults on controlled diets; salt loading in ten participants and five-day potassium deprivation with recovery in two groups of four.

limitations

Small controlled metabolic study; sodium balance, extracellular volume, phosphate handling and calcitriol were possible mediators rather than proven causal links.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Homo sapiens

plain_language

Potassium deprivation changed calcium retention even when alkali withdrawal was not the only explanation.

primary_references

[lemann-1991-calciuria] Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults [corrected] (1991). https://pubmed.ncbi.nlm.nih.gov/1648646/ DOI: 10.1038/ki.1991.123

tissue_or_cell_type

kidney and urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1274–1286

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Healthy adults on controlled diets; salt loading in ten participants and five-day potassium deprivation with recovery in two groups of four. · source_derived_draft · unverified_draft

### human-k-withdrawal-increases-calciuria Five-day dietary potassium withdrawal increased fasting and daily urinary calcium excretion whether the withdrawn salt was KCl or KHCO3. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Potassium deprivation changed calcium retention even when alkali withdrawal was not the only explanation. organism: Homo sapiens tissue_or_cell_type: kidney and urine experimental_model: Healthy adults on controlled diets; salt loading in ten participants and five-day potassium deprivation with recovery in two groups of four. limitations: Small controlled metabolic study; sodium balance, extracellular volume, phosphate handling and calcitriol were possible mediators rather than proven causal links. cross_nutrient: Potassium deprivation increases renal calcium loss in a controlled human dietary model. experimental-exposure: Healthy adults on controlled diets; salt loading in ten participants and five-day potassium deprivation with recovery in two groups of four. endpoint: Five-day dietary potassium withdrawal increased fasting and daily urinary calcium excretion whether the withdrawn salt was KCl or KHCO3. [lemann-1991-calciuria] Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults [corrected] (1991). https://pubmed.ncbi.nlm.nih.gov/1648646/ DOI: 10.1038/ki.1991.123

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium -> calcium/phosphate/PTH observations.

experimental_model

Concurrent mineral and hormone measurements.

limitations

Co-occurrence does not establish that PTH caused every excretion change.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Homo sapiens

plain_language

Potassium depletion affected calcium-phosphate regulation alongside sodium handling.

primary_references

[k-krishna1991] Potassium depletion exacerbates essential hypertension (1991). https://pubmed.ncbi.nlm.nih.gov/2058867/ DOI: 10.7326/0003-4819-115-2-77

tissue_or_cell_type

Plasma and urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1534–1544

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Concurrent mineral and hormone measurements. · source_derived_draft · unverified_draft

### k-depletion-human-mineral-pth-response The depletion period also increased urinary calcium and phosphate and plasma immunoreactive PTH. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Potassium depletion affected calcium-phosphate regulation alongside sodium handling. organism: Homo sapiens tissue_or_cell_type: Plasma and urine experimental_model: Concurrent mineral and hormone measurements. limitations: Co-occurrence does not establish that PTH caused every excretion change. cross_nutrient: Potassium -> calcium/phosphate/PTH observations. [k-krishna1991] Potassium depletion exacerbates essential hypertension (1991). https://pubmed.ncbi.nlm.nih.gov/2058867/ DOI: 10.7326/0003-4819-115-2-77

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Citrate affects urinary calcium chemistry, but this depletion experiment measured citrate handling rather than stones.

endpoint

The potassium-depleted rats had reduced fractional urinary citrate excretion.

experimental-exposure

Rats given low-potassium diet for 14 days; urine citrate and renal cortical brush-border membrane vesicle transport kinetics.

experimental_model

Rats given low-potassium diet for 14 days; urine citrate and renal cortical brush-border membrane vesicle transport kinetics.

limitations

The transport and excretion measurements were parallel; downstream stone formation was not tested.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rattus norvegicus

plain_language

Less filtered citrate remained in urine during depletion.

primary_references

[levi-1991-citrate] Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter (1991). https://pubmed.ncbi.nlm.nih.gov/1683169/ DOI: 10.1152/ajprenal.1991.261.5.F767

tissue_or_cell_type

kidney and urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1204–1216

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rats given low-potassium diet for 14 days; urine citrate and renal cortical brush-border membrane vesicle transport kinetics. · source_derived_draft · unverified_draft

### k-depletion-lowers-citrate-excretion The potassium-depleted rats had reduced fractional urinary citrate excretion. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Less filtered citrate remained in urine during depletion. organism: Rattus norvegicus tissue_or_cell_type: kidney and urine experimental_model: Rats given low-potassium diet for 14 days; urine citrate and renal cortical brush-border membrane vesicle transport kinetics. limitations: The transport and excretion measurements were parallel; downstream stone formation was not tested. cross_nutrient: Citrate affects urinary calcium chemistry, but this depletion experiment measured citrate handling rather than stones. experimental-exposure: Rats given low-potassium diet for 14 days; urine citrate and renal cortical brush-border membrane vesicle transport kinetics. endpoint: The potassium-depleted rats had reduced fractional urinary citrate excretion. [levi-1991-citrate] Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter (1991). https://pubmed.ncbi.nlm.nih.gov/1683169/ DOI: 10.1152/ajprenal.1991.261.5.F767

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium depletion of the bath alters calcium-dependent signaling.

experimental_model

Isolated hearts; enzyme assay and inhibitor intervention.

limitations

Pharmacology is not genetic specificity; clinical efficacy was not tested.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rabbit and rat experimental series

plain_language

Calcium-sensitive kinase signaling contributed to electrical instability.

primary_references

[pezhouman-2015-camkii] Molecular Basis of Hypokalemia-Induced Ventricular Fibrillation (2015). https://pubmed.ncbi.nlm.nih.gov/26269574/ DOI: 10.1161/CIRCULATIONAHA.115.016217

tissue_or_cell_type

Ventricular myocardium

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 645–655

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated hearts; enzyme assay and inhibitor intervention. · source_derived_draft · unverified_draft

### k-low-activates-camkii Rabbit hearts exposed to 2.7 mM K showed increased CaMKII activity; KN-93 prevented low-K early afterdepolarizations and ventricular arrhythmia. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-sensitive kinase signaling contributed to electrical instability. organism: Rabbit and rat experimental series tissue_or_cell_type: Ventricular myocardium experimental_model: Isolated hearts; enzyme assay and inhibitor intervention. limitations: Pharmacology is not genetic specificity; clinical efficacy was not tested. cross_nutrient: Potassium depletion of the bath alters calcium-dependent signaling. [pezhouman-2015-camkii] Molecular Basis of Hypokalemia-Induced Ventricular Fibrillation (2015). https://pubmed.ncbi.nlm.nih.gov/26269574/ DOI: 10.1161/CIRCULATIONAHA.115.016217

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

The calcium response to potassium depends on cellular transport organization.

experimental_model

Rat myocytes, 5.0 to 2.7 mM K, 3 minutes.

limitations

Architecture-dependent findings should not be generalized to all heart cells.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rat

plain_language

Internal membrane architecture changed how low potassium disturbed calcium.

primary_references

[tazmini-2020-cardiac] Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC7098435/ DOI: 10.1161/CIRCRESAHA.119.315641

tissue_or_cell_type

Atrial/ventricular myocardium

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 669–679

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat myocytes, 5.0 to 2.7 mM K, 3 minutes. · source_derived_draft · unverified_draft

### k-low-calcium-waves-tubules Low-K exposure increased calcium waves in ventricular and tubulated atrial cells, with a weaker response in untubulated atrial cells. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Internal membrane architecture changed how low potassium disturbed calcium. organism: Rat tissue_or_cell_type: Atrial/ventricular myocardium experimental_model: Rat myocytes, 5.0 to 2.7 mM K, 3 minutes. limitations: Architecture-dependent findings should not be generalized to all heart cells. cross_nutrient: The calcium response to potassium depends on cellular transport organization. [tazmini-2020-cardiac] Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC7098435/ DOI: 10.1161/CIRCRESAHA.119.315641

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Rat ventricular voltage and calcium recordings.

limitations

Do not equate hyperpolarization with protection from arrhythmia.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rat

plain_language

A more negative resting voltage did not prevent calcium accumulation.

primary_references

[aronsen-2015-cardiac] Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+,K+-ATPase alpha2 activity (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4376427/ DOI: 10.1113/jphysiol.2014.279893

tissue_or_cell_type

Ventricle

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 634–643

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat ventricular voltage and calcium recordings. · source_derived_draft · unverified_draft

### k-low-cardiac-hyperpolarization Acute low-K superfusion hyperpolarized rat ventricular resting voltage despite increasing calcium transients. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A more negative resting voltage did not prevent calcium accumulation. organism: Rat tissue_or_cell_type: Ventricle experimental_model: Rat ventricular voltage and calcium recordings. limitations: Do not equate hyperpolarization with protection from arrhythmia. [aronsen-2015-cardiac] Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+,K+-ATPase alpha2 activity (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4376427/ DOI: 10.1113/jphysiol.2014.279893

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Potassium-to-sodium-to-calcium coupling is experimentally supported; dietary effect magnitude is untested.

experimental_model

Rat ventricular ion assays plus modeling.

limitations

NCX microdomain interpretation; source ouabain units differ between methods and figure legends.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rat

plain_language

Potassium-dependent sodium pumping helps the exchanger remove calcium.

primary_references

[aronsen-2015-cardiac] Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+,K+-ATPase alpha2 activity (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4376427/ DOI: 10.1113/jphysiol.2014.279893

tissue_or_cell_type

Ventricular myocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 622–632

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat ventricular ion assays plus modeling. · source_derived_draft · unverified_draft

### k-low-cardiac-ncx-calcium Pump inhibition during low-K exposure increased sodium sensed by NCX and favored cellular calcium loading. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Potassium-dependent sodium pumping helps the exchanger remove calcium. organism: Rat tissue_or_cell_type: Ventricular myocytes experimental_model: Rat ventricular ion assays plus modeling. limitations: NCX microdomain interpretation; source ouabain units differ between methods and figure legends. cross_nutrient: Potassium-to-sodium-to-calcium coupling is experimentally supported; dietary effect magnitude is untested. [aronsen-2015-cardiac] Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+,K+-ATPase alpha2 activity (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4376427/ DOI: 10.1113/jphysiol.2014.279893

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Sodium entry and calcium loading interact during low extracellular potassium.

experimental_model

Low-K cardiac inhibition experiments and computational model.

limitations

The complete feedback sequence is model-supported, not every step directly measured.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rabbit/rat and mathematical model

plain_language

Persistent sodium entry helped sustain low-potassium electrical instability.

primary_references

[pezhouman-2015-camkii] Molecular Basis of Hypokalemia-Induced Ventricular Fibrillation (2015). https://pubmed.ncbi.nlm.nih.gov/26269574/ DOI: 10.1161/CIRCULATIONAHA.115.016217

tissue_or_cell_type

Ventricular myocardium

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 657–667

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Low-K cardiac inhibition experiments and computational model. · source_derived_draft · unverified_draft

### k-low-late-sodium-feedback GS-967 suppressed hypokalemic early afterdepolarizations; simulations implicated CaMKII-enhanced late sodium current in a sodium/calcium feedback loop. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Persistent sodium entry helped sustain low-potassium electrical instability. organism: Rabbit/rat and mathematical model tissue_or_cell_type: Ventricular myocardium experimental_model: Low-K cardiac inhibition experiments and computational model. limitations: The complete feedback sequence is model-supported, not every step directly measured. cross_nutrient: Sodium entry and calcium loading interact during low extracellular potassium. [pezhouman-2015-camkii] Molecular Basis of Hypokalemia-Induced Ventricular Fibrillation (2015). https://pubmed.ncbi.nlm.nih.gov/26269574/ DOI: 10.1161/CIRCULATIONAHA.115.016217

cross_nutrient

Calcium-regulated channel activity -> local potassium signal.

experimental_model

Rat isolated arteries; potassium electrodes and blockers.

limitations

Pharmacology does not uniquely identify an SK/IK gene; not a dietary intervention.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rattus norvegicus

plain_language

Potassium can act locally as a signal between vessel cells.

primary_references

[k-edwards1998] K+ is an endothelium-derived hyperpolarizing factor in rat arteries (1998). https://pubmed.ncbi.nlm.nih.gov/9834033/ DOI: 10.1038/24388

tissue_or_cell_type

Arterial endothelium and myoendothelial space

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1580–1590

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat isolated arteries; potassium electrodes and blockers. · source_derived_draft · unverified_draft

### k-vascular-endothelial-release Acetylcholine produced a local potassium rise and hyperpolarization sensitive to combined calcium-activated potassium-channel blockers in rat arteries. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Potassium can act locally as a signal between vessel cells. organism: Rattus norvegicus tissue_or_cell_type: Arterial endothelium and myoendothelial space experimental_model: Rat isolated arteries; potassium electrodes and blockers. limitations: Pharmacology does not uniquely identify an SK/IK gene; not a dietary intervention. cross_nutrient: Calcium-regulated channel activity -> local potassium signal. [k-edwards1998] K+ is an endothelium-derived hyperpolarizing factor in rat arteries (1998). https://pubmed.ncbi.nlm.nih.gov/9834033/ DOI: 10.1038/24388

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently.

endpoint

Dietary potassium restriction increased urinary calcium excretion in the male-mouse experiments.

experimental-exposure

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

experimental_model

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

limitations

Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mus musculus

plain_language

The kidneys lost more calcium when dietary potassium was restricted.

primary_references

[murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

tissue_or_cell_type

kidney, blood and trabecular skeleton

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1288–1300

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. · source_derived_draft · unverified_draft

### mouse-k-restriction-calciuria Dietary potassium restriction increased urinary calcium excretion in the male-mouse experiments. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The kidneys lost more calcium when dietary potassium was restricted. organism: Mus musculus tissue_or_cell_type: kidney, blood and trabecular skeleton experimental_model: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. limitations: Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated. cross_nutrient: Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently. experimental-exposure: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. endpoint: Dietary potassium restriction increased urinary calcium excretion in the male-mouse experiments. [murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently.

endpoint

Dietary potassium restriction reduced measured plasma total calcium in the male mice.

experimental-exposure

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

experimental_model

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

limitations

Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mus musculus

plain_language

Blood total calcium fell alongside increased urinary calcium loss.

primary_references

[murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

tissue_or_cell_type

kidney, blood and trabecular skeleton

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1302–1314

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. · source_derived_draft · unverified_draft

### mouse-k-restriction-low-calcium Dietary potassium restriction reduced measured plasma total calcium in the male mice. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blood total calcium fell alongside increased urinary calcium loss. organism: Mus musculus tissue_or_cell_type: kidney, blood and trabecular skeleton experimental_model: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. limitations: Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated. cross_nutrient: Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently. experimental-exposure: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. endpoint: Dietary potassium restriction reduced measured plasma total calcium in the male mice. [murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently.

endpoint

The potassium-restricted male mice showed increased plasma parathyroid hormone.

experimental-exposure

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

experimental_model

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

limitations

Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mus musculus

plain_language

The calcium-regulating hormone response accompanied altered calcium balance.

primary_references

[murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

tissue_or_cell_type

kidney, blood and trabecular skeleton

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1316–1328

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. · source_derived_draft · unverified_draft

### mouse-k-restriction-pth The potassium-restricted male mice showed increased plasma parathyroid hormone. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The calcium-regulating hormone response accompanied altered calcium balance. organism: Mus musculus tissue_or_cell_type: kidney, blood and trabecular skeleton experimental_model: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. limitations: Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated. cross_nutrient: Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently. experimental-exposure: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. endpoint: The potassium-restricted male mice showed increased plasma parathyroid hormone. [murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently.

endpoint

Prolonged low-potassium feeding reduced trabecular bone mineral density in the male-mouse study.

experimental-exposure

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

experimental_model

Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model.

limitations

Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mus musculus

plain_language

The mineral imbalance extended to a measured skeletal endpoint.

primary_references

[murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

tissue_or_cell_type

kidney, blood and trabecular skeleton

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1330–1342

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. · source_derived_draft · unverified_draft

### mouse-k-restriction-trabecular-bone Prolonged low-potassium feeding reduced trabecular bone mineral density in the male-mouse study. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mineral imbalance extended to a measured skeletal endpoint. organism: Mus musculus tissue_or_cell_type: kidney, blood and trabecular skeleton experimental_model: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. limitations: Male mouse model; co-occurring renal transporter and endocrine changes do not prove a complete causal chain or a human fracture effect. NCC-specific mediation is incompletely isolated. cross_nutrient: Dietary potassium restriction altered renal calcium balance, circulating PTH and trabecular mineral density; each endpoint is recorded independently. experimental-exposure: Male mice; two-week potassium-free discovery study and four/eight-week low-potassium study; urine/plasma minerals, renal proteomics, skeletal imaging, and constitutively active SPAK model. endpoint: Prolonged low-potassium feeding reduced trabecular bone mineral density in the male-mouse study. [murali-2026-calcium] Dietary potassium restriction causes hypercalciuria, hypocalcemia, and bone loss in male mice (2026). https://insight.jci.org/articles/view/196339 DOI: 10.1172/jci.insight.196339

cross_nutrient

Citrate/alkali coadministration with potassium modifies calcium-stone formation in hypocitraturic stone formers.

endpoint

Potassium citrate reduced new stone formation relative to placebo among participants followed for three years in the hypocitraturic calcium-stone trial.

experimental-exposure

Fifty-seven people with recurrent calcium stones and hypocitraturia randomized to potassium citrate 30-60 mEq/day or placebo; three-year outcomes in 18 and 20 respectively.

experimental_model

Fifty-seven people with recurrent calcium stones and hypocitraturia randomized to potassium citrate 30-60 mEq/day or placebo; three-year outcomes in 18 and 20 respectively.

limitations

57 randomized but 38 contributed the cited three-year comparison; potassium, citrate and alkalinization were cointerventions. Not a potassium-cation-only effect or treatment recommendation.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Homo sapiens

plain_language

The combined salt changed a stone outcome in a selected clinical group.

primary_references

[barcelo-1993-stones] Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis (1993). https://www.sciencedirect.com/science/article/pii/S0022534717358883 DOI: 10.1016/S0022-5347(17)35888-3

tissue_or_cell_type

urinary tract

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 1438–1450

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fifty-seven people with recurrent calcium stones and hypocitraturia randomized to potassium citrate 30-60 mEq/day or placebo; three-year outcomes in 18 and 20 respectively. · source_derived_draft · unverified_draft

### potassium-citrate-reduces-calcium-stone-formation Potassium citrate reduced new stone formation relative to placebo among participants followed for three years in the hypocitraturic calcium-stone trial. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The combined salt changed a stone outcome in a selected clinical group. organism: Homo sapiens tissue_or_cell_type: urinary tract experimental_model: Fifty-seven people with recurrent calcium stones and hypocitraturia randomized to potassium citrate 30-60 mEq/day or placebo; three-year outcomes in 18 and 20 respectively. limitations: 57 randomized but 38 contributed the cited three-year comparison; potassium, citrate and alkalinization were cointerventions. Not a potassium-cation-only effect or treatment recommendation. cross_nutrient: Citrate/alkali coadministration with potassium modifies calcium-stone formation in hypocitraturic stone formers. experimental-exposure: Fifty-seven people with recurrent calcium stones and hypocitraturia randomized to potassium citrate 30-60 mEq/day or placebo; three-year outcomes in 18 and 20 respectively. endpoint: Potassium citrate reduced new stone formation relative to placebo among participants followed for three years in the hypocitraturic calcium-stone trial. [barcelo-1993-stones] Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis (1993). https://www.sciencedirect.com/science/article/pii/S0022534717358883 DOI: 10.1016/S0022-5347(17)35888-3

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

A calcium-activated K channel connects tubular flow to K elimination.

evidence_location

Figure 5; sex context Figure 8.

experimental_model

Cell-specific knockout; high-K adaptation; microperfusion

limitations

Chronic blood K elevation occurred only in males; whole-animal urinary outputs showed compensation.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mus musculus

plain_language

Flow-dependent potassium secretion needs BK channels in intercalated cells.

primary_references

[carrisoza-2020-intercalated-bk] Intercalated cell BKalpha subunit is required for flow-induced K+ secretion (2020). https://insight.jci.org/articles/view/130553 DOI: 10.1172/jci.insight.130553

tissue_or_cell_type

CCD intercalated cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 356–367

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-specific knockout; high-K adaptation; microperfusion · source_derived_draft · unverified_draft

### renal-intercalated-bk-flow-secretion Intercalated-cell BKalpha deletion abolished flow-stimulated K secretion in isolated mouse CCDs from both sexes. Condition category: machinery_impairment nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Flow-dependent potassium secretion needs BK channels in intercalated cells. organism: Mus musculus tissue_or_cell_type: CCD intercalated cells experimental_model: Cell-specific knockout; high-K adaptation; microperfusion limitations: Chronic blood K elevation occurred only in males; whole-animal urinary outputs showed compensation. cross_nutrient: A calcium-activated K channel connects tubular flow to K elimination. evidence_location: Figure 5; sex context Figure 8. [carrisoza-2020-intercalated-bk] Intercalated cell BKalpha subunit is required for flow-induced K+ secretion (2020). https://insight.jci.org/articles/view/130553 DOI: 10.1172/jci.insight.130553

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Low K increases urinary calcium output under the tested sodium background.

evidence_location

Primary abstract; final-week balance results.

experimental_model

Four-week 0.2% versus 4% K diet; both 8% NaCl

limitations

Weanling males; unusual salt/mineral diets; causal transport site and BP mediation unproven.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Rattus norvegicus

plain_language

In this high-salt setting, lower potassium intake increased calcium loss in urine.

primary_references

[wu-1995-k-calcium] Potassium depletion and salt-sensitive hypertension in Dahl rats: effect on calcium, magnesium, and phosphate excretions (1995). https://pubmed.ncbi.nlm.nih.gov/7581265/ DOI: 10.3109/10641969509033647

tissue_or_cell_type

Kidney/urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 510–521

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four-week 0.2% versus 4% K diet; both 8% NaCl · source_derived_draft · unverified_draft

### renal-low-k-increases-calcium-loss-high-salt Low versus high dietary K increased calcium excretion in both salt-sensitive and salt-resistant Dahl rats on high NaCl. Condition category: nutrient_deficiency nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this high-salt setting, lower potassium intake increased calcium loss in urine. organism: Rattus norvegicus tissue_or_cell_type: Kidney/urine experimental_model: Four-week 0.2% versus 4% K diet; both 8% NaCl limitations: Weanling males; unusual salt/mineral diets; causal transport site and BP mediation unproven. cross_nutrient: Low K increases urinary calcium output under the tested sodium background. evidence_location: Primary abstract; final-week balance results. [wu-1995-k-calcium] Potassium depletion and salt-sensitive hypertension in Dahl rats: effect on calcium, magnesium, and phosphate excretions (1995). https://pubmed.ncbi.nlm.nih.gov/7581265/ DOI: 10.3109/10641969509033647

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Pharmacological intracellular calcium buffering.

limitations

This is not a dietary calcium-deficiency threshold.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

Removing available signaling calcium weakened the response.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 254–260

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pharmacological intracellular calcium buffering. · source_derived_draft · unverified_draft

## resveratrol-calcium-chelation Removing available signaling calcium weakened the response. Intracellular calcium chelation with BAPTA-AM reduced AMPK and ACC phosphorylation induced by 50 micromolar resveratrol in mouse C2C12 myotubes. Model: Pharmacological intracellular calcium buffering. Limitations: This is not a dietary calcium-deficiency threshold. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

50 micromolar resveratrol cell experiments.

limitations

Supports PLC involvement; this inhibitor alone does not isolate PLC-epsilon.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

A phospholipase-linked step lies upstream of calcium signaling.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 270–276

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 50 micromolar resveratrol cell experiments. · source_derived_draft · unverified_draft

## resveratrol-plc-calcium A phospholipase-linked step lies upstream of calcium signaling. The PLC inhibitor U73122 reduced the intracellular calcium rise and AMPK/ACC phosphorylation after resveratrol in mouse C2C12 cells. Model: 50 micromolar resveratrol cell experiments. Limitations: Supports PLC involvement; this inhibitor alone does not isolate PLC-epsilon. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Pharmacological channel inhibition.

limitations

Does not establish direct resveratrol binding to Ryr2.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

Stored calcium release connects to the energy-sensing kinase.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

trigger_kind

machinery_impairment Imported condition classification; unverified.

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 278–284

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pharmacological channel inhibition. · source_derived_draft · unverified_draft

## resveratrol-ryr-block Stored calcium release connects to the energy-sensing kinase. Ryanodine prevented resveratrol-induced AMPK/ACC phosphorylation in mouse C2C12 myotubes, supporting a ryanodine-receptor calcium-release route. Model: Pharmacological channel inhibition. Limitations: Does not establish direct resveratrol binding to Ryr2. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

evidence_span

{"source_cache": "artifacts/curcumin-research/10484074.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7f693540f3a0c4db6b93f1ce8c2adaadd1647a6234091da685497bdf66c2b1a", "start_char": 0, "end_char": 1375, "text_sha256": "a7f693540f3a0c4db6b93f1ce8c2adaadd1647a6234091da685497bdf66c2b1a"}

experimental_model

Isolated platelet aggregation and signaling assays

exposure

Curcumin: PAF/arachidonic-acid aggregation IC50 about 20-25 micromolar, thromboxane IC50 about 70 micromolar

limitations

In-vitro concentrations are not proof of clinical bleeding risk or an anticoagulant treatment effect; fluorescence-based calcium readout is assay-specific.

nutrient_topic

Curcumin research collection; topical membership is not evidence of a direct dietary effect. · Curcumin

organism

Platelets; donor species not resolved in indexed abstract

plain_language

A calcium-signaling measurement changed; this is not calcium depletion.

primary_references

[curcumin-p10484074] Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. (1999). https://pubmed.ncbi.nlm.nih.gov/10484074/ DOI: 10.1016/s0006-2952(99)00206-3

tissue_or_cell_type

Platelet activation and calcium signaling

Curcumin: metabolism, signaling and nutrient connections (2026-09-17) · lines 1009–1020

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated platelet aggregation and signaling assays · source_derived_draft · unverified_draft

### curcumin-platelet-calcium At 100 micromolar, curcumin reduced ionophore-triggered intracellular calcium mobilization. Condition category: normal nutrient_topic: Curcumin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium-signaling measurement changed; this is not calcium depletion. organism: Platelets; donor species not resolved in indexed abstract tissue_or_cell_type: Platelet activation and calcium signaling experimental_model: Isolated platelet aggregation and signaling assays limitations: In-vitro concentrations are not proof of clinical bleeding risk or an anticoagulant treatment effect; fluorescence-based calcium readout is assay-specific. exposure: Curcumin: PAF/arachidonic-acid aggregation IC50 about 20-25 micromolar, thromboxane IC50 about 70 micromolar evidence_span: {"source_cache": "artifacts/curcumin-research/10484074.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7f693540f3a0c4db6b93f1ce8c2adaadd1647a6234091da685497bdf66c2b1a", "start_char": 0, "end_char": 1375, "text_sha256": "a7f693540f3a0c4db6b93f1ce8c2adaadd1647a6234091da685497bdf66c2b1a"} [curcumin-p10484074] Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. (1999). https://pubmed.ncbi.nlm.nih.gov/10484074/ DOI: 10.1016/s0006-2952(99)00206-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse genetic loss-of-function.

limitations

Separate from human TRPM5 and from steviol-glycoside effects in other preparations.

nutrient_topic

Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate

plain_language

An ion channel is another gate after receptor recognition.

primary_references

Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

trigger_kind

machinery_impairment Imported condition classification; unverified.

Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic loss-of-function. · source_derived_draft · unverified_draft

## monosodium-glutamate-trpm5-loss An ion channel is another gate after receptor recognition. Trpm5 knockout disrupted the same tested taste modalities in the mouse study. Model: Mouse genetic loss-of-function. Limitations: Separate from human TRPM5 and from steviol-glycoside effects in other preparations. Evidence access: Primary abstract Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0

evidence_access

Primary abstract

experimental_model

Primary mouse I cells; stereoselective L- versus D-phenylalanine responses.

limitations

Cell assay responses do not establish that calcium supplements enhance satiety in humans.

nutrient_topic

L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine

plain_language

Gut amino-acid sensing can depend on both the amino acid and calcium.

primary_references

The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 278–284

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary mouse I cells; stereoselective L- versus D-phenylalanine responses. · source_derived_draft · unverified_draft

## l-phenylalanine-casr-cck Gut amino-acid sensing can depend on both the amino acid and calcium. L-phenylalanine stimulated CaSR-dependent calcium signaling and CCK release in primary mouse duodenal I cells; CCK responses were greater at 2.5 than at 1.26 mM extracellular calcium. Model: Primary mouse I cells; stereoselective L- versus D-phenylalanine responses. Limitations: Cell assay responses do not establish that calcium supplements enhance satiety in humans. Evidence access: Primary abstract The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

CaSR-null compared with wild-type primary mouse intestinal I cells.

limitations

This is receptor failure, not phenylalanine or calcium dietary deficiency.

nutrient_topic

L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine

plain_language

Removing one sensor disables that route without disabling every secretion trigger.

primary_references

The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 286–292

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · CaSR-null compared with wild-type primary mouse intestinal I cells. · source_derived_draft · unverified_draft

## l-phenylalanine-casr-loss Removing one sensor disables that route without disabling every secretion trigger. CaSR knockout abolished the phenylalanine-evoked calcium response in primary mouse I cells and prevented the normal stimulatory CCK response; responses to KCl and tryptone were preserved. Model: CaSR-null compared with wild-type primary mouse intestinal I cells. Limitations: This is receptor failure, not phenylalanine or calcium dietary deficiency. Evidence access: Primary abstract The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21252045/ · DOI 10.1152/ajpgi.00342.2010

evidence_access

Primary full text

experimental_model

Isolated human platelets; agonist-challenge experiments.

limitations

Metabolite exposure is not phenylalanine exposure; this does not establish that dietary phenylalanine causes thrombosis.

nutrient_topic

L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine

plain_language

A downstream microbial-host metabolite can alter platelet responsiveness in an assay.

primary_references

A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 374–380

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human platelets; agonist-challenge experiments. · source_derived_draft · unverified_draft

## l-phenylalanine-pagln-platelets A downstream microbial-host metabolite can alter platelet responsiveness in an assay. PAGln at 100 micromolar for 30 minutes enhanced agonist-induced human platelet responses, including calcium signaling. Model: Isolated human platelets; agonist-challenge experiments. Limitations: Metabolite exposure is not phenylalanine exposure; this does not establish that dietary phenylalanine causes thrombosis. Evidence access: Primary full text A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32142679/ · DOI 10.1016/j.cell.2020.02.016

evidence_access

Primary abstract

experimental_model

Mouse STC-1 cells, live-cell signaling and pharmacologic experiments.

limitations

Exposure details beyond the accessed abstract are unresolved; this is not direct human gut evidence.

nutrient_topic

L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine

plain_language

A gut-cell model used a receptor-to-calcium pathway to release a hormone.

primary_references

Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34953208/ · DOI 10.1016/j.bbrc.2021.12.043

L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 310–316

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse STC-1 cells, live-cell signaling and pharmacologic experiments. · source_derived_draft · unverified_draft

## l-phenylalanine-stc-gpr142 A gut-cell model used a receptor-to-calcium pathway to release a hormone. In STC-1 enteroendocrine cells, phenylalanine stimulated a GPR142/Gq-linked calcium response contributing to GLP-1 release. Model: Mouse STC-1 cells, live-cell signaling and pharmacologic experiments. Limitations: Exposure details beyond the accessed abstract are unresolved; this is not direct human gut evidence. Evidence access: Primary abstract Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34953208/ · DOI 10.1016/j.bbrc.2021.12.043

evidence_access

Primary full text, Figure 5

experimental_model

Rat ex-vivo colon organ-bath pharmacology.

limitations

Pharmacological dependence does not establish a direct binding site or a specific calcium-channel isoform.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

A downstream microbial product acted through a calcium-channel-dependent mechanism.

primary_references

Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 650–656

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat ex-vivo colon organ-bath pharmacology. · source_derived_draft · unverified_draft

## tryptophan-hydroxyindole-calcium A downstream microbial product acted through a calcium-channel-dependent mechanism. 5-Hydroxyindole stimulated rat colonic contraction, and 1 micromolar nifedipine inhibited the response. Model: Rat ex-vivo colon organ-bath pharmacology. Limitations: Pharmacological dependence does not establish a direct binding site or a specific calcium-channel isoform. Evidence access: Primary full text, Figure 5 Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33481771/ · DOI 10.1371/journal.pbio.3001070

evidence_access

Primary abstract

experimental_model

Rat CA1 neuronal single-channel recording; 1.8 mM calcium.

limitations

Quinolinate is not tryptophan itself; bath concentration is not a dietary dose.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

One downstream metabolite activates an excitatory receptor.

primary_references

Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons. · 1990 · https://pubmed.ncbi.nlm.nih.gov/1700844/ · DOI 10.1016/0304-3940(90)90098-t

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 274–280

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rat CA1 neuronal single-channel recording; 1.8 mM calcium. · source_derived_draft · unverified_draft

## tryptophan-quinolinate-nmda One downstream metabolite activates an excitatory receptor. Quinolinate at 75 micromolar opened NMDA channels in cultured rat hippocampal neurons in calcium-containing, magnesium-free recording solution. Model: Rat CA1 neuronal single-channel recording; 1.8 mM calcium. Limitations: Quinolinate is not tryptophan itself; bath concentration is not a dietary dose. Evidence access: Primary abstract Quinolinate activation of N-methyl-D-aspartate ion channels in rat hippocampal neurons. · 1990 · https://pubmed.ncbi.nlm.nih.gov/1700844/ · DOI 10.1016/0304-3940(90)90098-t

evidence_access

Primary abstract

experimental_model

Human enzyme crystallography; the calcium-bound structure used 0.7 M CaCl2 crystallization conditions.

limitations

The high-calcium structure does not establish inhibition by normal dietary calcium.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

Two minerals can bind differently to the same enzyme.

primary_references

How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15291819/ · DOI 10.1111/j.0014-2956.2004.04277.x

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 54–60

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human enzyme crystallography; the calcium-bound structure used 0.7 M CaCl2 crystallization conditions. · source_derived_draft · unverified_draft

## l-serine-psph-metal Two minerals can bind differently to the same enzyme. Human PSPH uses an active-site Mg2+ ion; replacing it with Ca2+ changes coordination of catalytic Asp20 in a way that impedes nucleophilic attack. Model: Human enzyme crystallography; the calcium-bound structure used 0.7 M CaCl2 crystallization conditions. Limitations: The high-calcium structure does not establish inhibition by normal dietary calcium. Evidence access: Primary abstract How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase. · 2004 · https://pubmed.ncbi.nlm.nih.gov/15291819/ · DOI 10.1111/j.0014-2956.2004.04277.x

evidence_access

Primary abstract

experimental_model

Purified human wild-type and variant PSPH; kinetic interpretation of physiological ion ranges.

limitations

This qualifies physiological extrapolation from binding assays; it does not deny the earlier calcium-bound structure.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

A required mineral need not be the rate-limiting input when its binding site is already occupied.

primary_references

Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 62–68

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human wild-type and variant PSPH; kinetic interpretation of physiological ion ranges. · source_derived_draft · unverified_draft

## l-serine-psph-physiology A required mineral need not be the rate-limiting input when its binding site is already occupied. The 2024 human PSPH study found near-saturation with Mg2+ under physiological conditions and judged ordinary Mg2+/Ca2+ fluctuations unlikely to regulate activity substantially. Model: Purified human wild-type and variant PSPH; kinetic interpretation of physiological ion ranges. Limitations: This qualifies physiological extrapolation from binding assays; it does not deny the earlier calcium-bound structure. Evidence access: Primary abstract Effect of l-serine and magnesium ions on the functional properties of human phosphoserine phosphatase and its pathogenetic variants. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38278334/ · DOI 10.1016/j.bbadis.2024.167034

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Genetic mouse models, including Grhpr knockout and a 1% hydroxyproline diet.

limitations

Hydroxyproline loading is not equivalent to free proline intake; human efficacy of pathway inhibition was not established.

nutrient_topic

L-Proline collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Proline

plain_language

A collagen-derived amino acid can feed an oxalate-producing pathway under specific conditions.

primary_references

The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31821850/ · DOI 10.1016/j.bbadis.2019.165633

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 294–300

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Genetic mouse models, including Grhpr knockout and a 1% hydroxyproline diet. · source_derived_draft · unverified_draft

## l-proline-hypdh-oxalate A collagen-derived amino acid can feed an oxalate-producing pathway under specific conditions. Prodh2 deletion reduced urinary oxalate in mouse hyperoxaluria models; combined Grhpr/Prodh2 deletion prevented kidney calcium-oxalate deposition during a 1% hydroxyproline diet. Model: Genetic mouse models, including Grhpr knockout and a 1% hydroxyproline diet. Limitations: Hydroxyproline loading is not equivalent to free proline intake; human efficacy of pathway inhibition was not established. Evidence access: Primary abstract The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria. · 2020 · https://pubmed.ncbi.nlm.nih.gov/31821850/ · DOI 10.1016/j.bbadis.2019.165633

evidence_access

Primary full text; supplementary Figure 3 description

experimental_model

Mouse islet calcium imaging at low versus stimulatory glucose.

limitations

This does not establish zero human hypoglycemia risk under all combinations.

nutrient_topic

Stevia collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Stevia

plain_language

The metabolic trigger still matters when a potentiator is present.

primary_references

Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28361903/ · DOI 10.1038/ncomms14733