AKT serine/threonine kinase family

cross_nutrient

false

experimental_model

Human cultured-cell metabolomics and isotope tracing, PANK4 editing/re-expression and immunopurified human PANK4 phosphatase assays

exposure

PI3K–AKT signalling and PANK4 phosphorylation manipulations; no nutrient dosing trial.

limitations

Primary abstract with supporting cellular assays; mechanism is not a rationale for treating insulin signalling or increasing B5 intake.

nutrient_topic

Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. · Pantothenate (vitamin B5)

organism

Homo sapiens

plain_language

Growth-factor signalling can ease the PANK4 brake on CoA production.

primary_references

[b5-bio-dibble2022] PI3K drives the de novo synthesis of coenzyme A from vitamin B5. (2022). https://pubmed.ncbi.nlm.nih.gov/35896750/ DOI: 10.1038/s41586-022-04984-8

tissue_or_cell_type

Human cultured-cell models

Pantothenic acid (vitamin B5): coenzyme A, deficiency and nutrient interactions (2026-09-17) · lines 691–702

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cultured-cell metabolomics and isotope tracing, PANK4 editing/re-expression and immunopurified human PANK4 phosphatase assays · source_derived_draft · unverified_draft

### b5-bio-akt-pank4-regulation AKT phosphorylation of PANK4 relieved its suppression of de novo CoA synthesis in the study models. Condition category: normal nutrient_topic: Pantothenic acid (vitamin B5) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Growth-factor signalling can ease the PANK4 brake on CoA production. organism: Homo sapiens tissue_or_cell_type: Human cultured-cell models experimental_model: Human cultured-cell metabolomics and isotope tracing, PANK4 editing/re-expression and immunopurified human PANK4 phosphatase assays limitations: Primary abstract with supporting cellular assays; mechanism is not a rationale for treating insulin signalling or increasing B5 intake. exposure: PI3K–AKT signalling and PANK4 phosphorylation manipulations; no nutrient dosing trial. cross_nutrient: false [b5-bio-dibble2022] PI3K drives the de novo synthesis of coenzyme A from vitamin B5. (2022). https://pubmed.ncbi.nlm.nih.gov/35896750/ DOI: 10.1038/s41586-022-04984-8

evidence_access

Primary full text

experimental_model

Human HEK293 cells; time-dependent signaling, siRNA and recombinant-kinase validation.

limitations

Basal activation differs from insulin-stimulated activation. Recombinant assay construct species is not inferred from the human host cells.

nutrient_topic

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

plain_language

A microbial product changed a kinase pathway, and removing one kinase interrupted the response.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 322–328

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293 cells; time-dependent signaling, siRNA and recombinant-kinase validation. · source_derived_draft · unverified_draft

## histidine-imp-akt A microbial product changed a kinase pathway, and removing one kinase interrupted the response. In HEK293 experiments, imidazole propionate increased basal Akt phosphorylation; p38-gamma knockdown blocked the Akt and inhibitory AMPK phosphorylation responses. Model: Human HEK293 cells; time-dependent signaling, siRNA and recombinant-kinase validation. Limitations: Basal activation differs from insulin-stimulated activation. Recombinant assay construct species is not inferred from the human host cells. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

evidence_span

{"source_cache": "artifacts/inositol-research/21145457.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0de0a9c3ea11cd8ce59bccff69a41139b11e11182fd9fd66016ec72ba329a5ce", "start_char": 0, "end_char": 889, "text_sha256": "0de0a9c3ea11cd8ce59bccff69a41139b11e11182fd9fd66016ec72ba329a5ce"}

experimental_model

Biochemical Akt regulation and targeted mouse Ip6k1 deletion

exposure

5-InsP7 and Ip6k1 knockout

limitations

Whole-gene deletion is not equivalent to adding or withdrawing free myo-inositol; the reported therapeutic proposal is not established treatment.

nutrient_topic

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

organism

Mammalian enzymology and Mus musculus

plain_language

An inositol-derived signal can restrain insulin-pathway signaling rather than always increasing it.

primary_references

[ino-p21145457] Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. (2010). https://pubmed.ncbi.nlm.nih.gov/21145457/ DOI: 10.1016/j.cell.2010.11.032

tissue_or_cell_type

Muscle, adipose tissue and liver

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 782–793

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical Akt regulation and targeted mouse Ip6k1 deletion · source_derived_draft · unverified_draft

### ino-ip7-akt 5-InsP7 inhibited PDK1-dependent Akt phosphorylation and activation in the reported biochemical pathway. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: An inositol-derived signal can restrain insulin-pathway signaling rather than always increasing it. organism: Mammalian enzymology and Mus musculus tissue_or_cell_type: Muscle, adipose tissue and liver experimental_model: Biochemical Akt regulation and targeted mouse Ip6k1 deletion limitations: Whole-gene deletion is not equivalent to adding or withdrawing free myo-inositol; the reported therapeutic proposal is not established treatment. exposure: 5-InsP7 and Ip6k1 knockout evidence_span: {"source_cache": "artifacts/inositol-research/21145457.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0de0a9c3ea11cd8ce59bccff69a41139b11e11182fd9fd66016ec72ba329a5ce", "start_char": 0, "end_char": 889, "text_sha256": "0de0a9c3ea11cd8ce59bccff69a41139b11e11182fd9fd66016ec72ba329a5ce"} [ino-p21145457] Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. (2010). https://pubmed.ncbi.nlm.nih.gov/21145457/ DOI: 10.1016/j.cell.2010.11.032

evidence_span

{"source_cache": "artifacts/glucan-research/25258083.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872", "start_char": 0, "end_char": 1225, "text_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872"}

experimental_model

Histone modification profiling and genome-wide transcriptome of trained human monocytes, with pathway inhibition and a myeloid conditional knockout

exposure

Beta-glucan training with inhibition of Akt, mTOR or HIF-1 alpha, and metformin as an AMPK activator

limitations

The metformin result is an experimental inhibition of an induced response, not a clinical interaction study.

nutrient_topic

Beta-glucan research collection; topical membership is not evidence of a direct clinical effect, and each preparation is recorded as its own entity with no family link joining any pair. · Beta-glucan

organism

Human cells and mouse

plain_language

The rewiring costs energy: block the cell from burning glucose the fast way and the training does not take.

primary_references

[bg-p25258083] mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. (2014). https://pubmed.ncbi.nlm.nih.gov/25258083/ DOI: 10.1126/science.1250684

tissue_or_cell_type

Monocyte

Beta-glucan: a structural family rather than an agent, what decides whether a bound glucan actually signals, the complement route that a cereal and a yeast preparation share, and the unequal human evidence behind each (2026-09-22) · lines 437–448

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Histone modification profiling and genome-wide transcriptome of trained human monocytes, with pathway inhibition and a myeloid conditional knockout · source_derived_draft · unverified_draft

### bg-training-needs-aerobic-glycolysis Trained monocytes display high glucose consumption, high lactate production and a high ratio of NAD+ to NADH, reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin through a dectin-1-Akt-HIF-1 alpha pathway, inhibition of Akt, mTOR or HIF-1 alpha blocked monocyte induction of trained immunity whereas the AMP-activated protein kinase activator metformin inhibited the innate immune response to fungal infection, and mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Condition category: normal nutrient_topic: Beta-glucan research collection; topical membership is not evidence of a direct clinical effect, and each preparation is recorded as its own entity with no family link joining any pair. plain_language: The rewiring costs energy: block the cell from burning glucose the fast way and the training does not take. organism: Human cells and mouse tissue_or_cell_type: Monocyte experimental_model: Histone modification profiling and genome-wide transcriptome of trained human monocytes, with pathway inhibition and a myeloid conditional knockout limitations: The metformin result is an experimental inhibition of an induced response, not a clinical interaction study. exposure: Beta-glucan training with inhibition of Akt, mTOR or HIF-1 alpha, and metformin as an AMPK activator evidence_span: {"source_cache": "artifacts/glucan-research/25258083.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872", "start_char": 0, "end_char": 1225, "text_sha256": "68c4cae9a0e4477a52864e63ecaf5ec977752b5d3246a9ba54aa22d160e41872"} [bg-p25258083] mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. (2014). https://pubmed.ncbi.nlm.nih.gov/25258083/ DOI: 10.1126/science.1250684

evidence_span

{"source_cache": "artifacts/gaba-research/21709230.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "926bc916592c55cf6089bcb240ec5545e0ff3850e6d927bb82efacfc61841175", "start_char": 0, "end_char": 1117, "text_sha256": "926bc916592c55cf6089bcb240ec5545e0ff3850e6d927bb82efacfc61841175"}

experimental_model

Islet cell electrophysiology and signalling with GABA therapy in diabetes-prone and severely diabetic mice

exposure

GABA given therapeutically, with membrane potential, calcium influx and survival pathway readouts in beta cells

limitations

A mouse therapy study. Its electrophysiological claim about beta cells is stated as a contrast with alpha cells and brain rather than shown alongside a measured chloride gradient.

nutrient_topic

GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in. · Gamma-aminobutyric acid

organism

Mouse

plain_language

In the insulin-producing cell the same molecule does the opposite of what it does in the brain, and the cells survive better for it.

primary_references

[gb-p21709230] GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. (2011). https://pubmed.ncbi.nlm.nih.gov/21709230/ DOI: 10.1073/pnas.1102715108

tissue_or_cell_type

Pancreatic islet and immune system

GABA: a ligand with no sign of its own, the cofactor that limits its synthesis, the barrier that keeps it out of the brain, and the immune settings where the same molecule protects and harms (2026-09-22) · lines 430–441

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Islet cell electrophysiology and signalling with GABA therapy in diabetes-prone and severely diabetic mice · source_derived_draft · unverified_draft

### gb-gaba-depolarises-the-beta-cell Unlike in adult brain or islet alpha-cells in which GABA exerts hyperpolarizing effects, in islet beta-cells GABA produces membrane depolarization and calcium influx leading to the activation of PI3-kinase and Akt-dependent growth and survival pathways, this provides a potential mechanism underlying findings that GABA therapy preserves beta-cell mass and prevents the development of type 1 diabetes, remarkably in severely diabetic mice GABA restores beta-cell mass and reverses the disease, and GABA suppresses insulitis and systemic inflammatory cytokine production. Condition category: normal nutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in. plain_language: In the insulin-producing cell the same molecule does the opposite of what it does in the brain, and the cells survive better for it. organism: Mouse tissue_or_cell_type: Pancreatic islet and immune system experimental_model: Islet cell electrophysiology and signalling with GABA therapy in diabetes-prone and severely diabetic mice limitations: A mouse therapy study. Its electrophysiological claim about beta cells is stated as a contrast with alpha cells and brain rather than shown alongside a measured chloride gradient. exposure: GABA given therapeutically, with membrane potential, calcium influx and survival pathway readouts in beta cells evidence_span: {"source_cache": "artifacts/gaba-research/21709230.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "926bc916592c55cf6089bcb240ec5545e0ff3850e6d927bb82efacfc61841175", "start_char": 0, "end_char": 1117, "text_sha256": "926bc916592c55cf6089bcb240ec5545e0ff3850e6d927bb82efacfc61841175"} [gb-p21709230] GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. (2011). https://pubmed.ncbi.nlm.nih.gov/21709230/ DOI: 10.1073/pnas.1102715108

evidence_access

Primary abstract

experimental_model

Human primary osteoblast signaling experiments.

limitations

Does not prove direct binding to Akt or beta-catenin; Akt isoform not resolved here.

nutrient_topic

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

plain_language

A receptor signal can reach a transcriptional regulator through Akt.

primary_references

An Akt-dependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate-induced osteogenic effects in human osteoblasts. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21566129/ · DOI 10.1074/jbc.M111.251116

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 182–188

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

## strontium-human-beta-catenin A receptor signal can reach a transcriptional regulator through Akt. An Akt-dependent signaling cascade through CaSR promoted beta-catenin nuclear translocation in strontium-treated primary human osteoblasts. Model: Human primary osteoblast signaling experiments. Limitations: Does not prove direct binding to Akt or beta-catenin; Akt isoform not resolved here. Evidence access: Primary abstract An Akt-dependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate-induced osteogenic effects in human osteoblasts. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21566129/ · DOI 10.1074/jbc.M111.251116

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

Human endothelial-cell experiments accompanying diabetic-rat study.

limitations

Pathway association does not establish direct inhibition of ERK or Akt by berberine at human exposure.

nutrient_topic

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

plain_language

Protection from one compound’s cellular toxicity can accompany lower signaling activity.

primary_references

Vanadyl Acetylacetonate and Berberine Synergistically Ameliorate Diabetes-induced Vascular Dysfunction and Reduce Endothelial Toxicity through ERK and Akt Regulation. · 2026 · https://pubmed.ncbi.nlm.nih.gov/40775562/ · DOI 10.1007/s12011-025-04774-z

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 350–356

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human endothelial-cell experiments accompanying diabetic-rat study. · source_derived_draft · unverified_draft

## vanadium-berberine-endothelium Protection from one compound’s cellular toxicity can accompany lower signaling activity. In HUVEC experiments, berberine reduced vanadyl-acetylacetonate-associated apoptosis, junction/cytoskeleton damage and permeability changes, with lower excessive ERK/Akt phosphorylation. Model: Human endothelial-cell experiments accompanying diabetic-rat study. Limitations: Pathway association does not establish direct inhibition of ERK or Akt by berberine at human exposure. Evidence access: Primary abstract Vanadyl Acetylacetonate and Berberine Synergistically Ameliorate Diabetes-induced Vascular Dysfunction and Reduce Endothelial Toxicity through ERK and Akt Regulation. · 2026 · https://pubmed.ncbi.nlm.nih.gov/40775562/ · DOI 10.1007/s12011-025-04774-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human osteoblast-like cultures.

limitations

LY294002 has off-target effects and is not an inhibitor specific to the entire PI3K–Akt–mTOR chain.

nutrient_topic

Silica collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Silica and soluble silicon

plain_language

The cell response was sensitive to PI3K-pathway blockade.

primary_references

Orthosilicic Acid Accelerates Bone Formation in Human Osteoblast-Like Cells Through the PI3K-Akt-mTOR Pathway. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30421162/ · DOI 10.1007/s12011-018-1574-9

trigger_kind

machinery_impairment Imported condition classification; unverified.

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 176–182

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

## silica-ly294002-block The cell response was sensitive to PI3K-pathway blockade. LY294002 reduced pathway signals and osteogenic markers during orthosilicic acid treatment. Model: Human osteoblast-like cultures. Limitations: LY294002 has off-target effects and is not an inhibitor specific to the entire PI3K–Akt–mTOR chain. Evidence access: Primary abstract Orthosilicic Acid Accelerates Bone Formation in Human Osteoblast-Like Cells Through the PI3K-Akt-mTOR Pathway. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30421162/ · DOI 10.1007/s12011-018-1574-9

evidence_access

Primary abstract

experimental_model

Human osteoblast-like cell study.

limitations

No direct binding target or dietary requirement is established.

nutrient_topic

Silica collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Silica and soluble silicon

plain_language

A growth-related pathway accompanied matrix production.

primary_references

Orthosilicic Acid Accelerates Bone Formation in Human Osteoblast-Like Cells Through the PI3K-Akt-mTOR Pathway. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30421162/ · DOI 10.1007/s12011-018-1574-9

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 168–174

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human osteoblast-like cell study. · source_derived_draft · unverified_draft

## silica-pi3k-mtor A growth-related pathway accompanied matrix production. Orthosilicic acid increased PI3K, phosphorylated Akt and mTOR together with osteogenic markers. Model: Human osteoblast-like cell study. Limitations: No direct binding target or dietary requirement is established. Evidence access: Primary abstract Orthosilicic Acid Accelerates Bone Formation in Human Osteoblast-Like Cells Through the PI3K-Akt-mTOR Pathway. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30421162/ · DOI 10.1007/s12011-018-1574-9

experimental_model

High-K mouse/human T-cell cultures; PP2A perturbations.

limitations

PP2A dependence does not demonstrate direct K binding; no diet manipulation.

nutrient_topic

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

organism

Mouse and human

plain_language

Local potassium accumulation dampened T-cell activation signals.

primary_references

[eil-2016-tcells] Ionic immune suppression within the tumour microenvironment limits T cell effector function (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC5204372/ DOI: 10.1038/nature19364

tissue_or_cell_type

T cells

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 902–911

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High-K mouse/human T-cell cultures; PP2A perturbations. · source_derived_draft · unverified_draft

### k-tcell-pp2a-suppression Elevated intracellular K suppressed TCR-driven AKT-mTOR signaling through a PP2A-dependent process. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Local potassium accumulation dampened T-cell activation signals. organism: Mouse and human tissue_or_cell_type: T cells experimental_model: High-K mouse/human T-cell cultures; PP2A perturbations. limitations: PP2A dependence does not demonstrate direct K binding; no diet manipulation. [eil-2016-tcells] Ionic immune suppression within the tumour microenvironment limits T cell effector function (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC5204372/ DOI: 10.1038/nature19364

cross_nutrient

Human protein kinase CK2 complex (upstream_kinase); AKT serine/threonine kinase family (downstream_kinase_family); Human ERK2 / MAPK1 (downstream_kinase); Human ERK1 / MAPK3 (downstream_kinase); Cytosolic labile zinc availability (increased_pool)

evidence_span

{"source_cache": "artifacts/zinc-signaling-sources/22317921-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "a8e31db38c22019d7ebef8ff165e2b3dc0b3a338e18514f0bf0c48cc5215944d"}

experimental_model

Human breast-cell model with ZIP7/CK2 perturbations

exposure

Signaling stimuli and ZIP7/CK2 phosphorylation comparisons.

limitations

Cellular signaling study; it does not establish dietary zinc supplementation as an anticancer intervention. Intracellular release is different from net dietary uptake.

nutrient_topic

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

organism

Homo sapiens

plain_language

Zinc redistribution connected a storage compartment to kinase signaling.

primary_references

[zn-sig-22317921] Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. (2012). https://pubmed.ncbi.nlm.nih.gov/22317921/ DOI: 10.1126/scisignal.2002585

tissue_or_cell_type

Endoplasmic reticulum and cytoplasm

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 999–1011

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human breast-cell model with ZIP7/CK2 perturbations · source_derived_draft · unverified_draft

### zn-sig-zip7-release ZIP7 phosphorylation was linked to release of stored zinc and downstream AKT and ERK1/2 phosphorylation in the studied human cells. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc redistribution connected a storage compartment to kinase signaling. organism: Homo sapiens tissue_or_cell_type: Endoplasmic reticulum and cytoplasm experimental_model: Human breast-cell model with ZIP7/CK2 perturbations limitations: Cellular signaling study; it does not establish dietary zinc supplementation as an anticancer intervention. Intracellular release is different from net dietary uptake. exposure: Signaling stimuli and ZIP7/CK2 phosphorylation comparisons. cross_nutrient: Human protein kinase CK2 complex (upstream_kinase); AKT serine/threonine kinase family (downstream_kinase_family); Human ERK2 / MAPK1 (downstream_kinase); Human ERK1 / MAPK3 (downstream_kinase); Cytosolic labile zinc availability (increased_pool) evidence_span: {"source_cache": "artifacts/zinc-signaling-sources/22317921-abstract.txt", "locator": "Primary indexed abstract", "file_sha256": "a8e31db38c22019d7ebef8ff165e2b3dc0b3a338e18514f0bf0c48cc5215944d"} [zn-sig-22317921] Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. (2012). https://pubmed.ncbi.nlm.nih.gov/22317921/ DOI: 10.1126/scisignal.2002585

evidence_access

Primary full text

experimental_model

HEK293 expression and phosphorylation assays; the paper labels the construct site S485.

limitations

Construct site numbering is retained without silently mapping it to a human endogenous isoform. No universal AMPK inhibition across all tissues.

nutrient_topic

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

plain_language

Changing the inhibitory phosphorylation site interrupted the measured drug interaction.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, 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 · HEK293 expression and phosphorylation assays; the paper labels the construct site S485. · source_derived_draft · unverified_draft

## histidine-imp-ampk Changing the inhibitory phosphorylation site interrupted the measured drug interaction. In HEK293 cells, imidazole propionate suppressed metformin-induced AMPK activation; expression of the study-labeled AMPK S485A mutant prevented suppression of activating T172 phosphorylation. Model: HEK293 expression and phosphorylation assays; the paper labels the construct site S485. Limitations: Construct site numbering is retained without silently mapping it to a human endogenous isoform. No universal AMPK inhibition across all tissues. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

evidence_access

Primary full text

experimental_model

Human-cell signaling, kinase assays and inhibitor/knockdown experiments.

limitations

Does not eliminate mTOR signaling from all imidazole-propionate effects; model and time point matter.

nutrient_topic

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

plain_language

Two routes from the same metabolite have different timing and intermediates.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, 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 · Human-cell signaling, kinase assays and inhibitor/knockdown experiments. · source_derived_draft · unverified_draft

## histidine-imp-mtor-boundary Two routes from the same metabolite have different timing and intermediates. The study distinguished p38-gamma-dependent basal Akt activation from mTORC1-dependent IRS loss; direct mTORC2 activation was not detected in the tested kinase assay. Model: Human-cell signaling, kinase assays and inhibitor/knockdown experiments. Limitations: Does not eliminate mTOR signaling from all imidazole-propionate effects; model and time point matter. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

cross_nutrient

Insulin (stimulus)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/yoshino2021.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "e4999dc5b9d3392d8180280727c424044b35249bb24c999c3bc863cd23e6c856", "start_char": 7141, "end_char": 7815, "text_sha256": "31871685ed5bb9ceb845b035d50807218311c0fad543f690e5ab924ba9872d0d"}

experimental_model

Randomized double-blind trial; 25 overweight or obese postmenopausal women with prediabetes completed

exposure

NMN 250 mg/day for 10 weeks; 13 NMN and 12 placebo participants

limitations

Small selected female cohort. Tissue NAD concentration, NAD turnover and clinical outcomes differ. No lifespan or diabetes-prevention endpoint. Positive muscle findings do not establish whole-body or cross-population benefit.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

The muscle response was accompanied by changes in insulin-signaling proteins.

primary_references

[nia-clin-yoshino2021] Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. (2021). https://pubmed.ncbi.nlm.nih.gov/33888596/ DOI: 10.1126/science.abe9985

tissue_or_cell_type

Skeletal muscle, PBMCs, liver and adipose insulin sensitivity

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1501–1513

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind trial; 25 overweight or obese postmenopausal women with prediabetes completed · source_derived_draft · unverified_draft

### nia-clin-nmn-muscle-signal Muscle insulin-stimulated AKT and mTOR phosphorylation and total abundance increased after NMN but not placebo. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The muscle response was accompanied by changes in insulin-signaling proteins. organism: Homo sapiens tissue_or_cell_type: Skeletal muscle, PBMCs, liver and adipose insulin sensitivity experimental_model: Randomized double-blind trial; 25 overweight or obese postmenopausal women with prediabetes completed limitations: Small selected female cohort. Tissue NAD concentration, NAD turnover and clinical outcomes differ. No lifespan or diabetes-prevention endpoint. Positive muscle findings do not establish whole-body or cross-population benefit. exposure: NMN 250 mg/day for 10 weeks; 13 NMN and 12 placebo participants cross_nutrient: Insulin (stimulus) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/yoshino2021.txt", "locator": "Primary full report; exact character range, zero-based and end-exclusive", "file_sha256": "e4999dc5b9d3392d8180280727c424044b35249bb24c999c3bc863cd23e6c856", "start_char": 7141, "end_char": 7815, "text_sha256": "31871685ed5bb9ceb845b035d50807218311c0fad543f690e5ab924ba9872d0d"} [nia-clin-yoshino2021] Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. (2021). https://pubmed.ncbi.nlm.nih.gov/33888596/ DOI: 10.1126/science.abe9985

availability_state

machinery_impairment Imported condition classification; unverified.

dose

Hericenone E with low NGF and K252a

duration

Differentiation assay

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

Rat PC12 pheochromocytoma cells

limitations

Partial blockade suggests Trk involvement but not sole dependence; PC12 exposure does not establish human brain target engagement.

nutrient_topic

Hericenones & Erinacines chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Hericenones and erinacines

organism

Rat PC12 pheochromocytoma cells

plain_language

K252a partially blocked hericenone-E-associated neuritogenesis, while hericenone E increased NGF secretion and ERK/Akt phosphorylation.

primary_references

Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways. (2014). https://pubmed.ncbi.nlm.nih.gov/25288148/ DOI: 10.1039/c4fo00452c

route

In vitro

tissue

NGF secretion, neurite outgrowth, ERK and Akt

trigger_kind

machinery_impairment Imported condition classification; unverified.

Hericenones & Erinacines: mechanism of action and interactions (2026-09-20) · lines 44–53

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Rat PC12 pheochromocytoma cells · source_derived_draft · unverified_draft

## hericenones-erinacines-hericenone-e-ngf K252a partially blocked hericenone-E-associated neuritogenesis, while hericenone E increased NGF secretion and ERK/Akt phosphorylation. Model/species: Rat PC12 pheochromocytoma cells Tissue/system: NGF secretion, neurite outgrowth, ERK and Akt Exposure: Hericenone E with low NGF and K252a Route: In vitro Duration: Differentiation assay Limits: Partial blockade suggests Trk involvement but not sole dependence; PC12 exposure does not establish human brain target engagement. Primary reference: Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways. (2014). https://pubmed.ncbi.nlm.nih.gov/25288148/ DOI: 10.1039/c4fo00452c Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_span

{"source_cache": "artifacts/zeaxanthin-research/24810054.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f185c805dd5d825445cb40e547b794fbc595388aff6e2d29ac81c2eab8b8348", "start_char": 5813, "end_char": 15716, "text_sha256": "89e6abf1967c10b359cb62d935d5b839cf53acf42576d9db3d463bff9f474e38"}

experimental_model

Cell challenge with siRNA and pathway inhibitors

exposure

Zeaxanthin commonly 10 micromolar for 24 h; 300 micromolar t-BHP challenge for 6 h; study-specific inhibitors

limitations

Pharmacological cell exposures are not dietary concentrations. PI3K/Akt inhibitor evidence is not direct zeaxanthin binding to a kinase. Liposome GSTP1 protection and this cellular GSH-dependent response are different mechanisms.

nutrient_topic

Zeaxanthin research collection; topical membership is not evidence of a direct dietary effect. · Dietary (3R,3-prime-R)-zeaxanthin

organism

Human ARPE-19 cell line

plain_language

Activating a pathway and needing it for protection are different tests.

primary_references

[zeaxanthin-p24810054] Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death. (2014). https://pubmed.ncbi.nlm.nih.gov/24810054/ DOI: 10.1038/cddis.2014.190

tissue_or_cell_type

Retinal pigment epithelial model

Zeaxanthin: metabolism, signaling and nutrient connections (2026-09-17) · lines 470–481

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell challenge with siRNA and pathway inhibitors · source_derived_draft · unverified_draft

### zeaxanthin-pi3k-block LY294002 blocked zeaxanthin-associated survival protection; U0126 did not show the same effect. Condition category: normal nutrient_topic: Zeaxanthin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Activating a pathway and needing it for protection are different tests. organism: Human ARPE-19 cell line tissue_or_cell_type: Retinal pigment epithelial model experimental_model: Cell challenge with siRNA and pathway inhibitors limitations: Pharmacological cell exposures are not dietary concentrations. PI3K/Akt inhibitor evidence is not direct zeaxanthin binding to a kinase. Liposome GSTP1 protection and this cellular GSH-dependent response are different mechanisms. exposure: Zeaxanthin commonly 10 micromolar for 24 h; 300 micromolar t-BHP challenge for 6 h; study-specific inhibitors evidence_span: {"source_cache": "artifacts/zeaxanthin-research/24810054.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f185c805dd5d825445cb40e547b794fbc595388aff6e2d29ac81c2eab8b8348", "start_char": 5813, "end_char": 15716, "text_sha256": "89e6abf1967c10b359cb62d935d5b839cf53acf42576d9db3d463bff9f474e38"} [zeaxanthin-p24810054] Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death. (2014). https://pubmed.ncbi.nlm.nih.gov/24810054/ DOI: 10.1038/cddis.2014.190