Nutrient chapter

Vitamin C

Vitamin C supports connective-tissue enzymes and selected cellular redox reactions. Absorption, recycling and enzyme availability connect it with other nutrients. Reduced ascorbate, ascorbic acid and oxidized dehydroascorbic acid are recorded separately. Independent measured endpoint or substance; model, assay and exposure are retained in each linked finding.

153 recorded mechanisms · 33 availability situations · 2 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Rat SVCT1 expressed in Xenopus oocytes mediated stereospecific, concentrative uptake of reduced L-ascorbate driven by the sodium electrochemical gradient.
Rat sodium-dependent vitamin C transporter 1 / Slc23a1 → L-Ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution
exposure
Heterologous cDNA expression and uptake assays
limitations
Primary abstract only; no inferred human kinetic constants.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus protein in Xenopus laevis
plain_language
SVCT1 uses a sodium gradient to bring reduced vitamin C into cells.
primary_references
[tsukaguchi1999] A family of mammalian Na+-dependent L-ascorbic acid transporters. (1999). https://pubmed.ncbi.nlm.nih.gov/10331392/ DOI: 10.1038/19986
tissue_or_cell_type
Oocyte plasma membrane
transport_effect
raises Stereospecific concentrative uptake driven by the sodium electrochemical gradient.
transport_pool
the expressing cell Stereospecific concentrative uptake driven by the sodium electrochemical gradient.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 104–115
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution · source_derived_draft · unverified_draft
### vc-transport-svct1-uptake Rat SVCT1 expressed in Xenopus oocytes mediated stereospecific, concentrative uptake of reduced L-ascorbate driven by the sodium electrochemical gradient. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: SVCT1 uses a sodium gradient to bring reduced vitamin C into cells. organism: Rattus norvegicus protein in Xenopus laevis tissue_or_cell_type: Oocyte plasma membrane experimental_model: Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution limitations: Primary abstract only; no inferred human kinetic constants. exposure: Heterologous cDNA expression and uptake assays cross_nutrient: true [tsukaguchi1999] A family of mammalian Na+-dependent L-ascorbic acid transporters. (1999). https://pubmed.ncbi.nlm.nih.gov/10331392/ DOI: 10.1038/19986
Complete structured claim and evidence
Rat SVCT2 expressed in Xenopus oocytes mediated stereospecific, concentrative uptake of reduced L-ascorbate driven by the sodium electrochemical gradient.
Rat sodium-dependent vitamin C transporter 2 / Slc23a2 → L-Ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution
exposure
Heterologous cDNA expression and uptake assays
limitations
Primary abstract only; no inferred human kinetic constants.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus protein in Xenopus laevis
plain_language
SVCT2 uses a sodium gradient to bring reduced vitamin C into cells.
primary_references
[tsukaguchi1999] A family of mammalian Na+-dependent L-ascorbic acid transporters. (1999). https://pubmed.ncbi.nlm.nih.gov/10331392/ DOI: 10.1038/19986
tissue_or_cell_type
Oocyte plasma membrane
transport_effect
raises Stereospecific concentrative uptake driven by the sodium electrochemical gradient.
transport_pool
the expressing cell Stereospecific concentrative uptake driven by the sodium electrochemical gradient.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 117–128
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution · source_derived_draft · unverified_draft
### vc-transport-svct2-uptake Rat SVCT2 expressed in Xenopus oocytes mediated stereospecific, concentrative uptake of reduced L-ascorbate driven by the sodium electrochemical gradient. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: SVCT2 uses a sodium gradient to bring reduced vitamin C into cells. organism: Rattus norvegicus protein in Xenopus laevis tissue_or_cell_type: Oocyte plasma membrane experimental_model: Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution limitations: Primary abstract only; no inferred human kinetic constants. exposure: Heterologous cDNA expression and uptake assays cross_nutrient: true [tsukaguchi1999] A family of mammalian Na+-dependent L-ascorbic acid transporters. (1999). https://pubmed.ncbi.nlm.nih.gov/10331392/ DOI: 10.1038/19986
Complete structured claim and evidence
Rat SVCT2 tissue distribution included brain and eye, whereas SVCT1 distribution favored intestinal, kidney and liver epithelia.
Rat sodium-dependent vitamin C transporter 2 / Slc23a2 → Brain source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution
exposure
Tissue-distribution analysis
limitations
Primary abstract only; no inferred human kinetic constants.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
The two vitamin C transporters have different tissue distributions.
primary_references
[tsukaguchi1999] A family of mammalian Na+-dependent L-ascorbic acid transporters. (1999). https://pubmed.ncbi.nlm.nih.gov/10331392/ DOI: 10.1038/19986
tissue_or_cell_type
Brain, eye, intestine, kidney and liver
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 130–141
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution · source_derived_draft · unverified_draft
### vc-transport-svct-distribution Rat SVCT2 tissue distribution included brain and eye, whereas SVCT1 distribution favored intestinal, kidney and liver epithelia. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two vitamin C transporters have different tissue distributions. organism: Rattus norvegicus tissue_or_cell_type: Brain, eye, intestine, kidney and liver experimental_model: Rat cDNA transporters expressed in Xenopus oocytes; mammalian tissue distribution limitations: Primary abstract only; no inferred human kinetic constants. exposure: Tissue-distribution analysis cross_nutrient: false [tsukaguchi1999] A family of mammalian Na+-dependent L-ascorbic acid transporters. (1999). https://pubmed.ncbi.nlm.nih.gov/10331392/ DOI: 10.1038/19986
Complete structured claim and evidence
Slc23a1 deletion raised renal ascorbate fractional excretion about 16–18-fold in female mice and 6–7-fold in males; female reabsorption was essentially abolished.
Mouse Slc23a1 gene → Renal ascorbate fractional excretion source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Slc23a1 knockout mice and wild-type controls
exposure
Slc23a1 knockout versus wild type
limitations
Sex-specific renal clearances; inulin clearance was unchanged. This is transporter loss, not low intake.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Removing SVCT1 made mice lose more filtered vitamin C in urine.
primary_references
[corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
tissue_or_cell_type
Kidney
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 143–154
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc23a1 knockout mice and wild-type controls · source_derived_draft · unverified_draft
### vc-transport-svct1-renal-loss Slc23a1 deletion raised renal ascorbate fractional excretion about 16–18-fold in female mice and 6–7-fold in males; female reabsorption was essentially abolished. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing SVCT1 made mice lose more filtered vitamin C in urine. organism: Mus musculus tissue_or_cell_type: Kidney experimental_model: Slc23a1 knockout mice and wild-type controls limitations: Sex-specific renal clearances; inulin clearance was unchanged. This is transporter loss, not low intake. exposure: Slc23a1 knockout versus wild type cross_nutrient: false [corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
Complete structured claim and evidence
Plasma ascorbate was approximately 50–70% lower in Slc23a1-null mice than wild-type mice.
Mouse Slc23a1 gene → Plasma ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Slc23a1 knockout mice and wild-type controls
exposure
Slc23a1 knockout versus wild type
limitations
Mouse concentration phenotype; do not use as a human deficiency threshold.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Renal vitamin C wasting lowered circulating vitamin C in these mice.
primary_references
[corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
tissue_or_cell_type
Plasma
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 156–167
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc23a1 knockout mice and wild-type controls · source_derived_draft · unverified_draft
### vc-transport-svct1-plasma Plasma ascorbate was approximately 50–70% lower in Slc23a1-null mice than wild-type mice. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Renal vitamin C wasting lowered circulating vitamin C in these mice. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Slc23a1 knockout mice and wild-type controls limitations: Mouse concentration phenotype; do not use as a human deficiency threshold. exposure: Slc23a1 knockout versus wild type cross_nutrient: false [corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
Complete structured claim and evidence
Pups born to Slc23a1-null dams had approximately 45% perinatal mortality, including heterozygous and homozygous-null pups.
Mouse Slc23a1 gene → Perinatal survival source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Slc23a1 knockout mice and wild-type controls
exposure
Breeding Slc23a1-null dams
limitations
Genotype of dam and pup must be distinguished; this does not define human pregnancy requirements.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Maternal loss of the renal vitamin C transporter threatened newborn survival.
primary_references
[corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
tissue_or_cell_type
Maternal-fetal system
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 169–180
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc23a1 knockout mice and wild-type controls · source_derived_draft · unverified_draft
### vc-transport-svct1-maternal-survival Pups born to Slc23a1-null dams had approximately 45% perinatal mortality, including heterozygous and homozygous-null pups. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Maternal loss of the renal vitamin C transporter threatened newborn survival. organism: Mus musculus tissue_or_cell_type: Maternal-fetal system experimental_model: Slc23a1 knockout mice and wild-type controls limitations: Genotype of dam and pup must be distinguished; this does not define human pregnancy requirements. exposure: Breeding Slc23a1-null dams cross_nutrient: false [corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
Complete structured claim and evidence
Providing Slc23a1-null pregnant mice 330 mg/L ascorbate in drinking water from mating to delivery prevented the excess perinatal mortality of their null offspring.
L-Ascorbate → Perinatal survival source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Slc23a1 knockout mice and wild-type controls
exposure
Slc23a1-null dams; 330 mg/L drinking-water ascorbate during pregnancy
limitations
Animal rescue dose; not a human dosing recommendation or correction of the deleted transporter.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Additional vitamin C rescued survival in this maternal transporter-loss model.
primary_references
[corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
tissue_or_cell_type
Maternal-fetal system
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 182–193
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc23a1 knockout mice and wild-type controls · source_derived_draft · unverified_draft
### vc-transport-svct1-maternal-rescue Providing Slc23a1-null pregnant mice 330 mg/L ascorbate in drinking water from mating to delivery prevented the excess perinatal mortality of their null offspring. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Additional vitamin C rescued survival in this maternal transporter-loss model. organism: Mus musculus tissue_or_cell_type: Maternal-fetal system experimental_model: Slc23a1 knockout mice and wild-type controls limitations: Animal rescue dose; not a human dosing recommendation or correction of the deleted transporter. exposure: Slc23a1-null dams; 330 mg/L drinking-water ascorbate during pregnancy cross_nutrient: false [corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
Complete structured claim and evidence
Slc23a1-null mice increased endogenous ascorbate synthesis despite losing as much as 70% of their body ascorbate stores in urine daily.
Mouse Slc23a1 gene → Ascorbate biosynthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Slc23a1 knockout mice and wild-type controls
exposure
Slc23a1 knockout
limitations
Compensation depends on intact murine biosynthesis; humans cannot be assumed to compensate this way.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
These mice could partly compensate for urinary loss by making more vitamin C.
primary_references
[corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
tissue_or_cell_type
Whole body/liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 195–206
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc23a1 knockout mice and wild-type controls · source_derived_draft · unverified_draft
### vc-transport-svct1-synthesis-compensation Slc23a1-null mice increased endogenous ascorbate synthesis despite losing as much as 70% of their body ascorbate stores in urine daily. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: These mice could partly compensate for urinary loss by making more vitamin C. organism: Mus musculus tissue_or_cell_type: Whole body/liver experimental_model: Slc23a1 knockout mice and wild-type controls limitations: Compensation depends on intact murine biosynthesis; humans cannot be assumed to compensate this way. exposure: Slc23a1 knockout cross_nutrient: false [corpe2010] Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. (2010). https://pubmed.ncbi.nlm.nih.gov/20200446/ DOI: 10.1172/jci39191
Complete structured claim and evidence
Embryonic fibroblasts from SVCT2-null mice retained less than 5% of normal ascorbic-acid uptake.
Mouse Slc23a2 gene → Cellular ascorbate uptake source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
SVCT2-null mouse embryos, newborns and embryonic fibroblasts
exposure
Homozygous SVCT2 gene deletion
limitations
Historical gene naming corrected to Slc23a2; abstract-limited assay details.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Without SVCT2, these embryonic cells took up very little reduced vitamin C.
primary_references
[sotiriou2002] Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. (2002). https://pubmed.ncbi.nlm.nih.gov/11984597/ DOI: 10.1038/0502-514
tissue_or_cell_type
Embryonic fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 208–219
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SVCT2-null mouse embryos, newborns and embryonic fibroblasts · source_derived_draft · unverified_draft
### vc-transport-svct2-fibroblast-loss Embryonic fibroblasts from SVCT2-null mice retained less than 5% of normal ascorbic-acid uptake. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Without SVCT2, these embryonic cells took up very little reduced vitamin C. organism: Mus musculus tissue_or_cell_type: Embryonic fibroblasts experimental_model: SVCT2-null mouse embryos, newborns and embryonic fibroblasts limitations: Historical gene naming corrected to Slc23a2; abstract-limited assay details. exposure: Homozygous SVCT2 gene deletion cross_nutrient: false [sotiriou2002] Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. (2002). https://pubmed.ncbi.nlm.nih.gov/11984597/ DOI: 10.1038/0502-514
Complete structured claim and evidence
SVCT2-null mice died within minutes of birth with respiratory failure and intraparenchymal brain hemorrhage.
Mouse Slc23a2 gene → Perinatal survival source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
SVCT2-null mouse embryos, newborns and embryonic fibroblasts
exposure
Homozygous SVCT2 gene deletion
limitations
Multiorgan model; hemorrhage was not simply established as generalized scurvy, and individual lethal pathways were not isolated.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Severe loss of cellular vitamin C transport was lethal around birth in mice.
primary_references
[sotiriou2002] Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. (2002). https://pubmed.ncbi.nlm.nih.gov/11984597/ DOI: 10.1038/0502-514
tissue_or_cell_type
Newborn brain and lung
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 221–232
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SVCT2-null mouse embryos, newborns and embryonic fibroblasts · source_derived_draft · unverified_draft
### vc-transport-svct2-neonatal-phenotype SVCT2-null mice died within minutes of birth with respiratory failure and intraparenchymal brain hemorrhage. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Severe loss of cellular vitamin C transport was lethal around birth in mice. organism: Mus musculus tissue_or_cell_type: Newborn brain and lung experimental_model: SVCT2-null mouse embryos, newborns and embryonic fibroblasts limitations: Multiorgan model; hemorrhage was not simply established as generalized scurvy, and individual lethal pathways were not isolated. exposure: Homozygous SVCT2 gene deletion cross_nutrient: false [sotiriou2002] Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. (2002). https://pubmed.ncbi.nlm.nih.gov/11984597/ DOI: 10.1038/0502-514
Complete structured claim and evidence
Maternal prenatal ascorbic-acid supplementation did not raise fetal blood ascorbate in SVCT2-null mouse fetuses.
L-Ascorbate → Fetal blood ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
SVCT2-null mouse embryos, newborns and embryonic fibroblasts
exposure
Prenatal maternal supplementation with SVCT2-null fetuses
limitations
Supports a placental transport role but is not a placenta-specific deletion; dose is not resolved in the accessible abstract.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Increasing maternal supply did not overcome the fetus’s missing SVCT2 machinery.
primary_references
[sotiriou2002] Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. (2002). https://pubmed.ncbi.nlm.nih.gov/11984597/ DOI: 10.1038/0502-514
tissue_or_cell_type
Placenta/fetal blood
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 234–245
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SVCT2-null mouse embryos, newborns and embryonic fibroblasts · source_derived_draft · unverified_draft
### vc-transport-svct2-prenatal-nonrescue Maternal prenatal ascorbic-acid supplementation did not raise fetal blood ascorbate in SVCT2-null mouse fetuses. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Increasing maternal supply did not overcome the fetus’s missing SVCT2 machinery. organism: Mus musculus tissue_or_cell_type: Placenta/fetal blood experimental_model: SVCT2-null mouse embryos, newborns and embryonic fibroblasts limitations: Supports a placental transport role but is not a placenta-specific deletion; dose is not resolved in the accessible abstract. exposure: Prenatal maternal supplementation with SVCT2-null fetuses cross_nutrient: false [sotiriou2002] Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. (2002). https://pubmed.ncbi.nlm.nih.gov/11984597/ DOI: 10.1038/0502-514
Complete structured claim and evidence
Mammalian GLUT1 expressed in Xenopus oocytes transported DHA with apparent Km 1.1 ± 0.2 mM; reduced ascorbate was not transported in the screen.
Mammalian GLUT1 orthologs → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression
exposure
Heterologous GLUT expression and DHA uptake
limitations
In vitro apparent kinetics; donor species unresolved, so retained as ortholog group rather than a human-specific claim.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Xenopus laevis host; mammalian clone donor not verified
plain_language
GLUT1 can carry oxidized vitamin C; it does not substitute directly for an ascorbate transporter.
primary_references
[rumsey1997] Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. (1997). https://pubmed.ncbi.nlm.nih.gov/9228080/ DOI: 10.1074/jbc.272.30.18982
tissue_or_cell_type
Oocyte membrane
transport_effect
raises DHA transport measured in expressing oocytes with an apparent Km of 1.1 mM.
transport_pool
the expressing cell DHA transport measured in expressing oocytes with an apparent Km of 1.1 mM.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 247–258
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression · source_derived_draft · unverified_draft
### vc-transport-glut1-dha Mammalian GLUT1 expressed in Xenopus oocytes transported DHA with apparent Km 1.1 ± 0.2 mM; reduced ascorbate was not transported in the screen. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: GLUT1 can carry oxidized vitamin C; it does not substitute directly for an ascorbate transporter. organism: Xenopus laevis host; mammalian clone donor not verified tissue_or_cell_type: Oocyte membrane experimental_model: Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression limitations: In vitro apparent kinetics; donor species unresolved, so retained as ortholog group rather than a human-specific claim. exposure: Heterologous GLUT expression and DHA uptake cross_nutrient: false [rumsey1997] Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. (1997). https://pubmed.ncbi.nlm.nih.gov/9228080/ DOI: 10.1074/jbc.272.30.18982
Complete structured claim and evidence
Mammalian GLUT3 expressed in Xenopus oocytes transported DHA with apparent Km 1.7 ± 0.3 mM; reduced ascorbate was not transported in the screen.
Mammalian GLUT3 orthologs → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression
exposure
Heterologous GLUT expression and DHA uptake
limitations
In vitro apparent kinetics; donor species unresolved, so retained as ortholog group rather than a human-specific claim.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Xenopus laevis host; mammalian clone donor not verified
plain_language
GLUT3 can carry oxidized vitamin C; it does not substitute directly for an ascorbate transporter.
primary_references
[rumsey1997] Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. (1997). https://pubmed.ncbi.nlm.nih.gov/9228080/ DOI: 10.1074/jbc.272.30.18982
tissue_or_cell_type
Oocyte membrane
transport_effect
raises DHA transport measured in expressing oocytes with an apparent Km of 1.7 mM.
transport_pool
the expressing cell DHA transport measured in expressing oocytes with an apparent Km of 1.7 mM.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 260–271
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression · source_derived_draft · unverified_draft
### vc-transport-glut3-dha Mammalian GLUT3 expressed in Xenopus oocytes transported DHA with apparent Km 1.7 ± 0.3 mM; reduced ascorbate was not transported in the screen. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: GLUT3 can carry oxidized vitamin C; it does not substitute directly for an ascorbate transporter. organism: Xenopus laevis host; mammalian clone donor not verified tissue_or_cell_type: Oocyte membrane experimental_model: Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression limitations: In vitro apparent kinetics; donor species unresolved, so retained as ortholog group rather than a human-specific claim. exposure: Heterologous GLUT expression and DHA uptake cross_nutrient: false [rumsey1997] Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. (1997). https://pubmed.ncbi.nlm.nih.gov/9228080/ DOI: 10.1074/jbc.272.30.18982
Complete structured claim and evidence
D-glucose inhibited GLUT1- and GLUT3-mediated DHA uptake in the oocyte expression system.
D-glucose → Cellular dehydroascorbic acid uptake source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression
exposure
D-glucose during heterologous-transporter DHA uptake
limitations
Not evidence that eating carbohydrate causes vitamin C deficiency; do not generalize across transporters, redox forms or tissue kinetics.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Xenopus laevis host; mammalian clones
plain_language
Glucose competed with oxidized vitamin C uptake in this laboratory transport model.
primary_references
[rumsey1997] Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. (1997). https://pubmed.ncbi.nlm.nih.gov/9228080/ DOI: 10.1074/jbc.272.30.18982
tissue_or_cell_type
Oocyte membrane
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 273–284
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression · source_derived_draft · unverified_draft
### vc-transport-glut-glucose-inhibition D-glucose inhibited GLUT1- and GLUT3-mediated DHA uptake in the oocyte expression system. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glucose competed with oxidized vitamin C uptake in this laboratory transport model. organism: Xenopus laevis host; mammalian clones tissue_or_cell_type: Oocyte membrane experimental_model: Mammalian GLUT cDNAs expressed in Xenopus laevis oocytes; CHO overexpression limitations: Not evidence that eating carbohydrate causes vitamin C deficiency; do not generalize across transporters, redox forms or tissue kinetics. exposure: D-glucose during heterologous-transporter DHA uptake cross_nutrient: true [rumsey1997] Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. (1997). https://pubmed.ncbi.nlm.nih.gov/9228080/ DOI: 10.1074/jbc.272.30.18982
Complete structured claim and evidence
Isolated rat adipocytes transported DHA and reduced the internalized vitamin completely to ascorbate; the study identified GLUT4-mediated DHA transport.
Rat glucose transporter 4 / Slc2a4 → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Isolated rat adipocytes and GLUT4-expressing Xenopus oocytes
exposure
Isolated adipocyte uptake assays
limitations
Intact adipocyte evidence complements heterologous GLUT4 experiments; not a clinical diabetes result.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
Rat fat cells can take up oxidized vitamin C through their insulin-sensitive glucose transport pathway.
primary_references
[rumsey2000] Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes. (2000). https://pubmed.ncbi.nlm.nih.gov/10862609/ DOI: 10.1074/jbc.m000988200
tissue_or_cell_type
Adipocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 286–297
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated rat adipocytes and GLUT4-expressing Xenopus oocytes · source_derived_draft · unverified_draft
### vc-transport-rat-adipocyte-glut4 Isolated rat adipocytes transported DHA and reduced the internalized vitamin completely to ascorbate; the study identified GLUT4-mediated DHA transport. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Rat fat cells can take up oxidized vitamin C through their insulin-sensitive glucose transport pathway. organism: Rattus norvegicus tissue_or_cell_type: Adipocytes experimental_model: Isolated rat adipocytes and GLUT4-expressing Xenopus oocytes limitations: Intact adipocyte evidence complements heterologous GLUT4 experiments; not a clinical diabetes result. exposure: Isolated adipocyte uptake assays cross_nutrient: false [rumsey2000] Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes. (2000). https://pubmed.ncbi.nlm.nih.gov/10862609/ DOI: 10.1074/jbc.m000988200
Complete structured claim and evidence
Preincubation of isolated rat adipocytes with 0.67 µM insulin increased DHA transport 6–8-fold; intracellular DHA reduction was complete both before and after insulin.
Insulin → Cellular dehydroascorbic acid uptake source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Isolated rat adipocytes and GLUT4-expressing Xenopus oocytes
exposure
0.67 µM insulin preincubation
limitations
Pharmacological cell exposure; no claim about human vitamin C requirements in diabetes.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
Insulin increased oxidized vitamin C entry into rat fat cells, rather than simply speeding its internal reduction.
primary_references
[rumsey2000] Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes. (2000). https://pubmed.ncbi.nlm.nih.gov/10862609/ DOI: 10.1074/jbc.m000988200
tissue_or_cell_type
Adipocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 299–310
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated rat adipocytes and GLUT4-expressing Xenopus oocytes · source_derived_draft · unverified_draft
### vc-transport-insulin-dha-uptake Preincubation of isolated rat adipocytes with 0.67 µM insulin increased DHA transport 6–8-fold; intracellular DHA reduction was complete both before and after insulin. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Insulin increased oxidized vitamin C entry into rat fat cells, rather than simply speeding its internal reduction. organism: Rattus norvegicus tissue_or_cell_type: Adipocytes experimental_model: Isolated rat adipocytes and GLUT4-expressing Xenopus oocytes limitations: Pharmacological cell exposure; no claim about human vitamin C requirements in diabetes. exposure: 0.67 µM insulin preincubation cross_nutrient: true [rumsey2000] Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes. (2000). https://pubmed.ncbi.nlm.nih.gov/10862609/ DOI: 10.1074/jbc.m000988200
Complete structured claim and evidence
Human erythrocytes rapidly took up supplied DHA and accumulated ascorbate to concentrations up to 2 mM in the ex vivo assay.
Dehydroascorbic acid → L-Ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Human volunteer erythrocytes ex vivo
exposure
Exogenous DHA concentration series
limitations
Assay loading capacity is not the normal circulating erythrocyte concentration.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Red cells can recover reduced vitamin C from its oxidized form.
primary_references
[may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x
tissue_or_cell_type
Erythrocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 312–323
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human volunteer erythrocytes ex vivo · source_derived_draft · unverified_draft
### vc-transport-rbc-dha-recycling Human erythrocytes rapidly took up supplied DHA and accumulated ascorbate to concentrations up to 2 mM in the ex vivo assay. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Red cells can recover reduced vitamin C from its oxidized form. organism: Homo sapiens tissue_or_cell_type: Erythrocytes experimental_model: Human volunteer erythrocytes ex vivo limitations: Assay loading capacity is not the normal circulating erythrocyte concentration. exposure: Exogenous DHA concentration series cross_nutrient: true [may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x
Complete structured claim and evidence
During DHA reduction by human erythrocytes, 5 mM D-glucose maintained GSH and NADH concentrations whereas NADPH still declined; without glucose all three fell.
D-glucose → Dehydroascorbic acid reduction to ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Human volunteer erythrocytes ex vivo
exposure
DHA challenge with or without 5 mM glucose
limitations
Metabolic support and transporter competition are different processes; this does not imply dietary sugar supplementation is needed.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Glucose metabolism helped sustain the reducing resources used to recycle vitamin C.
primary_references
[may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x
tissue_or_cell_type
Erythrocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 325–336
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human volunteer erythrocytes ex vivo · source_derived_draft · unverified_draft
### vc-transport-rbc-glucose-support During DHA reduction by human erythrocytes, 5 mM D-glucose maintained GSH and NADH concentrations whereas NADPH still declined; without glucose all three fell. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glucose metabolism helped sustain the reducing resources used to recycle vitamin C. organism: Homo sapiens tissue_or_cell_type: Erythrocytes experimental_model: Human volunteer erythrocytes ex vivo limitations: Metabolic support and transporter competition are different processes; this does not imply dietary sugar supplementation is needed. exposure: DHA challenge with or without 5 mM glucose cross_nutrient: true [may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x
Complete structured claim and evidence
Diethyl maleate depletion of erythrocyte GSH by 75–90% reduced the combined uptake and conversion of DHA to ascorbate in human cells.
Diethyl maleate → Dehydroascorbic acid reduction to ascorbate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
true
experimental_model
Human volunteer erythrocytes ex vivo
exposure
Up to 1 mM diethyl maleate ex vivo
limitations
Chemical depletion, not dietary deficiency; combined uptake/reduction readout does not isolate membrane transport.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Depleting glutathione impaired the red cells’ vitamin C recycling capacity.
primary_references
[may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x
tissue_or_cell_type
Erythrocytes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 338–349
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human volunteer erythrocytes ex vivo · source_derived_draft · unverified_draft
### vc-transport-rbc-gsh-depletion Diethyl maleate depletion of erythrocyte GSH by 75–90% reduced the combined uptake and conversion of DHA to ascorbate in human cells. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Depleting glutathione impaired the red cells’ vitamin C recycling capacity. organism: Homo sapiens tissue_or_cell_type: Erythrocytes experimental_model: Human volunteer erythrocytes ex vivo limitations: Chemical depletion, not dietary deficiency; combined uptake/reduction readout does not isolate membrane transport. exposure: Up to 1 mM diethyl maleate ex vivo cross_nutrient: true [may2001] Mechanisms of ascorbic acid recycling in human erythrocytes. (2001). https://pubmed.ncbi.nlm.nih.gov/11687303/ DOI: 10.1016/s0304-4165(01)00188-x
Complete structured claim and evidence
Purified human placental glutaredoxin catalyzed GSH-dependent reduction of DHA to ascorbate.
Human glutaredoxin 1 / GLRX → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Purified human placental glutaredoxin and bovine liver PDI; additional porcine/bovine glutaredoxins
exposure
Purified enzyme plus DHA and GSH
limitations
In vitro activity does not establish its share of total placental recycling.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Glutaredoxin can use glutathione to restore reduced vitamin C.
primary_references
[wells1990] Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity. (1990). https://pubmed.ncbi.nlm.nih.gov/2394726/ DOI: 10.1016/s0021-9258(18)55401-6
tissue_or_cell_type
Placental enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 351–362
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human placental glutaredoxin and bovine liver PDI; additional porcine/bovine glutaredoxins · source_derived_draft · unverified_draft
### vc-transport-human-glutaredoxin-dha Purified human placental glutaredoxin catalyzed GSH-dependent reduction of DHA to ascorbate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutaredoxin can use glutathione to restore reduced vitamin C. organism: Homo sapiens tissue_or_cell_type: Placental enzyme preparation experimental_model: Purified human placental glutaredoxin and bovine liver PDI; additional porcine/bovine glutaredoxins limitations: In vitro activity does not establish its share of total placental recycling. exposure: Purified enzyme plus DHA and GSH cross_nutrient: true [wells1990] Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity. (1990). https://pubmed.ncbi.nlm.nih.gov/2394726/ DOI: 10.1016/s0021-9258(18)55401-6
Complete structured claim and evidence
Purified bovine liver protein disulfide isomerase catalyzed DHA reduction with GSH; apparent DHA Km was 1.0 mM.
Bovine protein disulfide isomerase / P4HB → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Purified human placental glutaredoxin and bovine liver PDI; additional porcine/bovine glutaredoxins
exposure
Purified PDI, DHA and GSH
limitations
Do not infer intact human endoplasmic-reticulum flux from this enzyme-capacity result.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus
plain_language
A bovine protein-folding enzyme also recycled oxidized vitamin C in a purified assay.
primary_references
[wells1990] Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity. (1990). https://pubmed.ncbi.nlm.nih.gov/2394726/ DOI: 10.1016/s0021-9258(18)55401-6
tissue_or_cell_type
Liver enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 364–375
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human placental glutaredoxin and bovine liver PDI; additional porcine/bovine glutaredoxins · source_derived_draft · unverified_draft
### vc-transport-bovine-pdi-dha Purified bovine liver protein disulfide isomerase catalyzed DHA reduction with GSH; apparent DHA Km was 1.0 mM. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A bovine protein-folding enzyme also recycled oxidized vitamin C in a purified assay. organism: Bos taurus tissue_or_cell_type: Liver enzyme preparation experimental_model: Purified human placental glutaredoxin and bovine liver PDI; additional porcine/bovine glutaredoxins limitations: Do not infer intact human endoplasmic-reticulum flux from this enzyme-capacity result. exposure: Purified PDI, DHA and GSH cross_nutrient: true [wells1990] Mammalian thioltransferase (glutaredoxin) and protein disulfide isomerase have dehydroascorbate reductase activity. (1990). https://pubmed.ncbi.nlm.nih.gov/2394726/ DOI: 10.1016/s0021-9258(18)55401-6
Complete structured claim and evidence
Purified rat liver thioredoxin reductase reduced DHA using NADPH, with apparent DHA Km 2.5 mM and turnover 90 min−1.
Rat thioredoxin reductase 1 / Txnrd1 → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver
exposure
Purified enzyme plus NADPH and DHA
limitations
Biochemical capacity; not the same as cellular rate at low DHA concentration.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
Thioredoxin reductase provides another route for recovering reduced vitamin C.
primary_references
[may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607
tissue_or_cell_type
Purified liver enzyme
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 377–388
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver · source_derived_draft · unverified_draft
### vc-transport-txnrd-dha Purified rat liver thioredoxin reductase reduced DHA using NADPH, with apparent DHA Km 2.5 mM and turnover 90 min−1. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Thioredoxin reductase provides another route for recovering reduced vitamin C. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzyme experimental_model: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver limitations: Biochemical capacity; not the same as cellular rate at low DHA concentration. exposure: Purified enzyme plus NADPH and DHA cross_nutrient: true [may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607
Complete structured claim and evidence
Adding 2.8 µM rat liver thioredoxin lowered apparent DHA Km of the thioredoxin-reductase system from 2.5 to 0.7 mM without materially increasing turnover.
Rat thioredoxin 1 / Txn1 → Dehydroascorbic acid reduction to ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver
exposure
2.8 µM thioredoxin added to NADPH/thioredoxin-reductase assay
limitations
Apparent kinetic effect is not proof of a faster whole-body recycling rate.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
Thioredoxin improved the system’s apparent affinity for oxidized vitamin C in this assay.
primary_references
[may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607
tissue_or_cell_type
Purified liver enzymes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 390–401
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver · source_derived_draft · unverified_draft
### vc-transport-thioredoxin-dha-affinity Adding 2.8 µM rat liver thioredoxin lowered apparent DHA Km of the thioredoxin-reductase system from 2.5 to 0.7 mM without materially increasing turnover. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Thioredoxin improved the system’s apparent affinity for oxidized vitamin C in this assay. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzymes experimental_model: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver limitations: Apparent kinetic effect is not proof of a faster whole-body recycling rate. exposure: 2.8 µM thioredoxin added to NADPH/thioredoxin-reductase assay cross_nutrient: true [may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607
Complete structured claim and evidence
Selenium-deficient rats had 33% less liver ascorbate together with an 88% fall in thioredoxin-reductase activity; liver GSH content was unchanged.
Selenium → Liver ascorbate content source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
experimental_model
Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver
exposure
Dietary selenium deficiency
limitations
Several selenoenzymes were affected, including glutathione peroxidase; cannot attribute the entire ascorbate decrease solely to thioredoxin reductase.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
Selenium shortage reduced a vitamin C recycling pathway and liver vitamin C in rats.
primary_references
[may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607
tissue_or_cell_type
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 403–414
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver · source_derived_draft · unverified_draft
### vc-transport-selenium-liver-ascorbate Selenium-deficient rats had 33% less liver ascorbate together with an 88% fall in thioredoxin-reductase activity; liver GSH content was unchanged. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium shortage reduced a vitamin C recycling pathway and liver vitamin C in rats. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver limitations: Several selenoenzymes were affected, including glutathione peroxidase; cannot attribute the entire ascorbate decrease solely to thioredoxin reductase. exposure: Dietary selenium deficiency cross_nutrient: true [may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607
Complete structured claim and evidence
Purified rat liver thioredoxin reductase decreased ascorbyl radical measured by electron paramagnetic resonance while consuming NADPH; DHA controls could not explain the signal.
Rat thioredoxin reductase 1 / Txnrd1 → Ascorbyl radical source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats
exposure
Low-micromolar ascorbyl radical generated by ascorbate oxidase
limitations
Purified assay; radical and DHA reduction are distinct reactions.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
The reductase can also recycle the one-electron vitamin C radical.
primary_references
[may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039
tissue_or_cell_type
Purified liver enzyme
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 416–427
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats · source_derived_draft · unverified_draft
### vc-transport-txnrd-radical Purified rat liver thioredoxin reductase decreased ascorbyl radical measured by electron paramagnetic resonance while consuming NADPH; DHA controls could not explain the signal. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The reductase can also recycle the one-electron vitamin C radical. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzyme experimental_model: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats limitations: Purified assay; radical and DHA reduction are distinct reactions. exposure: Low-micromolar ascorbyl radical generated by ascorbate oxidase cross_nutrient: true [may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039
Complete structured claim and evidence
Dialyzed liver cytosol from selenium-deficient rats lost NADPH-dependent ascorbyl-radical reducing activity attributed to thioredoxin reductase.
Selenium → Ascorbyl radical reduction to ascorbate source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
experimental_model
Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats
exposure
Dietary selenium depletion; isolated dialyzed cytosol
limitations
Activity assignment also used inhibitor sensitivity; this is a fraction assay, not a direct human outcome.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction.
primary_references
[may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039
tissue_or_cell_type
Liver cytosol
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 429–440
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats · source_derived_draft · unverified_draft
### vc-transport-selenium-cytosolic-radical Dialyzed liver cytosol from selenium-deficient rats lost NADPH-dependent ascorbyl-radical reducing activity attributed to thioredoxin reductase. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction. organism: Rattus norvegicus tissue_or_cell_type: Liver cytosol experimental_model: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats limitations: Activity assignment also used inhibitor sensitivity; this is a fraction assay, not a direct human outcome. exposure: Dietary selenium depletion; isolated dialyzed cytosol cross_nutrient: true [may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039
Complete structured claim and evidence
Rat liver microsomes reduced ascorbyl radical using NADH, and this activity was insensitive to selenium depletion.
NADH → Ascorbyl radical reduction to ascorbate source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
experimental_model
Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats
exposure
Control and selenium-deficient rat liver microsome assays
limitations
Responsible microsomal enzyme was not established in the abstract; do not assign the activity to TXNRD1.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus
plain_language
A membrane-associated recycling route remained active despite selenium shortage.
primary_references
[may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039
tissue_or_cell_type
Liver microsomal fraction
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 442–453
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats · source_derived_draft · unverified_draft
### vc-transport-microsomal-radical Rat liver microsomes reduced ascorbyl radical using NADH, and this activity was insensitive to selenium depletion. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A membrane-associated recycling route remained active despite selenium shortage. organism: Rattus norvegicus tissue_or_cell_type: Liver microsomal fraction experimental_model: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats limitations: Responsible microsomal enzyme was not established in the abstract; do not assign the activity to TXNRD1. exposure: Control and selenium-deficient rat liver microsome assays cross_nutrient: true [may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039
Complete structured claim and evidence
Chronic prenatal and postnatal vitamin C restriction lowered brain total vitamin C in day-70 female guinea pigs.
Vitamin C → Brain total vitamin C content source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70
exposure
Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70
limitations
Non-scorbutic dietary model; total vitamin C includes reduced and oxidized forms.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Long-term low intake reduced the brain vitamin C pool.
primary_references
[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
tissue_or_cell_type
Brain
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 455–466
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft
### vc-transport-diet-brain-vitc Chronic prenatal and postnatal vitamin C restriction lowered brain total vitamin C in day-70 female guinea pigs. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long-term low intake reduced the brain vitamin C pool. organism: Cavia porcellus tissue_or_cell_type: Brain experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: Non-scorbutic dietary model; total vitamin C includes reduced and oxidized forms. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
Complete structured claim and evidence
Chronically vitamin-C-restricted guinea pigs had a higher brain DHA percentage despite lower total brain vitamin C.
Vitamin C → Brain dehydroascorbic acid fraction source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70
exposure
Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70
limitations
A higher oxidized fraction does not establish higher absolute DHA concentration.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
A larger fraction of the smaller brain vitamin C pool was oxidized.
primary_references
[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
tissue_or_cell_type
Brain
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 468–479
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft
### vc-transport-diet-brain-dha-fraction Chronically vitamin-C-restricted guinea pigs had a higher brain DHA percentage despite lower total brain vitamin C. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A larger fraction of the smaller brain vitamin C pool was oxidized. organism: Cavia porcellus tissue_or_cell_type: Brain experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: A higher oxidized fraction does not establish higher absolute DHA concentration. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
Complete structured claim and evidence
Dietary vitamin C restriction did not significantly alter SVCT2 mRNA or protein in guinea pig hippocampus, cerebellum or frontal cortex at day 70.
Vitamin C → Brain SVCT2 expression source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70
exposure
Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70
limitations
No detected expression difference is not proof of unchanged transport flux, earlier expression, or every cell subtype.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
The measured brain regions did not compensate by detectably increasing SVCT2 abundance.
primary_references
[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
tissue_or_cell_type
Hippocampus, cerebellum and frontal cortex
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 481–492
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft
### vc-transport-diet-brain-svct2 Dietary vitamin C restriction did not significantly alter SVCT2 mRNA or protein in guinea pig hippocampus, cerebellum or frontal cortex at day 70. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured brain regions did not compensate by detectably increasing SVCT2 abundance. organism: Cavia porcellus tissue_or_cell_type: Hippocampus, cerebellum and frontal cortex experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: No detected expression difference is not proof of unchanged transport flux, earlier expression, or every cell subtype. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
Complete structured claim and evidence
Chronically vitamin-C-restricted guinea pigs had higher brain malondialdehyde than vitamin-C-sufficient controls at day 70.
Vitamin C → Brain malondialdehyde content source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70
exposure
Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70
limitations
An oxidative marker does not measure every developmental or neurological outcome.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Low vitamin C increased a marker of brain lipid oxidation.
primary_references
[brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
tissue_or_cell_type
Brain
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 494–505
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 · source_derived_draft · unverified_draft
### vc-transport-diet-brain-mda Chronically vitamin-C-restricted guinea pigs had higher brain malondialdehyde than vitamin-C-sufficient controls at day 70. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low vitamin C increased a marker of brain lipid oxidation. organism: Cavia porcellus tissue_or_cell_type: Brain experimental_model: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70 limitations: An oxidative marker does not measure every developmental or neurological outcome. exposure: Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70 cross_nutrient: false [brain2014] Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression. (2014). https://pubmed.ncbi.nlm.nih.gov/24787032/ DOI: 10.3390/nu6051809
Complete structured claim and evidence
Stomatin transfection increased DHA uptake in human A431 cells while GLUT1 abundance was unchanged; GLUT1 knockdown reduced uptake.
Human stomatin / STOM → Cellular dehydroascorbic acid uptake source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Human erythroid progenitors, mature RBCs and A431 stomatin transfection
exposure
Stomatin transfection; 30- and 300-second uptake assays
limitations
Cancer cell line; preferential-transport interpretation is disputed by later erythrocyte kinetics.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Stomatin changed oxidized vitamin C uptake without simply adding more GLUT1 protein.
primary_references
[montelhagen2008] Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. (2008). https://pubmed.ncbi.nlm.nih.gov/18358815/ DOI: 10.1016/j.cell.2008.01.042
tissue_or_cell_type
A431 cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 507–518
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythroid progenitors, mature RBCs and A431 stomatin transfection · source_derived_draft · unverified_draft
### vc-transport-stomatin-dha Stomatin transfection increased DHA uptake in human A431 cells while GLUT1 abundance was unchanged; GLUT1 knockdown reduced uptake. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Stomatin changed oxidized vitamin C uptake without simply adding more GLUT1 protein. organism: Homo sapiens tissue_or_cell_type: A431 cells experimental_model: Human erythroid progenitors, mature RBCs and A431 stomatin transfection limitations: Cancer cell line; preferential-transport interpretation is disputed by later erythrocyte kinetics. exposure: Stomatin transfection; 30- and 300-second uptake assays cross_nutrient: false [montelhagen2008] Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. (2008). https://pubmed.ncbi.nlm.nih.gov/18358815/ DOI: 10.1016/j.cell.2008.01.042
Complete structured claim and evidence
Montel-Hagen et al. reported that 5 mM glucose did not inhibit DHA accumulation in mature human erythrocytes and interpreted this as preferential DHA transport.
D-glucose → Cellular dehydroascorbic acid uptake source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Human erythroid progenitors, mature RBCs and A431 stomatin transfection
exposure
5 mM glucose with radiolabeled DHA; room-temperature uptake time courses
limitations
Published interpretation challenged by kinetic analyses that distinguish transport, intracellular reduction and sugar loading.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
One study reported that glucose did not compete with oxidized vitamin C uptake in mature red cells.
primary_references
[montelhagen2008] Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. (2008). https://pubmed.ncbi.nlm.nih.gov/18358815/ DOI: 10.1016/j.cell.2008.01.042
tissue_or_cell_type
Mature erythrocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 520–531
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythroid progenitors, mature RBCs and A431 stomatin transfection · source_derived_draft · unverified_draft
### vc-transport-rbc-glucose-noncompetition Montel-Hagen et al. reported that 5 mM glucose did not inhibit DHA accumulation in mature human erythrocytes and interpreted this as preferential DHA transport. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: One study reported that glucose did not compete with oxidized vitamin C uptake in mature red cells. organism: Homo sapiens tissue_or_cell_type: Mature erythrocytes experimental_model: Human erythroid progenitors, mature RBCs and A431 stomatin transfection limitations: Published interpretation challenged by kinetic analyses that distinguish transport, intracellular reduction and sugar loading. exposure: 5 mM glucose with radiolabeled DHA; room-temperature uptake time courses cross_nutrient: true [montelhagen2008] Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. (2008). https://pubmed.ncbi.nlm.nih.gov/18358815/ DOI: 10.1016/j.cell.2008.01.042
Complete structured claim and evidence
Human erythrocyte and inside-out-vesicle kinetic assays showed DHA and 3-O-methylglucose competing at both membrane faces, consistent with transport through the same GLUT1 complex.
3-O-Methyl-D-glucose → Dehydroascorbic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
experimental_model
Human erythrocytes, ghosts and inside-out membrane vesicles
exposure
Initial-rate substrate competition and trans-acceleration assays
limitations
3-O-methylglucose is a transport probe, not dietary glucose. This challenges segregated transport pools without denying vitamin C recycling.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
A later kinetic study found that sugar and oxidized vitamin C share the red-cell GLUT1 transport pathway.
primary_references
[sage2014] Human erythrocytes transport dehydroascorbic acid and sugars using the same transporter complex. (2014). https://pubmed.ncbi.nlm.nih.gov/24598365/ DOI: 10.1152/ajpcell.00044.2014
tissue_or_cell_type
Erythrocyte plasma membrane and inside-out vesicles
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 533–544
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocytes, ghosts and inside-out membrane vesicles · source_derived_draft · unverified_draft
### vc-transport-rbc-sugar-competition Human erythrocyte and inside-out-vesicle kinetic assays showed DHA and 3-O-methylglucose competing at both membrane faces, consistent with transport through the same GLUT1 complex. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A later kinetic study found that sugar and oxidized vitamin C share the red-cell GLUT1 transport pathway. organism: Homo sapiens tissue_or_cell_type: Erythrocyte plasma membrane and inside-out vesicles experimental_model: Human erythrocytes, ghosts and inside-out membrane vesicles limitations: 3-O-methylglucose is a transport probe, not dietary glucose. This challenges segregated transport pools without denying vitamin C recycling. exposure: Initial-rate substrate competition and trans-acceleration assays cross_nutrient: true [sage2014] Human erythrocytes transport dehydroascorbic acid and sugars using the same transporter complex. (2014). https://pubmed.ncbi.nlm.nih.gov/24598365/ DOI: 10.1152/ajpcell.00044.2014
Complete structured claim and evidence
Four weeks of two SunGold kiwifruit daily increased neutrophil vitamin C content in young men initially selected for plasma vitamin C below 50 µmol/L (p=0.016).
Dietary SunGold kiwifruit intervention → Neutrophil ascorbate content source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Young men with suboptimal plasma vitamin C; before/after kiwifruit intervention and isolated neutrophils
exposure
Two SunGold kiwifruit/day for four weeks; 14 men aged 18–30 enrolled
limitations
Before/after whole-food study; cannot isolate vitamin C from other constituents or equate plasma selection with cellular deficiency.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The food intervention increased vitamin C inside participants’ neutrophils.
primary_references
[bozonet2015] Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. (2015). https://pubmed.ncbi.nlm.nih.gov/25912037/ DOI: 10.3390/nu7042574
tissue_or_cell_type
Circulating neutrophils
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 546–557
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young men with suboptimal plasma vitamin C; before/after kiwifruit intervention and isolated neutrophils · source_derived_draft · unverified_draft
### vc-transport-kiwifruit-neutrophil-availability Four weeks of two SunGold kiwifruit daily increased neutrophil vitamin C content in young men initially selected for plasma vitamin C below 50 µmol/L (p=0.016). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The food intervention increased vitamin C inside participants’ neutrophils. organism: Homo sapiens tissue_or_cell_type: Circulating neutrophils experimental_model: Young men with suboptimal plasma vitamin C; before/after kiwifruit intervention and isolated neutrophils limitations: Before/after whole-food study; cannot isolate vitamin C from other constituents or equate plasma selection with cellular deficiency. exposure: Two SunGold kiwifruit/day for four weeks; 14 men aged 18–30 enrolled cross_nutrient: false [bozonet2015] Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. (2015). https://pubmed.ncbi.nlm.nih.gov/25912037/ DOI: 10.3390/nu7042574
Complete structured claim and evidence
Following the four-week kiwifruit intervention, stimulated neutrophil chemotaxis increased about 20% in paired ex vivo assays (n=12, p=0.041); unstimulated migration did not change.
Dietary SunGold kiwifruit intervention → Neutrophil chemotaxis source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Young men with suboptimal plasma vitamin C; before/after kiwifruit intervention and isolated neutrophils
exposure
Two SunGold kiwifruit/day for four weeks in men with initially suboptimal plasma vitamin C
limitations
Uncontrolled whole-food intervention; assay improvement does not establish fewer infections or a vitamin C-specific causal mechanism.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Participants’ isolated neutrophils moved more effectively toward the laboratory stimulus after the intervention.
primary_references
[bozonet2015] Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. (2015). https://pubmed.ncbi.nlm.nih.gov/25912037/ DOI: 10.3390/nu7042574
tissue_or_cell_type
Isolated peripheral-blood neutrophils
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 559–570
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young men with suboptimal plasma vitamin C; before/after kiwifruit intervention and isolated neutrophils · source_derived_draft · unverified_draft
### vc-transport-kiwifruit-neutrophil-chemotaxis Following the four-week kiwifruit intervention, stimulated neutrophil chemotaxis increased about 20% in paired ex vivo assays (n=12, p=0.041); unstimulated migration did not change. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Participants’ isolated neutrophils moved more effectively toward the laboratory stimulus after the intervention. organism: Homo sapiens tissue_or_cell_type: Isolated peripheral-blood neutrophils experimental_model: Young men with suboptimal plasma vitamin C; before/after kiwifruit intervention and isolated neutrophils limitations: Uncontrolled whole-food intervention; assay improvement does not establish fewer infections or a vitamin C-specific causal mechanism. exposure: Two SunGold kiwifruit/day for four weeks in men with initially suboptimal plasma vitamin C cross_nutrient: false [bozonet2015] Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. (2015). https://pubmed.ncbi.nlm.nih.gov/25912037/ DOI: 10.3390/nu7042574
Complete structured claim and evidence
Purified chick collagen prolyl hydroxylase completed approximately 15–30 rapid catalytic cycles in 5–10 seconds without added ascorbate before activity declined.
Chick collagen prolyl 4-hydroxylase preparation → Collagen-bound proline residues source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick-embryo collagen prolyl hydroxylase kinetics
exposure
Ascorbate omitted or added in purified-enzyme assays; initial 5–10 seconds versus approximately 1 minute.
limitations
Purified assay with cofactor omission; does not quantify a dietary requirement or establish an identical turnover number in human cells.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
The collagen enzyme can start working without vitamin C, but sustained work needs vitamin C support.
primary_references
[myllyla1978] The role of ascorbate in the prolyl hydroxylase reaction. (1978). https://pubmed.ncbi.nlm.nih.gov/212056/ DOI: 10.1016/0006-291x(78)91010-0
tissue_or_cell_type
Chick embryo enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 572–583
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick-embryo collagen prolyl hydroxylase kinetics · source_derived_draft · unverified_draft
### vc-enzyme-initial-p4h-turnover Purified chick collagen prolyl hydroxylase completed approximately 15–30 rapid catalytic cycles in 5–10 seconds without added ascorbate before activity declined. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The collagen enzyme can start working without vitamin C, but sustained work needs vitamin C support. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparation experimental_model: Purified chick-embryo collagen prolyl hydroxylase kinetics limitations: Purified assay with cofactor omission; does not quantify a dietary requirement or establish an identical turnover number in human cells. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Ascorbate omitted or added in purified-enzyme assays; initial 5–10 seconds versus approximately 1 minute. [myllyla1978] The role of ascorbate in the prolyl hydroxylase reaction. (1978). https://pubmed.ncbi.nlm.nih.gov/212056/ DOI: 10.1016/0006-291x(78)91010-0
Complete structured claim and evidence
In chick collagen hydroxylase assays, complete proline hydroxylation was coupled to 2-oxoglutarate decarboxylation while ascorbate was not consumed in most catalytic cycles.
Chick collagen prolyl 4-hydroxylase preparation → 2-Oxoglutarate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick prolyl and partially purified lysyl collagen hydroxylases
exposure
Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays.
limitations
This statement concerns coupled turnover; it must not be transferred to copper monooxygenases.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Vitamin C is not a one-for-one consumed ingredient in every successful collagen hydroxylation.
primary_references
[myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
tissue_or_cell_type
Chick embryo enzyme preparations
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 585–596
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick prolyl and partially purified lysyl collagen hydroxylases · source_derived_draft · unverified_draft
### vc-enzyme-coupled-ascorbate-use In chick collagen hydroxylase assays, complete proline hydroxylation was coupled to 2-oxoglutarate decarboxylation while ascorbate was not consumed in most catalytic cycles. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C is not a one-for-one consumed ingredient in every successful collagen hydroxylation. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparations experimental_model: Purified chick prolyl and partially purified lysyl collagen hydroxylases limitations: This statement concerns coupled turnover; it must not be transferred to copper monooxygenases. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays. [myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
Complete structured claim and evidence
Chick collagen prolyl hydroxylase consumed ascorbate stoichiometrically during uncoupled 2-oxoglutarate decarboxylation in the absence of peptide substrate.
Chick collagen prolyl 4-hydroxylase preparation → L-Ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick prolyl and partially purified lysyl collagen hydroxylases
exposure
Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays.
limitations
Substrate-free enzyme reaction; frequency and quantitative vitamin C cost of uncoupled cycles in human tissues were not measured.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Vitamin C is consumed when this collagen enzyme runs a reaction cycle without hydroxylating its peptide target.
primary_references
[myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
tissue_or_cell_type
Chick embryo enzyme preparations
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 598–609
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick prolyl and partially purified lysyl collagen hydroxylases · source_derived_draft · unverified_draft
### vc-enzyme-prolyl-uncoupled-consumption Chick collagen prolyl hydroxylase consumed ascorbate stoichiometrically during uncoupled 2-oxoglutarate decarboxylation in the absence of peptide substrate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C is consumed when this collagen enzyme runs a reaction cycle without hydroxylating its peptide target. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparations experimental_model: Purified chick prolyl and partially purified lysyl collagen hydroxylases limitations: Substrate-free enzyme reaction; frequency and quantitative vitamin C cost of uncoupled cycles in human tissues were not measured. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays. [myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
Complete structured claim and evidence
Chick collagen lysyl hydroxylase consumed ascorbate stoichiometrically during uncoupled 2-oxoglutarate decarboxylation in the absence of peptide substrate.
Chick collagen lysyl hydroxylase preparation → L-Ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick prolyl and partially purified lysyl collagen hydroxylases
exposure
Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays.
limitations
Substrate-free enzyme reaction; frequency and quantitative vitamin C cost of uncoupled cycles in human tissues were not measured.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Vitamin C is consumed when this collagen enzyme runs a reaction cycle without hydroxylating its peptide target.
primary_references
[myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
tissue_or_cell_type
Chick embryo enzyme preparations
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 611–622
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick prolyl and partially purified lysyl collagen hydroxylases · source_derived_draft · unverified_draft
### vc-enzyme-lysyl-uncoupled-consumption Chick collagen lysyl hydroxylase consumed ascorbate stoichiometrically during uncoupled 2-oxoglutarate decarboxylation in the absence of peptide substrate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C is consumed when this collagen enzyme runs a reaction cycle without hydroxylating its peptide target. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparations experimental_model: Purified chick prolyl and partially purified lysyl collagen hydroxylases limitations: Substrate-free enzyme reaction; frequency and quantitative vitamin C cost of uncoupled cycles in human tissues were not measured. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Peptide substrate present or absent; uncoupled 2-oxoglutarate decarboxylation assays. [myllyla1984] Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. (1984). https://pubmed.ncbi.nlm.nih.gov/6325436/ DOI: 10.1016/s0021-9258(18)91023-9
Complete structured claim and evidence
After 2-oxoglutarate-associated inactivation of chick prolyl hydroxylase, ascorbate decreased its ferric EPR signal and partly restored activity, supporting reduction of enzyme-bound Fe(III).
L-Ascorbate → Chick collagen prolyl 4-hydroxylase with oxidized enzyme-bound iron source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick collagen prolyl hydroxylase, EPR and activity measurements
exposure
400 micromolar 2-oxoglutarate; enzyme inactivation within 1 minute without ascorbate; 30-second EPR incubation at 37 C.
limitations
Protein-bound redox chemistry; no claim that serum iron or dietary iron supplementation predicts this state.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Vitamin C can restore the iron inside an inactive collagen enzyme to a working redox state.
primary_references
[dejong1982] Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. (1982). https://pubmed.ncbi.nlm.nih.gov/6285984/ DOI: 10.1016/0167-4838(82)90162-5
tissue_or_cell_type
Chick embryo enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 624–635
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick collagen prolyl hydroxylase, EPR and activity measurements · source_derived_draft · unverified_draft
### vc-enzyme-bound-iron-reactivation After 2-oxoglutarate-associated inactivation of chick prolyl hydroxylase, ascorbate decreased its ferric EPR signal and partly restored activity, supporting reduction of enzyme-bound Fe(III). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C can restore the iron inside an inactive collagen enzyme to a working redox state. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparation experimental_model: Purified chick collagen prolyl hydroxylase, EPR and activity measurements limitations: Protein-bound redox chemistry; no claim that serum iron or dietary iron supplementation predicts this state. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: 400 micromolar 2-oxoglutarate; enzyme inactivation within 1 minute without ascorbate; 30-second EPR incubation at 37 C. [dejong1982] Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. (1982). https://pubmed.ncbi.nlm.nih.gov/6285984/ DOI: 10.1016/0167-4838(82)90162-5
Complete structured claim and evidence
With 2-oxoglutarate present, added Fe(II) did not partly reactivate the inactivated chick prolyl hydroxylase as ascorbate did; reduction by Fe(II) was possible in the absence of 2-oxoglutarate.
Ferrous iron → Chick collagen prolyl 4-hydroxylase with oxidized enzyme-bound iron source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified chick collagen prolyl hydroxylase, EPR and activity measurements
exposure
400 micromolar 2-oxoglutarate; enzyme inactivation within 1 minute without ascorbate; 30-second EPR incubation at 37 C.
limitations
Context depends on 2-oxoglutarate; this is not a clinical comparison of iron and vitamin C supplements.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Gallus gallus
plain_language
Adding free iron did not substitute for vitamin C under the tested enzyme conditions.
primary_references
[dejong1982] Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. (1982). https://pubmed.ncbi.nlm.nih.gov/6285984/ DOI: 10.1016/0167-4838(82)90162-5
tissue_or_cell_type
Chick embryo enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 637–648
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick collagen prolyl hydroxylase, EPR and activity measurements · source_derived_draft · unverified_draft
### vc-enzyme-free-iron-not-replacement With 2-oxoglutarate present, added Fe(II) did not partly reactivate the inactivated chick prolyl hydroxylase as ascorbate did; reduction by Fe(II) was possible in the absence of 2-oxoglutarate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding free iron did not substitute for vitamin C under the tested enzyme conditions. organism: Gallus gallus tissue_or_cell_type: Chick embryo enzyme preparation experimental_model: Purified chick collagen prolyl hydroxylase, EPR and activity measurements limitations: Context depends on 2-oxoglutarate; this is not a clinical comparison of iron and vitamin C supplements. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: 400 micromolar 2-oxoglutarate; enzyme inactivation within 1 minute without ascorbate; 30-second EPR incubation at 37 C. [dejong1982] Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation. (1982). https://pubmed.ncbi.nlm.nih.gov/6285984/ DOI: 10.1016/0167-4838(82)90162-5
Complete structured claim and evidence
Prolonged ascorbate exposure increased collagenous protein synthesis about eightfold in cultured human skin fibroblasts without a significant change in noncollagen protein synthesis.
L-Ascorbate → Collagen protein synthesis source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Cultured human skin fibroblasts
exposure
Prolonged ascorbate exposure versus no added ascorbate; exact culture concentration not verified in accessible abstract.
limitations
Culture exposure does not establish oral-dose efficacy, tissue-strength gain or an eightfold response in people; precise concentration/duration not extracted.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
In this cell system vitamin C increased collagen production as well as supporting hydroxylation chemistry.
primary_references
[collagen1981] Regulation of collagen synthesis by ascorbic acid. (1981). https://pubmed.ncbi.nlm.nih.gov/6265920/ DOI: 10.1073/pnas.78.5.2879
tissue_or_cell_type
Skin fibroblasts
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 650–661
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human skin fibroblasts · source_derived_draft · unverified_draft
### vc-enzyme-fibroblast-collagen-synthesis Prolonged ascorbate exposure increased collagenous protein synthesis about eightfold in cultured human skin fibroblasts without a significant change in noncollagen protein synthesis. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this cell system vitamin C increased collagen production as well as supporting hydroxylation chemistry. organism: Homo sapiens tissue_or_cell_type: Skin fibroblasts experimental_model: Cultured human skin fibroblasts limitations: Culture exposure does not establish oral-dose efficacy, tissue-strength gain or an eightfold response in people; precise concentration/duration not extracted. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Prolonged ascorbate exposure versus no added ascorbate; exact culture concentration not verified in accessible abstract. [collagen1981] Regulation of collagen synthesis by ascorbic acid. (1981). https://pubmed.ncbi.nlm.nih.gov/6265920/ DOI: 10.1073/pnas.78.5.2879
Complete structured claim and evidence
Human skin fibroblast lysyl hydroxylase activity increased approximately threefold after the study ascorbate treatment.
L-Ascorbate → Human fibroblast lysyl hydroxylase activity source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Cultured human skin fibroblasts
exposure
Prolonged ascorbate exposure versus no added ascorbate; exact culture concentration not verified in accessible abstract.
limitations
Activity assay does not resolve human PLOD isoforms or distinguish all possible expression/stability effects.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Vitamin C also changed the amount of lysyl hydroxylase activity measured in these cells.
primary_references
[collagen1981] Regulation of collagen synthesis by ascorbic acid. (1981). https://pubmed.ncbi.nlm.nih.gov/6265920/ DOI: 10.1073/pnas.78.5.2879
tissue_or_cell_type
Skin fibroblasts
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 663–674
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human skin fibroblasts · source_derived_draft · unverified_draft
### vc-enzyme-fibroblast-lysyl-activity Human skin fibroblast lysyl hydroxylase activity increased approximately threefold after the study ascorbate treatment. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C also changed the amount of lysyl hydroxylase activity measured in these cells. organism: Homo sapiens tissue_or_cell_type: Skin fibroblasts experimental_model: Cultured human skin fibroblasts limitations: Activity assay does not resolve human PLOD isoforms or distinguish all possible expression/stability effects. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Prolonged ascorbate exposure versus no added ascorbate; exact culture concentration not verified in accessible abstract. [collagen1981] Regulation of collagen synthesis by ascorbic acid. (1981). https://pubmed.ncbi.nlm.nih.gov/6265920/ DOI: 10.1073/pnas.78.5.2879
Complete structured claim and evidence
In the same human fibroblast culture study, measured collagen prolyl hydroxylase activity decreased after ascorbate treatment even while collagen synthesis increased.
L-Ascorbate → Human fibroblast collagen prolyl hydroxylase activity source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Cultured human skin fibroblasts
exposure
Prolonged ascorbate exposure versus no added ascorbate; exact culture concentration not verified in accessible abstract.
limitations
A cell-adaptation/activity measurement; not evidence that ascorbate directly inhibits the purified enzyme.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
More collagen production did not mean that every hydroxylase activity assay increased.
primary_references
[collagen1981] Regulation of collagen synthesis by ascorbic acid. (1981). https://pubmed.ncbi.nlm.nih.gov/6265920/ DOI: 10.1073/pnas.78.5.2879
tissue_or_cell_type
Skin fibroblasts
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 676–687
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human skin fibroblasts · source_derived_draft · unverified_draft
### vc-enzyme-fibroblast-prolyl-activity In the same human fibroblast culture study, measured collagen prolyl hydroxylase activity decreased after ascorbate treatment even while collagen synthesis increased. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: More collagen production did not mean that every hydroxylase activity assay increased. organism: Homo sapiens tissue_or_cell_type: Skin fibroblasts experimental_model: Cultured human skin fibroblasts limitations: A cell-adaptation/activity measurement; not evidence that ascorbate directly inhibits the purified enzyme. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Prolonged ascorbate exposure versus no added ascorbate; exact culture concentration not verified in accessible abstract. [collagen1981] Regulation of collagen synthesis by ascorbic acid. (1981). https://pubmed.ncbi.nlm.nih.gov/6265920/ DOI: 10.1073/pnas.78.5.2879
Complete structured claim and evidence
Omission controls with recombinant human MBP-TMLH-a showed that ascorbate, Fe(II) and 2-oxoglutarate were each needed for efficient conversion of free trimethyllysine to 3-hydroxytrimethyllysine.
L-Ascorbate → Trimethyllysine hydroxylase / TMLHE source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C + iron support hydroxylation of a modified lysine precursor; downstream existing SHMT steps use B6-derived PLP and ALDH9A1 uses NAD+.
experimental_model
Recombinant human MBP-TMLH-a; mass spectrometry and NMR
exposure
500 micromolar trimethyllysine and 3 micromolar enzyme, FeSO4/2OG/ascorbate, 37 C for 30 minutes; cofactor omission controls.
limitations
New record isolates the ascorbate cofactor dependence; the existing substrate-to-product UUID is reused. Fusion-protein assay does not quantify whole-body flux.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The first carnitine-synthesis hydroxylation needs vitamin C support alongside iron and 2-oxoglutarate.
primary_references
[tmlh2016] Substrate scope for trimethyllysine hydroxylase catalysis. (2016). https://pubmed.ncbi.nlm.nih.gov/27730239/ DOI: 10.1039/c6cc07845a
tissue_or_cell_type
Cell-free recombinant enzyme
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 689–700
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MBP-TMLH-a; mass spectrometry and NMR · source_derived_draft · unverified_draft
### vc-enzyme-tmlh-ascorbate-dependency Omission controls with recombinant human MBP-TMLH-a showed that ascorbate, Fe(II) and 2-oxoglutarate were each needed for efficient conversion of free trimethyllysine to 3-hydroxytrimethyllysine. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The first carnitine-synthesis hydroxylation needs vitamin C support alongside iron and 2-oxoglutarate. organism: Homo sapiens tissue_or_cell_type: Cell-free recombinant enzyme experimental_model: Recombinant human MBP-TMLH-a; mass spectrometry and NMR limitations: New record isolates the ascorbate cofactor dependence; the existing substrate-to-product UUID is reused. Fusion-protein assay does not quantify whole-body flux. cross_nutrient: Vitamin C + iron support hydroxylation of a modified lysine precursor; downstream existing SHMT steps use B6-derived PLP and ALDH9A1 uses NAD+. exposure: 500 micromolar trimethyllysine and 3 micromolar enzyme, FeSO4/2OG/ascorbate, 37 C for 30 minutes; cofactor omission controls. [tmlh2016] Substrate scope for trimethyllysine hydroxylase catalysis. (2016). https://pubmed.ncbi.nlm.nih.gov/27730239/ DOI: 10.1039/c6cc07845a
Complete structured claim and evidence
Increasing ascorbate supplementation increased carnitine accumulation from gamma-butyrobetaine in primary guinea-pig hepatocytes after four hours.
L-Ascorbate → Guinea-pig hepatocyte carnitine content source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Primary cultured male guinea-pig hepatocyte monolayers
exposure
Ascorbate preloading followed by 4-hour gamma-butyrobetaine incubation; precursor range includes 0.05–1.0 mM and 5 mM.
limitations
Species-specific cell exposure; accumulation reflects production and other handling, not directly a human dietary dose-response.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Vitamin C helped isolated liver cells convert a supplied precursor into carnitine.
primary_references
[hepatocytes1991] The regulatory effect of ascorbate on the carnitine synthesis in primary cultured guinea pig hepatocytes. (1991). https://pubmed.ncbi.nlm.nih.gov/1765841/ DOI: 10.3177/jnsv.37.371
tissue_or_cell_type
Hepatocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 702–713
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary cultured male guinea-pig hepatocyte monolayers · source_derived_draft · unverified_draft
### vc-enzyme-hepatocyte-carnitine Increasing ascorbate supplementation increased carnitine accumulation from gamma-butyrobetaine in primary guinea-pig hepatocytes after four hours. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helped isolated liver cells convert a supplied precursor into carnitine. organism: Cavia porcellus tissue_or_cell_type: Hepatocytes experimental_model: Primary cultured male guinea-pig hepatocyte monolayers limitations: Species-specific cell exposure; accumulation reflects production and other handling, not directly a human dietary dose-response. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Ascorbate preloading followed by 4-hour gamma-butyrobetaine incubation; precursor range includes 0.05–1.0 mM and 5 mM. [hepatocytes1991] The regulatory effect of ascorbate on the carnitine synthesis in primary cultured guinea pig hepatocytes. (1991). https://pubmed.ncbi.nlm.nih.gov/1765841/ DOI: 10.3177/jnsv.37.371
Complete structured claim and evidence
Gamma-butyrobetaine supplementation lowered both reduced and total cellular vitamin C content during the guinea-pig hepatocyte carnitine-synthesis experiment.
gamma-Butyrobetaine → Guinea-pig hepatocyte ascorbate content source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Primary cultured male guinea-pig hepatocyte monolayers
exposure
Ascorbate preloading followed by 4-hour gamma-butyrobetaine incubation; precursor range includes 0.05–1.0 mM and 5 mM.
limitations
Pool decrease alone does not establish exact ascorbate stoichiometry or identify all oxidation, export and degradation pathways.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Supplying the carnitine precursor lowered the cells’ measured vitamin C pools.
primary_references
[hepatocytes1991] The regulatory effect of ascorbate on the carnitine synthesis in primary cultured guinea pig hepatocytes. (1991). https://pubmed.ncbi.nlm.nih.gov/1765841/ DOI: 10.3177/jnsv.37.371
tissue_or_cell_type
Hepatocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 715–726
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary cultured male guinea-pig hepatocyte monolayers · source_derived_draft · unverified_draft
### vc-enzyme-precursor-lowers-cell-ascorbate Gamma-butyrobetaine supplementation lowered both reduced and total cellular vitamin C content during the guinea-pig hepatocyte carnitine-synthesis experiment. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supplying the carnitine precursor lowered the cells’ measured vitamin C pools. organism: Cavia porcellus tissue_or_cell_type: Hepatocytes experimental_model: Primary cultured male guinea-pig hepatocyte monolayers limitations: Pool decrease alone does not establish exact ascorbate stoichiometry or identify all oxidation, export and degradation pathways. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Ascorbate preloading followed by 4-hour gamma-butyrobetaine incubation; precursor range includes 0.05–1.0 mM and 5 mM. [hepatocytes1991] The regulatory effect of ascorbate on the carnitine synthesis in primary cultured guinea pig hepatocytes. (1991). https://pubmed.ncbi.nlm.nih.gov/1765841/ DOI: 10.3177/jnsv.37.371
Complete structured claim and evidence
Guinea pigs with tissue vitamin C around 12% saturation had significantly lower muscle carnitine than animals near 100% saturation, without the customary overt hypovitaminosis-C signs in this experiment.
Vitamin C → Guinea-pig muscle carnitine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Guinea pigs with graded dietary vitamin C supply
exposure
Dietary regimens produced tissue vitamin C approximately 12% versus 100% saturation; regimen duration/dose not verified in abstract.
limitations
No direct synthesis-rate measurement; suggested explanation for human fatigue was not tested.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Low vitamin C coincided with lower muscle carnitine before obvious scurvy signs in these animals.
primary_references
[carnitine1980] Dietary ascorbic acid and muscle carnitine (beta-OH-gamma-(trimethylamino) butyric acid) in guinea-pigs. (1980). https://pubmed.ncbi.nlm.nih.gov/7378344/ DOI: 10.1079/bjn19800102
tissue_or_cell_type
Skeletal muscle
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 728–739
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea pigs with graded dietary vitamin C supply · source_derived_draft · unverified_draft
### vc-enzyme-low-c-muscle-carnitine Guinea pigs with tissue vitamin C around 12% saturation had significantly lower muscle carnitine than animals near 100% saturation, without the customary overt hypovitaminosis-C signs in this experiment. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low vitamin C coincided with lower muscle carnitine before obvious scurvy signs in these animals. organism: Cavia porcellus tissue_or_cell_type: Skeletal muscle experimental_model: Guinea pigs with graded dietary vitamin C supply limitations: No direct synthesis-rate measurement; suggested explanation for human fatigue was not tested. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Dietary regimens produced tissue vitamin C approximately 12% versus 100% saturation; regimen duration/dose not verified in abstract. [carnitine1980] Dietary ascorbic acid and muscle carnitine (beta-OH-gamma-(trimethylamino) butyric acid) in guinea-pigs. (1980). https://pubmed.ncbi.nlm.nih.gov/7378344/ DOI: 10.1079/bjn19800102
Complete structured claim and evidence
Hepatic carnitine was 148 +/- 9.8 nmol/g in vitamin-C-deficient guinea pigs versus 249 +/- 16.1 in controls; pair-fed animals measured 181 +/- 14.1 nmol/g (means +/- SEM).
Vitamin C → Guinea-pig liver carnitine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Guinea-pig vitamin C deficiency and pair-fed comparison
exposure
Vitamin C deficient, control and underfed pair-fed groups; duration not verified in abstract.
limitations
Do not infer that every between-group comparison was statistically significant from these means; biosynthesis was not directly measured.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Both vitamin C shortage and reduced food intake affected liver carnitine in this experiment.
primary_references
[carnitine1983] Combined effect of ascorbic acid deficiency and underfeeding on the hepatic carnitine level in guinea-pigs. (1983). https://pubmed.ncbi.nlm.nih.gov/6852178/ DOI: 10.1007/bf01965181
tissue_or_cell_type
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 741–752
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig vitamin C deficiency and pair-fed comparison · source_derived_draft · unverified_draft
### vc-enzyme-deficient-liver-carnitine Hepatic carnitine was 148 +/- 9.8 nmol/g in vitamin-C-deficient guinea pigs versus 249 +/- 16.1 in controls; pair-fed animals measured 181 +/- 14.1 nmol/g (means +/- SEM). Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both vitamin C shortage and reduced food intake affected liver carnitine in this experiment. organism: Cavia porcellus tissue_or_cell_type: Liver experimental_model: Guinea-pig vitamin C deficiency and pair-fed comparison limitations: Do not infer that every between-group comparison was statistically significant from these means; biosynthesis was not directly measured. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient, control and underfed pair-fed groups; duration not verified in abstract. [carnitine1983] Combined effect of ascorbic acid deficiency and underfeeding on the hepatic carnitine level in guinea-pigs. (1983). https://pubmed.ncbi.nlm.nih.gov/6852178/ DOI: 10.1007/bf01965181
Complete structured claim and evidence
Oral trimethyllysine increased urine-based estimated carnitine synthesis by 32–40 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response.
Free N-epsilon-trimethyl-L-lysine → Guinea-pig carnitine synthesis estimated from urinary output source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Guinea-pig dietary deficiency with pair feeding and precursor loading
exposure
Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls.
limitations
Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Even vitamin-C-deficient animals could make substantial carnitine when given this precursor.
primary_references
[carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5
tissue_or_cell_type
Whole animal; urine-based synthesis estimate
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 754–765
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig dietary deficiency with pair feeding and precursor loading · source_derived_draft · unverified_draft
### vc-enzyme-deficient-tml-response Oral trimethyllysine increased urine-based estimated carnitine synthesis by 32–40 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even vitamin-C-deficient animals could make substantial carnitine when given this precursor. organism: Cavia porcellus tissue_or_cell_type: Whole animal; urine-based synthesis estimate experimental_model: Guinea-pig dietary deficiency with pair feeding and precursor loading limitations: Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls. [carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5
Complete structured claim and evidence
Oral gamma-butyrobetaine increased urine-based estimated carnitine synthesis by 41–50 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response.
gamma-Butyrobetaine → Guinea-pig carnitine synthesis estimated from urinary output source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Guinea-pig dietary deficiency with pair feeding and precursor loading
exposure
Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls.
limitations
Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Even vitamin-C-deficient animals could make substantial carnitine when given this precursor.
primary_references
[carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5
tissue_or_cell_type
Whole animal; urine-based synthesis estimate
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 767–778
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig dietary deficiency with pair feeding and precursor loading · source_derived_draft · unverified_draft
### vc-enzyme-deficient-bb-response Oral gamma-butyrobetaine increased urine-based estimated carnitine synthesis by 41–50 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even vitamin-C-deficient animals could make substantial carnitine when given this precursor. organism: Cavia porcellus tissue_or_cell_type: Whole animal; urine-based synthesis estimate experimental_model: Guinea-pig dietary deficiency with pair feeding and precursor loading limitations: Estimate is derived from excretion during a large precursor load, not isotope-resolved basal flux; does not show all tissues are vitamin-C-independent. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls. [carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5
Complete structured claim and evidence
Without carnitine-precursor supplements, vitamin-C-deficient guinea pigs excreted approximately three times as much free and total carnitine as replete animals on days 19–28; pair feeding alone did not produce that pattern.
Vitamin C → Guinea-pig urinary carnitine excretion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Guinea-pig dietary deficiency with pair feeding and precursor loading
exposure
Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls.
limitations
Authors favored excessive excretion as an explanation for depletion; this does not isolate a renal transporter or quantify its contribution in human deficiency.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cavia porcellus
plain_language
Greater loss in urine can contribute to low carnitine during vitamin C deficiency.
primary_references
[carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5
tissue_or_cell_type
Whole animal; urine-based synthesis estimate
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 780–791
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Guinea-pig dietary deficiency with pair feeding and precursor loading · source_derived_draft · unverified_draft
### vc-enzyme-deficient-carnitine-excretion Without carnitine-precursor supplements, vitamin-C-deficient guinea pigs excreted approximately three times as much free and total carnitine as replete animals on days 19–28; pair feeding alone did not produce that pattern. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Greater loss in urine can contribute to low carnitine during vitamin C deficiency. organism: Cavia porcellus tissue_or_cell_type: Whole animal; urine-based synthesis estimate experimental_model: Guinea-pig dietary deficiency with pair feeding and precursor loading limitations: Authors favored excessive excretion as an explanation for depletion; this does not isolate a renal transporter or quantify its contribution in human deficiency. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Vitamin C deficient diet for 28 days; oral trimethyllysine or gamma-butyrobetaine 0.5 mmol/kg/day on days 19–28, with replete and pair-fed controls. [carnitine1995] The ability of guinea pigs to synthesize carnitine at a normal rate from epsilon-N-trimethyllysine or gamma-butyrobetaine in vivo is not compromised by experimental vitamin C deficiency. (1995). https://pubmed.ncbi.nlm.nih.gov/7752911/ DOI: 10.1016/0026-0495(95)90120-5
Complete structured claim and evidence
Ascorbate reduced enzyme-bound copper in purified bovine dopamine beta-hydroxylase from Cu(II) to Cu(I), as examined by X-ray absorption spectroscopy.
L-Ascorbate → Ascorbate-reduced bovine dopamine beta-hydroxylase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS
exposure
Ascorbate reduction of purified Cu(II)-DBH to Cu(I)-DBH.
limitations
Purified bovine enzyme, not a dietary copper-status measurement. Scott 1988 and Blumberg 1989 disagree on the detailed coordination change and heavy-atom ligation; this record retains only the shared Cu(II)-to-Cu(I) redox conclusion.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus
plain_language
Vitamin C supplies reducing power to copper held inside this neurotransmitter enzyme.
primary_references
[scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005 [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5
tissue_or_cell_type
Adrenal-medullary enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 793–805
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS · source_derived_draft · unverified_draft
### vc-enzyme-dbh-copper-reduction Ascorbate reduced enzyme-bound copper in purified bovine dopamine beta-hydroxylase from Cu(II) to Cu(I), as examined by X-ray absorption spectroscopy. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C supplies reducing power to copper held inside this neurotransmitter enzyme. organism: Bos taurus tissue_or_cell_type: Adrenal-medullary enzyme preparation experimental_model: Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS limitations: Purified bovine enzyme, not a dietary copper-status measurement. Scott 1988 and Blumberg 1989 disagree on the detailed coordination change and heavy-atom ligation; this record retains only the shared Cu(II)-to-Cu(I) redox conclusion. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Ascorbate reduction of purified Cu(II)-DBH to Cu(I)-DBH. [scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005 [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5
Complete structured claim and evidence
Coupling bovine DBH tyramine hydroxylation to semidehydroascorbate reductase identified semidehydroascorbate as the immediate enzymic oxidation product of ascorbate.
L-Ascorbate → Ascorbyl radical source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified bovine DBH coupled to rat-liver or Neurospora semidehydroascorbate reductase
exposure
Tyramine beta-hydroxylation with ascorbate; coupled pyridine-nucleotide oxidation and radical recycling assays.
limitations
Heterologous reductase-coupled assay; radical dismutation can subsequently produce DHA, so immediate product and net redox balance must be distinguished.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus; Rattus norvegicus; Neurospora crassa
plain_language
This copper enzyme takes single electrons from vitamin C, leaving an ascorbyl radical that can be recycled.
primary_references
[dbh1981] Mechanism of dopamine-beta-hydroxylation. Semidehydroascorbate as the enzyme oxidation product of ascorbate. (1981). https://pubmed.ncbi.nlm.nih.gov/6451628/ DOI: 10.1016/S0021-9258(19)69620-1
tissue_or_cell_type
Bovine adrenal-medullary enzyme plus heterologous reductase preparations
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 807–818
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified bovine DBH coupled to rat-liver or Neurospora semidehydroascorbate reductase · source_derived_draft · unverified_draft
### vc-enzyme-dbh-radical-product Coupling bovine DBH tyramine hydroxylation to semidehydroascorbate reductase identified semidehydroascorbate as the immediate enzymic oxidation product of ascorbate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This copper enzyme takes single electrons from vitamin C, leaving an ascorbyl radical that can be recycled. organism: Bos taurus; Rattus norvegicus; Neurospora crassa tissue_or_cell_type: Bovine adrenal-medullary enzyme plus heterologous reductase preparations experimental_model: Purified bovine DBH coupled to rat-liver or Neurospora semidehydroascorbate reductase limitations: Heterologous reductase-coupled assay; radical dismutation can subsequently produce DHA, so immediate product and net redox balance must be distinguished. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Tyramine beta-hydroxylation with ascorbate; coupled pyridine-nucleotide oxidation and radical recycling assays. [dbh1981] Mechanism of dopamine-beta-hydroxylation. Semidehydroascorbate as the enzyme oxidation product of ascorbate. (1981). https://pubmed.ncbi.nlm.nih.gov/6451628/ DOI: 10.1016/S0021-9258(19)69620-1
Complete structured claim and evidence
Adding 100 micromolar ascorbate to SH-SY5Y cultures increased intracellular norepinephrine over six hours in parallel with ascorbate accumulation.
L-Ascorbate → Norepinephrine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Human SH-SY5Y neuroblastoma cultures
exposure
100 micromolar ascorbate added to human SH-SY5Y culture; time course through six hours and longer; Fig.1.
limitations
Figure 1 measures cellular content; it is not a purified DBH flux assay or demonstration of symptom improvement in people.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Vitamin C increased the neurotransmitter pool in these cultured neuronal cells.
primary_references
[may2012] Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22925890/ DOI: 10.1016/j.bbrc.2012.08.054
tissue_or_cell_type
Neuronal tumor cell line
Vitamin C: mechanisms, 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 · Human SH-SY5Y neuroblastoma cultures · source_derived_draft · unverified_draft
### vc-enzyme-neuronal-ne-accumulation Adding 100 micromolar ascorbate to SH-SY5Y cultures increased intracellular norepinephrine over six hours in parallel with ascorbate accumulation. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C increased the neurotransmitter pool in these cultured neuronal cells. organism: Homo sapiens tissue_or_cell_type: Neuronal tumor cell line experimental_model: Human SH-SY5Y neuroblastoma cultures limitations: Figure 1 measures cellular content; it is not a purified DBH flux assay or demonstration of symptom improvement in people. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: 100 micromolar ascorbate added to human SH-SY5Y culture; time course through six hours and longer; Fig.1. [may2012] Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22925890/ DOI: 10.1016/j.bbrc.2012.08.054
Complete structured claim and evidence
In pooled SH-SY5Y immunoblots after 24 hours, TH protein rose to a maximum around 170% of control; statistical significance in Results/Fig.4 was reached at 1000 micromolar loading ascorbate (approximately 1.6–2.5 mM intracellular).
L-Ascorbate → Human tyrosine hydroxylase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Human SH-SY5Y neuroblastoma cultures
exposure
24-hour cell culture; 1000 micromolar medium loading reaches significance in pooled Fig.4B; intracellular approximately 1.6–2.5 mM.
limitations
Results/Fig.4 exposure is retained because Discussion describes significant effects at lower loading concentrations. No universal neuronal vitamin C threshold established.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
At the tested higher exposure, vitamin C increased the amount of an enzyme upstream of dopamine synthesis.
primary_references
[may2012] Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22925890/ DOI: 10.1016/j.bbrc.2012.08.054
tissue_or_cell_type
Neuronal tumor cell line
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 833–844
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human SH-SY5Y neuroblastoma cultures · source_derived_draft · unverified_draft
### vc-enzyme-neuronal-th-protein In pooled SH-SY5Y immunoblots after 24 hours, TH protein rose to a maximum around 170% of control; statistical significance in Results/Fig.4 was reached at 1000 micromolar loading ascorbate (approximately 1.6–2.5 mM intracellular). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: At the tested higher exposure, vitamin C increased the amount of an enzyme upstream of dopamine synthesis. organism: Homo sapiens tissue_or_cell_type: Neuronal tumor cell line experimental_model: Human SH-SY5Y neuroblastoma cultures limitations: Results/Fig.4 exposure is retained because Discussion describes significant effects at lower loading concentrations. No universal neuronal vitamin C threshold established. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: 24-hour cell culture; 1000 micromolar medium loading reaches significance in pooled Fig.4B; intracellular approximately 1.6–2.5 mM. [may2012] Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22925890/ DOI: 10.1016/j.bbrc.2012.08.054
Complete structured claim and evidence
Sepiapterin increased norepinephrine content in SH-SY5Y cultures and 50 micromolar ascorbate increased the response further after 24 hours.
Sepiapterin → Norepinephrine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Ascorbate interacts with the pterin cofactor pathway supporting amino-acid-derived catecholamine synthesis; sepiapterin is kept distinct from BH4.
experimental_model
Human SH-SY5Y neuroblastoma cultures
exposure
Sepiapterin dose series with or without 50 micromolar ascorbate, 24 hours; Fig.3C.
limitations
Fig.3C tests sepiapterin, not direct BH4 dosing; BH4 recycling by ascorbate is an interpretation rather than a measured reaction in this experiment.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Supporting a second cofactor pathway enhanced the neuronal response to vitamin C.
primary_references
[may2012] Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22925890/ DOI: 10.1016/j.bbrc.2012.08.054
tissue_or_cell_type
Neuronal tumor cell line
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 846–857
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human SH-SY5Y neuroblastoma cultures · source_derived_draft · unverified_draft
### vc-enzyme-sepiapterin-co-response Sepiapterin increased norepinephrine content in SH-SY5Y cultures and 50 micromolar ascorbate increased the response further after 24 hours. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supporting a second cofactor pathway enhanced the neuronal response to vitamin C. organism: Homo sapiens tissue_or_cell_type: Neuronal tumor cell line experimental_model: Human SH-SY5Y neuroblastoma cultures limitations: Fig.3C tests sepiapterin, not direct BH4 dosing; BH4 recycling by ascorbate is an interpretation rather than a measured reaction in this experiment. cross_nutrient: Ascorbate interacts with the pterin cofactor pathway supporting amino-acid-derived catecholamine synthesis; sepiapterin is kept distinct from BH4. exposure: Sepiapterin dose series with or without 50 micromolar ascorbate, 24 hours; Fig.3C. [may2012] Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22925890/ DOI: 10.1016/j.bbrc.2012.08.054
Complete structured claim and evidence
Bovine intermediate-pituitary granule amidation of D-Tyr-Val-Gly responded to ascorbate, with apparent substrate Km and Vmax changing as the ascorbate concentration changed.
L-Ascorbate → Bovine peptidylglycine alpha-amidating monooxygenase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Bovine intermediate-pituitary secretory-granule kinetic assay
exposure
Synthetic D-Tyr-Val-Gly amidation with varied ascorbate, oxygen and divalent-metal chelators/copper.
limitations
The old granule preparation is not a purified modern PAM-domain assay; synthetic substrate kinetics do not quantify all hormone amidation.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus
plain_language
Vitamin C helps the pituitary enzyme finish a peptide with an amide group.
primary_references
[pam1983] Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid. (1983). https://pubmed.ncbi.nlm.nih.gov/6576381/ DOI: 10.1073/pnas.80.16.5144
tissue_or_cell_type
Pituitary secretory granules
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 859–870
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine intermediate-pituitary secretory-granule kinetic assay · source_derived_draft · unverified_draft
### vc-enzyme-bovine-amidation-ascorbate Bovine intermediate-pituitary granule amidation of D-Tyr-Val-Gly responded to ascorbate, with apparent substrate Km and Vmax changing as the ascorbate concentration changed. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helps the pituitary enzyme finish a peptide with an amide group. organism: Bos taurus tissue_or_cell_type: Pituitary secretory granules experimental_model: Bovine intermediate-pituitary secretory-granule kinetic assay limitations: The old granule preparation is not a purified modern PAM-domain assay; synthetic substrate kinetics do not quantify all hormone amidation. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Synthetic D-Tyr-Val-Gly amidation with varied ascorbate, oxygen and divalent-metal chelators/copper. [pam1983] Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid. (1983). https://pubmed.ncbi.nlm.nih.gov/6576381/ DOI: 10.1073/pnas.80.16.5144
Complete structured claim and evidence
Pituitary peptide-amidating activity inhibited by divalent-metal chelators was restored above control by copper addition; the assayed reaction also required molecular oxygen.
Copper(II) ion → Bovine peptidylglycine alpha-amidating monooxygenase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Rat pituitary and bovine intermediate-pituitary secretory-granule preparations
exposure
Synthetic D-Tyr-Val-Gly amidation with varied ascorbate, oxygen and divalent-metal chelators/copper.
limitations
Study included rat and bovine preparations; this cofactor observation is scoped to those preparations rather than a human nutritional copper trial.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus; Bos taurus
plain_language
Vitamin C and copper participate together, and removing available metal stops this peptide-processing assay.
primary_references
[pam1983] Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid. (1983). https://pubmed.ncbi.nlm.nih.gov/6576381/ DOI: 10.1073/pnas.80.16.5144
tissue_or_cell_type
Pituitary secretory granules
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 872–883
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat pituitary and bovine intermediate-pituitary secretory-granule preparations · source_derived_draft · unverified_draft
### vc-enzyme-amidation-copper-recovery Pituitary peptide-amidating activity inhibited by divalent-metal chelators was restored above control by copper addition; the assayed reaction also required molecular oxygen. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C and copper participate together, and removing available metal stops this peptide-processing assay. organism: Rattus norvegicus; Bos taurus tissue_or_cell_type: Pituitary secretory granules experimental_model: Rat pituitary and bovine intermediate-pituitary secretory-granule preparations limitations: Study included rat and bovine preparations; this cofactor observation is scoped to those preparations rather than a human nutritional copper trial. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Synthetic D-Tyr-Val-Gly amidation with varied ascorbate, oxygen and divalent-metal chelators/copper. [pam1983] Identification in pituitary tissue of a peptide alpha-amidation activity that acts on glycine-extended peptides and requires molecular oxygen, copper, and ascorbic acid. (1983). https://pubmed.ncbi.nlm.nih.gov/6576381/ DOI: 10.1073/pnas.80.16.5144
Complete structured claim and evidence
Expression of the bovine PHM-only construct in HEK293 cells increased secreted PHM activity, demonstrating a functional hydroxylating domain separable from the PAL portion of PAM.
Bovine peptidylglycine alpha-amidating monooxygenase → Bovine PAM peptidylglycine alpha-hydroxylating monooxygenase domain source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified bovine pituitary PAL and bovine-domain expression constructs in HEK293 cells
exposure
Purified PAL with N-acetyl-Tyr-Val-alpha-hydroxyglycine; PHM or PAL-containing constructs expressed in HEK293.
limitations
Bovine protein expressed in human cells is not a human PAM protein; domain construct activity does not quantify tissue hormone synthesis.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus (protein); Homo sapiens (expression host)
plain_language
Peptide amidation begins with a separate vitamin-C-dependent hydroxylation step.
primary_references
[pal1991] Peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Purification, characterization, and expression. (1991). https://pubmed.ncbi.nlm.nih.gov/1902227/ DOI: 10.1016/s0021-9258(20)89524-6
tissue_or_cell_type
Bovine neurointermediate pituitary; heterologous HEK293
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 885–896
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified bovine pituitary PAL and bovine-domain expression constructs in HEK293 cells · source_derived_draft · unverified_draft
### vc-enzyme-pam-two-domains Expression of the bovine PHM-only construct in HEK293 cells increased secreted PHM activity, demonstrating a functional hydroxylating domain separable from the PAL portion of PAM. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Peptide amidation begins with a separate vitamin-C-dependent hydroxylation step. organism: Bos taurus (protein); Homo sapiens (expression host) tissue_or_cell_type: Bovine neurointermediate pituitary; heterologous HEK293 experimental_model: Purified bovine pituitary PAL and bovine-domain expression constructs in HEK293 cells limitations: Bovine protein expressed in human cells is not a human PAM protein; domain construct activity does not quantify tissue hormone synthesis. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Purified PAL with N-acetyl-Tyr-Val-alpha-hydroxyglycine; PHM or PAL-containing constructs expressed in HEK293. [pal1991] Peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Purification, characterization, and expression. (1991). https://pubmed.ncbi.nlm.nih.gov/1902227/ DOI: 10.1016/s0021-9258(20)89524-6
Complete structured claim and evidence
Purified bovine pituitary PAL catalyzed amidation of N-acetyl-Tyr-Val-alpha-hydroxyglycine, with reported Km 38 micromolar and turnover 220/s for this synthetic intermediate.
Bovine PAM peptidyl-alpha-hydroxyglycine alpha-amidating lyase domain → N-acetyl-Tyr-Val-alpha-hydroxyglycine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Purified bovine pituitary PAL and bovine-domain expression constructs in HEK293 cells
exposure
Purified PAL with N-acetyl-Tyr-Val-alpha-hydroxyglycine; PHM or PAL-containing constructs expressed in HEK293.
limitations
Kinetics belong to this substrate and preparation. PAL is not another ascorbate-consuming hydroxylase; metal inhibition/reactivation in this paper does not establish physiological metal occupancy.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus (protein); Homo sapiens (expression host)
plain_language
After hydroxylation, a second enzyme domain releases the finished peptide amide.
primary_references
[pal1991] Peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Purification, characterization, and expression. (1991). https://pubmed.ncbi.nlm.nih.gov/1902227/ DOI: 10.1016/s0021-9258(20)89524-6
tissue_or_cell_type
Bovine neurointermediate pituitary; heterologous HEK293
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 898–909
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified bovine pituitary PAL and bovine-domain expression constructs in HEK293 cells · source_derived_draft · unverified_draft
### vc-enzyme-pal-intermediate-cleavage Purified bovine pituitary PAL catalyzed amidation of N-acetyl-Tyr-Val-alpha-hydroxyglycine, with reported Km 38 micromolar and turnover 220/s for this synthetic intermediate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: After hydroxylation, a second enzyme domain releases the finished peptide amide. organism: Bos taurus (protein); Homo sapiens (expression host) tissue_or_cell_type: Bovine neurointermediate pituitary; heterologous HEK293 experimental_model: Purified bovine pituitary PAL and bovine-domain expression constructs in HEK293 cells limitations: Kinetics belong to this substrate and preparation. PAL is not another ascorbate-consuming hydroxylase; metal inhibition/reactivation in this paper does not establish physiological metal occupancy. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Purified PAL with N-acetyl-Tyr-Val-alpha-hydroxyglycine; PHM or PAL-containing constructs expressed in HEK293. [pal1991] Peptidyl-alpha-hydroxyglycine alpha-amidating lyase. Purification, characterization, and expression. (1991). https://pubmed.ncbi.nlm.nih.gov/1902227/ DOI: 10.1016/s0021-9258(20)89524-6
Complete structured claim and evidence
In time- and concentration-dependent purified-protein experiments, ascorbate inactivated the full amidation activity of recombinant rat 75-kDa PAM measured with dansyl-Tyr-Val-Gly.
L-Ascorbate → Recombinant rat type-A 75-kDa peptidylglycine amidating enzyme source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Recombinant rat type-A 75-kDa PAM, purified enzyme assays
exposure
Time/concentration series of ascorbate, DHA or H2O2; fluorescent peptide substrate or pre-hydroxylated intermediate.
limitations
Assay redox damage, not evidence that dietary vitamin C suppresses hormone amidation in vivo; accessible abstract does not specify full concentration range.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus (protein)
plain_language
The same vitamin that supports the enzyme can damage its hydroxylating activity under particular cell-free redox conditions.
primary_references
[pam1992] Selective inactivation of the hydroxylase activity of bifunctional rat peptidylglycine alpha-amidating enzyme. (1992). https://pubmed.ncbi.nlm.nih.gov/1567215/ DOI: 10.1016/0003-9861(92)90730-k
tissue_or_cell_type
Cell-free recombinant rat protein
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 911–922
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant rat type-A 75-kDa PAM, purified enzyme assays · source_derived_draft · unverified_draft
### vc-enzyme-pam-oxidative-inactivation In time- and concentration-dependent purified-protein experiments, ascorbate inactivated the full amidation activity of recombinant rat 75-kDa PAM measured with dansyl-Tyr-Val-Gly. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same vitamin that supports the enzyme can damage its hydroxylating activity under particular cell-free redox conditions. organism: Rattus norvegicus (protein) tissue_or_cell_type: Cell-free recombinant rat protein experimental_model: Recombinant rat type-A 75-kDa PAM, purified enzyme assays limitations: Assay redox damage, not evidence that dietary vitamin C suppresses hormone amidation in vivo; accessible abstract does not specify full concentration range. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Time/concentration series of ascorbate, DHA or H2O2; fluorescent peptide substrate or pre-hydroxylated intermediate. [pam1992] Selective inactivation of the hydroxylase activity of bifunctional rat peptidylglycine alpha-amidating enzyme. (1992). https://pubmed.ncbi.nlm.nih.gov/1567215/ DOI: 10.1016/0003-9861(92)90730-k
Complete structured claim and evidence
Under conditions that inactivated hydroxylase-dependent rat PAM amidation, ascorbate did not impair conversion of the pre-hydroxylated dansyl-Tyr-Val-alpha-hydroxyglycine intermediate to its amide.
L-Ascorbate → Recombinant rat type-A 75-kDa peptidylglycine amidating enzyme source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Recombinant rat type-A 75-kDa PAM, purified enzyme assays
exposure
Time/concentration series of ascorbate, DHA or H2O2; fluorescent peptide substrate or pre-hydroxylated intermediate.
limitations
Distinct-substrate assay localizes the defect; no claim that all PAM domains share the same redox/cofactor dependence.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Rattus norvegicus (protein)
plain_language
Bypassing the damaged hydroxylation step showed that the finishing lyase step still worked.
primary_references
[pam1992] Selective inactivation of the hydroxylase activity of bifunctional rat peptidylglycine alpha-amidating enzyme. (1992). https://pubmed.ncbi.nlm.nih.gov/1567215/ DOI: 10.1016/0003-9861(92)90730-k
tissue_or_cell_type
Cell-free recombinant rat protein
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 924–935
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant rat type-A 75-kDa PAM, purified enzyme assays · source_derived_draft · unverified_draft
### vc-enzyme-pam-lyase-spared Under conditions that inactivated hydroxylase-dependent rat PAM amidation, ascorbate did not impair conversion of the pre-hydroxylated dansyl-Tyr-Val-alpha-hydroxyglycine intermediate to its amide. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bypassing the damaged hydroxylation step showed that the finishing lyase step still worked. organism: Rattus norvegicus (protein) tissue_or_cell_type: Cell-free recombinant rat protein experimental_model: Recombinant rat type-A 75-kDa PAM, purified enzyme assays limitations: Distinct-substrate assay localizes the defect; no claim that all PAM domains share the same redox/cofactor dependence. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Time/concentration series of ascorbate, DHA or H2O2; fluorescent peptide substrate or pre-hydroxylated intermediate. [pam1992] Selective inactivation of the hydroxylase activity of bifunctional rat peptidylglycine alpha-amidating enzyme. (1992). https://pubmed.ncbi.nlm.nih.gov/1567215/ DOI: 10.1016/0003-9861(92)90730-k
Complete structured claim and evidence
Scott et al. interpreted the ascorbate-reduced bovine DBH spectrum as a decrease from roughly four to two N/O ligands plus a sulfur-containing ligand at 2.30 angstrom, compared with the oxidized enzyme.
L-Ascorbate → Ascorbate-reduced bovine dopamine beta-hydroxylase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS
exposure
Purified oxidized versus ascorbate-reduced bovine DBH; bulk X-ray absorption/EXAFS interpretation.
limitations
Historical average EXAFS interpretation explicitly challenged by Blumberg1989; not an endorsed ligand assignment or a claim about human dietary copper.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus
plain_language
This study proposed that reducing the copper also changed which nearby atoms coordinated it.
primary_references
[scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005
tissue_or_cell_type
Adrenal-medullary enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 937–948
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS · source_derived_draft · unverified_draft
### vc-enzyme-dbh-coordination-scott-interpretation Scott et al. interpreted the ascorbate-reduced bovine DBH spectrum as a decrease from roughly four to two N/O ligands plus a sulfur-containing ligand at 2.30 angstrom, compared with the oxidized enzyme. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This study proposed that reducing the copper also changed which nearby atoms coordinated it. organism: Bos taurus tissue_or_cell_type: Adrenal-medullary enzyme preparation experimental_model: Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS limitations: Historical average EXAFS interpretation explicitly challenged by Blumberg1989; not an endorsed ligand assignment or a claim about human dietary copper. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Purified oxidized versus ascorbate-reduced bovine DBH; bulk X-ray absorption/EXAFS interpretation. [scott1988] The copper sites of dopamine beta-hydroxylase: an X-ray absorption spectroscopic study. (1988). https://pubmed.ncbi.nlm.nih.gov/3179263/ DOI: 10.1021/bi00415a005
Complete structured claim and evidence
Blumberg et al. found little average coordination change after ascorbate reduction: four nitrogen ligands best fit both forms, at 1.97 angstrom oxidized and 2.05 angstrom reduced; they found no sulfur or chlorine ligation and explicitly opposed the earlier interpretation.
L-Ascorbate → Ascorbate-reduced bovine dopamine beta-hydroxylase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing.
experimental_model
Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS
exposure
Purified oxidized versus ascorbate-reduced bovine DBH; bulk X-ray absorption/EXAFS interpretation.
limitations
The abstract permits N/O ligation generally; four nitrogens was its best fit. Historical bulk spectroscopy, not a review of all later structural evidence or current consensus.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Bos taurus
plain_language
The later study agreed that copper was reduced but interpreted the surrounding atoms differently.
primary_references
[blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5
tissue_or_cell_type
Adrenal-medullary enzyme preparation
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 950–961
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS · source_derived_draft · unverified_draft
### vc-enzyme-dbh-coordination-blumberg-interpretation Blumberg et al. found little average coordination change after ascorbate reduction: four nitrogen ligands best fit both forms, at 1.97 angstrom oxidized and 2.05 angstrom reduced; they found no sulfur or chlorine ligation and explicitly opposed the earlier interpretation. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The later study agreed that copper was reduced but interpreted the surrounding atoms differently. organism: Bos taurus tissue_or_cell_type: Adrenal-medullary enzyme preparation experimental_model: Bovine dopamine beta-hydroxylase X-ray absorption and EXAFS limitations: The abstract permits N/O ligation generally; four nitrogens was its best fit. Historical bulk spectroscopy, not a review of all later structural evidence or current consensus. cross_nutrient: Vitamin C chemistry in collagen, modified-lysine/carnitine metabolism or copper-dependent peptide/catecholamine processing. exposure: Purified oxidized versus ascorbate-reduced bovine DBH; bulk X-ray absorption/EXAFS interpretation. [blumberg1989] X-ray absorption spectroscopic study of the active copper sites in dopamine beta-hydroxylase. (1989). https://pubmed.ncbi.nlm.nih.gov/2703478/ DOI: 10.1016/s0021-9258(18)83307-5
Complete structured claim and evidence
Vitamin C increased hydroxymethylcytosine production by recombinant human TET1 catalytic domain in the reported pH 8.0 assay containing Fe(II) and 2-oxoglutarate. This demonstrates assay enhancement, without establishing obligatory ascorbate binding.
L-Ascorbate → TET1 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 3a; Methods Tet activity assay
experimental_model
Purified recombinant human TET1 catalytic-domain assay; antibody detection of hydroxymethylated biotinylated DNA
exposure
10 min at 37°C; 1.2 µg enzyme, 178.2 ng DNA, 3.7 µM ammonium iron(II) sulfate, 1 mM 2-oxoglutarate, titrated vitamin C (Sigma A5960).
limitations
Purified-domain result; oxidation-prone buffer differs from cellular iron conditions. Exact plotted titration values not transcribed.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens protein
plain_language
Vitamin C helped the isolated human enzyme modify DNA under these test conditions.
primary_references
[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 963–975
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human TET1 catalytic-domain assay; antibody detection of hydroxymethylated biotinylated DNA · source_derived_draft · unverified_draft
### c-reg-tet1-human-activity Vitamin C increased hydroxymethylcytosine production by recombinant human TET1 catalytic domain in the reported pH 8.0 assay containing Fe(II) and 2-oxoglutarate. This demonstrates assay enhancement, without establishing obligatory ascorbate binding. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helped the isolated human enzyme modify DNA under these test conditions. organism: Homo sapiens protein tissue_or_cell_type: Cell-free experimental_model: Purified recombinant human TET1 catalytic-domain assay; antibody detection of hydroxymethylated biotinylated DNA limitations: Purified-domain result; oxidation-prone buffer differs from cellular iron conditions. Exact plotted titration values not transcribed. exposure: 10 min at 37°C; 1.2 µg enzyme, 178.2 ng DNA, 3.7 µM ammonium iron(II) sulfate, 1 mM 2-oxoglutarate, titrated vitamin C (Sigma A5960). cross_nutrient: true evidence_location: Figure 3a; Methods Tet activity assay [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
Complete structured claim and evidence
Adding L-ascorbic acid 2-phosphate to mouse ESC medium rapidly increased global DNA 5hmC and promoter-associated 5hmC, preceding later methylcytosine loss.
L-Ascorbic acid 2-phosphate → DNA 5-hydroxymethylcytosine residues source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figures 1–2
experimental_model
Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation
exposure
100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling.
limitations
5hmC abundance alone is not proof of completed demethylation; cultured ESCs are not adult human tissues.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
A stable vitamin C derivative increased an early DNA-demethylation intermediate in cultured mouse stem cells.
primary_references
[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
tissue_or_cell_type
Embryonic stem cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 977–989
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation · source_derived_draft · unverified_draft
### c-reg-esc-hydroxymethylation Adding L-ascorbic acid 2-phosphate to mouse ESC medium rapidly increased global DNA 5hmC and promoter-associated 5hmC, preceding later methylcytosine loss. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A stable vitamin C derivative increased an early DNA-demethylation intermediate in cultured mouse stem cells. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation limitations: 5hmC abundance alone is not proof of completed demethylation; cultured ESCs are not adult human tissues. exposure: 100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling. cross_nutrient: false evidence_location: Figures 1–2 [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
Complete structured claim and evidence
After vitamin C derivative treatment, numerous mouse ESC promoters lost methylcytosine; imprinted regions and IAP retroelements were relatively resistant, so the effect was not indiscriminate erasure of genomic methylation.
L-Ascorbic acid 2-phosphate → Gene-promoter DNA methylation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 2; resistant-region analysis
experimental_model
Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation; mC-DIP sequencing/qPCR and bisulfite validation
exposure
100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling.
limitations
Locus-selective cell-culture result; promoter demethylation did not automatically activate every affected gene.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin C changed selected DNA methylation patterns in these cells; protected regions retained their marks.
primary_references
[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
tissue_or_cell_type
Embryonic stem cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 991–1003
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation; mC-DIP sequencing/qPCR and bisulfite validation · source_derived_draft · unverified_draft
### c-reg-esc-promoter-demethylation After vitamin C derivative treatment, numerous mouse ESC promoters lost methylcytosine; imprinted regions and IAP retroelements were relatively resistant, so the effect was not indiscriminate erasure of genomic methylation. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C changed selected DNA methylation patterns in these cells; protected regions retained their marks. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Mouse Oct4-GiP ESCs in feeder-free 2i/LIF medium; DNA dot blot and hydroxymethyl-DNA immunoprecipitation; mC-DIP sequencing/qPCR and bisulfite validation limitations: Locus-selective cell-culture result; promoter demethylation did not automatically activate every affected gene. exposure: 100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling. cross_nutrient: false evidence_location: Figure 2; resistant-region analysis [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
Complete structured claim and evidence
Combined Tet1/Tet2 deletion in mouse ESCs abolished the vitamin-C-induced increase in 5hmC and promoter demethylation observed in wild-type cells; residual antibody signal was not interpreted as robust Tet activity.
Mouse Tet1 gene → DNA 5-hydroxymethylcytosine residues source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 3b–c
experimental_model
Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR
exposure
100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling.
limitations
Genetic loss of machinery, not low vitamin intake; other vitamin C effects and residual Tet3 were not excluded.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin C could not restore these DNA effects when the two relevant enzymes were genetically absent.
primary_references
[c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
tissue_or_cell_type
Embryonic stem cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1005–1017
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR · source_derived_draft · unverified_draft
### c-reg-tet-dko-blocks-response Combined Tet1/Tet2 deletion in mouse ESCs abolished the vitamin-C-induced increase in 5hmC and promoter demethylation observed in wild-type cells; residual antibody signal was not interpreted as robust Tet activity. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C could not restore these DNA effects when the two relevant enzymes were genetically absent. organism: Mus musculus tissue_or_cell_type: Embryonic stem cells experimental_model: Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR limitations: Genetic loss of machinery, not low vitamin intake; other vitamin C effects and residual Tet3 were not excluded. exposure: 100 µg/mL L-ascorbic acid 2-phosphate (A8960), medium replaced daily; 12-h and 72-h sampling. cross_nutrient: false evidence_location: Figure 3b–c [c-reg-blaschke] Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. (2013). https://pubmed.ncbi.nlm.nih.gov/23812591/ DOI: 10.1038/nature12362
Complete structured claim and evidence
Ascorbate restored murine TET1-CD activity with ferric iron or under pH 8.0 conditions that rapidly oxidized Fe(II); iron-redox measurements support provision of reduced iron as the rescue mechanism.
L-Ascorbate → Mouse Tet1 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 1D–E; Figure S1A–C
experimental_model
Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay
exposure
1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0.
limitations
This does not directly measure free iron inside cells or establish a dietary iron/ascorbate requirement.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus protein expressed in Escherichia coli
plain_language
Vitamin C helped restore the usable iron needed by this isolated DNA-modifying enzyme.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1019–1031
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay · source_derived_draft · unverified_draft
### c-reg-tet-iron-reduction-rescue Ascorbate restored murine TET1-CD activity with ferric iron or under pH 8.0 conditions that rapidly oxidized Fe(II); iron-redox measurements support provision of reduced iron as the rescue mechanism. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helped restore the usable iron needed by this isolated DNA-modifying enzyme. organism: Mus musculus protein expressed in Escherichia coli tissue_or_cell_type: Cell-free experimental_model: Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay limitations: This does not directly measure free iron inside cells or establish a dietary iron/ascorbate requirement. exposure: 1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0. cross_nutrient: true evidence_location: Figure 1D–E; Figure S1A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
At pH 6.8 with sufficient Fe(II), murine TET1-CD remained active without ascorbate and adding ascorbate did not increase the measured activity; substrate-free preincubation also did not rapidly destroy activity.
L-Ascorbate → Mouse Tet1 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 1D; Figure S1B–D
experimental_model
Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay
exposure
1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0. Substrate-free preincubation up to 30 min.
limitations
A conditional biochemical null result; it does not negate ascorbate enhancement in cells or more oxidizing buffers.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus protein expressed in Escherichia coli
plain_language
With usable iron maintained in this assay, the enzyme did not require extra vitamin C to keep working.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1033–1045
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay · source_derived_draft · unverified_draft
### c-reg-tet-sufficient-ferrous-iron At pH 6.8 with sufficient Fe(II), murine TET1-CD remained active without ascorbate and adding ascorbate did not increase the measured activity; substrate-free preincubation also did not rapidly destroy activity. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: With usable iron maintained in this assay, the enzyme did not require extra vitamin C to keep working. organism: Mus musculus protein expressed in Escherichia coli tissue_or_cell_type: Cell-free experimental_model: Recombinant murine TET1 catalytic domain expressed in E. coli; methylated 86-mer DNA ELISA assay limitations: A conditional biochemical null result; it does not negate ascorbate enhancement in cells or more oxidizing buffers. exposure: 1.5 µM TET1-CD, 0.5 µM DNA, 1 mM 2-oxoglutarate, 10 or 100 µM iron; sodium L-ascorbate 1 mM; pH 6.8 versus pH 8.0. Substrate-free preincubation up to 30 min. cross_nutrient: true evidence_location: Figure 1D; Figure S1B–D [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Retinol supplementation increased Tet2 transcription in mouse naïve ESCs within 8 h and after 72 h; Tet3 also responded, whereas evidence did not support direct retinol stimulation of TET catalytic efficiency.
All-trans-retinol → Mouse Tet2 gene source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 3A–C
experimental_model
Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification
exposure
Retinol titration 0–50 ng/mL; 8-h and 72-h transcript assays.
limitations
Retinoid signaling and response depend on culture context; no claim that vitamin A supplementation demethylates adult human tissues.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin A raised expression of DNA-modifying enzymes through a different route from vitamin C’s iron-redox effect.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Naïve embryonic stem cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1047–1059
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification · source_derived_draft · unverified_draft
### c-reg-retinol-tet2-expression Retinol supplementation increased Tet2 transcription in mouse naïve ESCs within 8 h and after 72 h; Tet3 also responded, whereas evidence did not support direct retinol stimulation of TET catalytic efficiency. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A raised expression of DNA-modifying enzymes through a different route from vitamin C’s iron-redox effect. organism: Mus musculus tissue_or_cell_type: Naïve embryonic stem cells experimental_model: Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification limitations: Retinoid signaling and response depend on culture context; no claim that vitamin A supplementation demethylates adult human tissues. exposure: Retinol titration 0–50 ng/mL; 8-h and 72-h transcript assays. cross_nutrient: true evidence_location: Figure 3A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Deleting a 104-bp intronic segment encompassing the mouse Tet2 retinoic-acid response element prevented the normal retinol-dependent Tet2 mRNA increase, supporting a cis-regulatory requirement.
Mouse Tet2 gene → Mouse Tet2 gene source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Figure 3E–F
experimental_model
CRISPR Tet2 ΔRARE naïve ESCs compared with wild type
exposure
Retinol titration as in Figure 3F; 104-bp deletion NCBI37 chr3:133197151–133197253.
limitations
Deletion tests the segment rather than one isolated nucleotide; this is engineered machinery impairment, not vitamin A deficiency.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
The vitamin A response depended on a specific DNA control sequence in the Tet2 gene.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Naïve embryonic stem cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1061–1073
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CRISPR Tet2 ΔRARE naïve ESCs compared with wild type · source_derived_draft · unverified_draft
### c-reg-tet2-rare-deletion Deleting a 104-bp intronic segment encompassing the mouse Tet2 retinoic-acid response element prevented the normal retinol-dependent Tet2 mRNA increase, supporting a cis-regulatory requirement. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The vitamin A response depended on a specific DNA control sequence in the Tet2 gene. organism: Mus musculus tissue_or_cell_type: Naïve embryonic stem cells experimental_model: CRISPR Tet2 ΔRARE naïve ESCs compared with wild type limitations: Deletion tests the segment rather than one isolated nucleotide; this is engineered machinery impairment, not vitamin A deficiency. exposure: Retinol titration as in Figure 3F; 104-bp deletion NCBI37 chr3:133197151–133197253. cross_nutrient: true evidence_location: Figure 3E–F [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Ascorbate co-treatment increased Oct4:GFP-positive colony formation during KLF4-driven mouse EpiSC reprogramming and shifted the optimum toward lower retinol concentration; higher retinol suppressed colony formation rather than improving it indefinitely.
L-Ascorbate → Reprogramming to induced pluripotency source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 4A–C
experimental_model
KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts
exposure
50 µg/mL ascorbate with 0–50 ng/mL retinol; day-6 colony endpoint; combined optimum reported near 3.13 ng/mL retinol.
limitations
Reprogramming reporter assay, not demonstrated tissue rejuvenation or therapy; relationship to DNA modification is supported by complementary experiments, not sole-cause proof.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin A and C worked together in this stem-cell culture protocol, but more vitamin A was not always better.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Epiblast stem-cell culture
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1075–1087
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts · source_derived_draft · unverified_draft
### c-reg-retinol-ascorbate-reprogramming Ascorbate co-treatment increased Oct4:GFP-positive colony formation during KLF4-driven mouse EpiSC reprogramming and shifted the optimum toward lower retinol concentration; higher retinol suppressed colony formation rather than improving it indefinitely. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A and C worked together in this stem-cell culture protocol, but more vitamin A was not always better. organism: Mus musculus tissue_or_cell_type: Epiblast stem-cell culture experimental_model: KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts limitations: Reprogramming reporter assay, not demonstrated tissue rejuvenation or therapy; relationship to DNA modification is supported by complementary experiments, not sole-cause proof. exposure: 50 µg/mL ascorbate with 0–50 ng/mL retinol; day-6 colony endpoint; combined optimum reported near 3.13 ng/mL retinol. cross_nutrient: true evidence_location: Figure 4A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Vitamin C treatment reduced H3K36me2/3 in mouse embryonic fibroblasts during culture and reprogramming, linking the intervention to histone methylation changes.
Vitamin C → Histone H3 dimethylated at K36 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Primary abstract H3K36me2/3 result
experimental_model
Mouse embryonic fibroblasts in culture and reprogramming; primary abstract-level result
exposure
Vitamin C-supplemented cell culture; exact preparation, dose and duration not recovered from accessible primary abstract.
limitations
No direct claim that Kdm2a/b remove H3K36me3; the combined cellular mark change may involve other enzymes. Abstract-only exposure resolution.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin C changed methyl marks on histone proteins in cultured mouse fibroblasts.
primary_references
[c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005
tissue_or_cell_type
Embryonic fibroblasts
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1089–1101
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse embryonic fibroblasts in culture and reprogramming; primary abstract-level result · source_derived_draft · unverified_draft
### c-reg-h3k36-mark-reduction Vitamin C treatment reduced H3K36me2/3 in mouse embryonic fibroblasts during culture and reprogramming, linking the intervention to histone methylation changes. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C changed methyl marks on histone proteins in cultured mouse fibroblasts. organism: Mus musculus tissue_or_cell_type: Embryonic fibroblasts experimental_model: Mouse embryonic fibroblasts in culture and reprogramming; primary abstract-level result limitations: No direct claim that Kdm2a/b remove H3K36me3; the combined cellular mark change may involve other enzymes. Abstract-only exposure resolution. exposure: Vitamin C-supplemented cell culture; exact preparation, dose and duration not recovered from accessible primary abstract. cross_nutrient: false evidence_location: Primary abstract H3K36me2/3 result [c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005
Complete structured claim and evidence
Jhdm1a/1b gain- and loss-of-function experiments identified these histone demethylases as functional effectors of vitamin-C-enhanced mouse somatic-cell reprogramming. Loss-of-function reduced the response rather than being corrected by vitamin C alone.
Mouse Kdm2a gene → Reprogramming to induced pluripotency source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Primary abstract gain/loss-of-function result
experimental_model
Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function
exposure
Genetic gain/loss interventions during vitamin C-supported reprogramming; exact construct, dose and timing not recovered.
limitations
Abstract-level mechanistic assignment; no quantitative effect size or specific knockdown efficiency asserted.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
The histone enzymes were part of the machinery through which vitamin C helped cells reprogram.
primary_references
[c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005
tissue_or_cell_type
Embryonic fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1103–1115
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function · source_derived_draft · unverified_draft
### c-reg-jhdm-reprogramming-effectors Jhdm1a/1b gain- and loss-of-function experiments identified these histone demethylases as functional effectors of vitamin-C-enhanced mouse somatic-cell reprogramming. Loss-of-function reduced the response rather than being corrected by vitamin C alone. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The histone enzymes were part of the machinery through which vitamin C helped cells reprogram. organism: Mus musculus tissue_or_cell_type: Embryonic fibroblasts experimental_model: Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function limitations: Abstract-level mechanistic assignment; no quantitative effect size or specific knockdown efficiency asserted. exposure: Genetic gain/loss interventions during vitamin C-supported reprogramming; exact construct, dose and timing not recovered. cross_nutrient: false evidence_location: Primary abstract gain/loss-of-function result [c-reg-wang] The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. (2011). https://pubmed.ncbi.nlm.nih.gov/22100412/ DOI: 10.1016/j.stem.2011.10.005
Complete structured claim and evidence
Ascorbate increased the initial rate and extent of PHD2-catalyzed hydroxylation at both tested human HIF-1 alpha prolyl sites in purified-enzyme peptide experiments.
L-Ascorbate → HIF-1 alpha prolyl hydroxylation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract rate/extent and substrate comparisons
experimental_model
Purified enzyme with human HIF-1 alpha-derived peptide substrate
exposure
Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract.
limitations
Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Human HIF-1 alpha substrate; purified recombinant hydroxylase
plain_language
Vitamin C increased the activity of an isolated oxygen-sensing proline hydroxylase.
primary_references
[c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1117–1129
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified enzyme with human HIF-1 alpha-derived peptide substrate · source_derived_draft · unverified_draft
### c-reg-phd2-ascorbate Ascorbate increased the initial rate and extent of PHD2-catalyzed hydroxylation at both tested human HIF-1 alpha prolyl sites in purified-enzyme peptide experiments. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C increased the activity of an isolated oxygen-sensing proline hydroxylase. organism: Human HIF-1 alpha substrate; purified recombinant hydroxylase tissue_or_cell_type: Cell-free experimental_model: Purified enzyme with human HIF-1 alpha-derived peptide substrate limitations: Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF. exposure: Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract. cross_nutrient: true evidence_location: Primary abstract rate/extent and substrate comparisons [c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609
Complete structured claim and evidence
Ascorbate increased the initial rate and extent of FIH-catalyzed asparaginyl hydroxylation of human HIF-1 alpha peptide; the study separately tested a consensus ankyrin-repeat peptide.
L-Ascorbate → HIF-1 alpha asparaginyl hydroxylation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract rate/extent and substrate comparisons
experimental_model
Purified enzyme with human HIF-1 alpha-derived peptide substrate
exposure
Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract.
limitations
Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Human HIF-1 alpha substrate; purified recombinant hydroxylase
plain_language
Vitamin C also supported a different HIF enzyme that modifies an asparagine site.
primary_references
[c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1131–1143
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified enzyme with human HIF-1 alpha-derived peptide substrate · source_derived_draft · unverified_draft
### c-reg-fih-ascorbate Ascorbate increased the initial rate and extent of FIH-catalyzed asparaginyl hydroxylation of human HIF-1 alpha peptide; the study separately tested a consensus ankyrin-repeat peptide. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C also supported a different HIF enzyme that modifies an asparagine site. organism: Human HIF-1 alpha substrate; purified recombinant hydroxylase tissue_or_cell_type: Cell-free experimental_model: Purified enzyme with human HIF-1 alpha-derived peptide substrate limitations: Peptide hydroxylation does not directly establish HIF degradation or transcription changes in intact cells; ankyrin probe is not physiological HIF. exposure: Ascorbate versus omission/alternative reducing agents; exact concentrations and enzyme constructs not recovered from primary abstract. cross_nutrient: true evidence_location: Primary abstract rate/extent and substrate comparisons [c-reg-flashman] Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. (2010). https://pubmed.ncbi.nlm.nih.gov/20055761/ DOI: 10.1042/bj20091609
Complete structured claim and evidence
Reduced glutathione stimulated all three tested PHD isoforms in the absence of ascorbate; millimolar GSH could substitute in the peptide assay, indicating reductant redundancy in this setting.
GSH → HIF-1 alpha prolyl hydroxylation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 2A–B; hydroxylation Methods
experimental_model
Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding
exposure
10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM.
limitations
Alternative reductant effects vary with substrate and assay; this is not a nutritional substitution recommendation or proof of in-vivo compensation mechanism.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens proteins
plain_language
These oxygen-sensing enzymes could use support from glutathione when vitamin C was absent in the test tube.
primary_references
[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1145–1157
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding · source_derived_draft · unverified_draft
### c-reg-gsh-substitutes-phd Reduced glutathione stimulated all three tested PHD isoforms in the absence of ascorbate; millimolar GSH could substitute in the peptide assay, indicating reductant redundancy in this setting. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: These oxygen-sensing enzymes could use support from glutathione when vitamin C was absent in the test tube. organism: Homo sapiens proteins tissue_or_cell_type: Cell-free experimental_model: Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding limitations: Alternative reductant effects vary with substrate and assay; this is not a nutritional substitution recommendation or proof of in-vivo compensation mechanism. exposure: 10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM. cross_nutrient: true evidence_location: Figure 2A–B; hydroxylation Methods [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
Complete structured claim and evidence
HPLC showed only a small decline in ascorbate during the PHD2 peptide reaction, independent of hydroxyl-acceptor substrate, providing no evidence that coupled prolyl hydroxylation consumed ascorbate stoichiometrically.
EGLN1 / PHD2 → L-Ascorbate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 2C
experimental_model
Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding; HPLC of reaction ascorbate
exposure
10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM. Ascorbate measured before and after 1 h.
limitations
Minor air oxidation remained possible; result does not exclude ascorbate consumption during uncoupled or oxidative-damage reactions.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens protein
plain_language
Vitamin C was not used up once for every hydroxylation event in this enzyme assay.
primary_references
[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
tissue_or_cell_type
Cell-free
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1159–1171
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding; HPLC of reaction ascorbate · source_derived_draft · unverified_draft
### c-reg-phd-ascorbate-not-stoichiometric HPLC showed only a small decline in ascorbate during the PHD2 peptide reaction, independent of hydroxyl-acceptor substrate, providing no evidence that coupled prolyl hydroxylation consumed ascorbate stoichiometrically. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C was not used up once for every hydroxylation event in this enzyme assay. organism: Homo sapiens protein tissue_or_cell_type: Cell-free experimental_model: Recombinant human PHD enzymes; HIF-1 alpha 556–574 peptide hydroxylation detected by VHL/elongin B/C binding; HPLC of reaction ascorbate limitations: Minor air oxidation remained possible; result does not exclude ascorbate consumption during uncoupled or oxidative-damage reactions. exposure: 10 µM FeSO4, 0.5 mM 2-oxoglutarate, pH 7.5, room temperature, 1 h; ascorbate omission/titration and GSH titration; standard ascorbate 2 mM. Ascorbate measured before and after 1 h. cross_nutrient: true evidence_location: Figure 2C [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
Complete structured claim and evidence
HeLa cells maintained in serum-free, ascorbate-free defined medium retained hypoxic HIF-1 alpha stabilization and HIF-dependent reporter activation relative to cells supplied with 50 µM ascorbate.
L-Ascorbate → HIF-dependent transcription source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 1B–C
experimental_model
HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter
exposure
0 versus 50 µM ascorbate; 0.2% versus 21% oxygen for 6-h protein assay, graded oxygen for 24-h reporter assay.
limitations
Cell-culture omission, not a controlled human dietary deficiency; residual adaptive reductant pathways were not eliminated.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Removing vitamin C from this adapted cancer-cell culture did not switch off its measured low-oxygen response.
primary_references
[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
tissue_or_cell_type
Cervical carcinoma cells
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1173–1185
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter · source_derived_draft · unverified_draft
### c-reg-hela-hypoxia-preserved HeLa cells maintained in serum-free, ascorbate-free defined medium retained hypoxic HIF-1 alpha stabilization and HIF-dependent reporter activation relative to cells supplied with 50 µM ascorbate. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing vitamin C from this adapted cancer-cell culture did not switch off its measured low-oxygen response. organism: Homo sapiens tissue_or_cell_type: Cervical carcinoma cells experimental_model: HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter limitations: Cell-culture omission, not a controlled human dietary deficiency; residual adaptive reductant pathways were not eliminated. exposure: 0 versus 50 µM ascorbate; 0.2% versus 21% oxygen for 6-h protein assay, graded oxygen for 24-h reporter assay. cross_nutrient: false evidence_location: Figure 1B–C [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
Complete structured claim and evidence
Male Gulo-null mice deprived of vitamin C for approximately five weeks retained a robust plasma erythropoietin response to 24 h at 8% oxygen, similar to supplemented controls, despite plasma ascorbate at or below 1 µM and scorbutic weight loss.
L-Ascorbate → Circulating erythropoietin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 5C–D; Animal studies
experimental_model
Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls
exposure
Maintenance 0.33 g/L ascorbic acid drinking water; withdrawal about 35–36 days; 8% inspired oxygen for 24 h.
limitations
Dietary deficiency in a synthesis-null animal; does not establish that every HIF target or tissue is unaffected, nor a safe human deficiency threshold.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Even severely vitamin-C-depleted mice retained this measured hormonal response to low oxygen.
primary_references
[c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
tissue_or_cell_type
Plasma erythropoietin; kidney Epo mRNA supporting endpoint
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1187–1199
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls · source_derived_draft · unverified_draft
### c-reg-gulo-depletion-epo-preserved Male Gulo-null mice deprived of vitamin C for approximately five weeks retained a robust plasma erythropoietin response to 24 h at 8% oxygen, similar to supplemented controls, despite plasma ascorbate at or below 1 µM and scorbutic weight loss. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Even severely vitamin-C-depleted mice retained this measured hormonal response to low oxygen. organism: Mus musculus tissue_or_cell_type: Plasma erythropoietin; kidney Epo mRNA supporting endpoint experimental_model: Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls limitations: Dietary deficiency in a synthesis-null animal; does not establish that every HIF target or tissue is unaffected, nor a safe human deficiency threshold. exposure: Maintenance 0.33 g/L ascorbic acid drinking water; withdrawal about 35–36 days; 8% inspired oxygen for 24 h. cross_nutrient: false evidence_location: Figure 5C–D; Animal studies [c-reg-nytko] Vitamin C is dispensable for oxygen sensing in vivo. (2011). https://pubmed.ncbi.nlm.nih.gov/21346252/ DOI: 10.1182/blood-2010-09-307637
Complete structured claim and evidence
Aqueous ascorbate reduced bilayer alpha-tocopheroxyl radical back to alpha-tocopherol in oxidizing soybean phosphatidylcholine liposomes; the reported apparent bimolecular rate constant was about 2 × 10^5 M^-1 s^-1 under those conditions.
L-Ascorbate → Alpha-tocopherol source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract radical accessibility and kinetic result
experimental_model
Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements
exposure
Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M.
limitations
Membrane composition, radical initiator and assay conditions determine kinetics; no human clinical benefit or universal membrane rate is established.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Glycine max lipid preparation; cell-free
plain_language
Vitamin C recycled the vitamin E radical back into vitamin E across this artificial membrane-water interface.
primary_references
[c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9
tissue_or_cell_type
Artificial liposomes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1201–1213
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements · source_derived_draft · unverified_draft
### c-reg-tocopherol-radical-recycling Aqueous ascorbate reduced bilayer alpha-tocopheroxyl radical back to alpha-tocopherol in oxidizing soybean phosphatidylcholine liposomes; the reported apparent bimolecular rate constant was about 2 × 10^5 M^-1 s^-1 under those conditions. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C recycled the vitamin E radical back into vitamin E across this artificial membrane-water interface. organism: Glycine max lipid preparation; cell-free tissue_or_cell_type: Artificial liposomes experimental_model: Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements limitations: Membrane composition, radical initiator and assay conditions determine kinetics; no human clinical benefit or universal membrane rate is established. exposure: Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M. cross_nutrient: true evidence_location: Primary abstract radical accessibility and kinetic result [c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9
Complete structured claim and evidence
The inhibitory effect of alpha-tocopherol on liposome lipid peroxidation persisted while aqueous ascorbic acid remained available, consistent with continued tocopherol-radical recycling.
L-Ascorbate → Lipid peroxidation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract final result
experimental_model
Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements
exposure
Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M.
limitations
This persistence endpoint is separate from the radical-reduction reaction and does not establish a supplementation effect in people.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Glycine max lipid preparation; cell-free
plain_language
Vitamin C prolonged vitamin E’s protection against oxidation in the liposome experiment.
primary_references
[c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9
tissue_or_cell_type
Artificial liposomes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1215–1227
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements · source_derived_draft · unverified_draft
### c-reg-tocopherol-antiperoxidation-persistence The inhibitory effect of alpha-tocopherol on liposome lipid peroxidation persisted while aqueous ascorbic acid remained available, consistent with continued tocopherol-radical recycling. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C prolonged vitamin E’s protection against oxidation in the liposome experiment. organism: Glycine max lipid preparation; cell-free tissue_or_cell_type: Artificial liposomes experimental_model: Soybean L-alpha-phosphatidylcholine liposomes undergoing Fe(III)-triethylenetetramine-initiated peroxidation; EPR, optical and polarographic measurements limitations: This persistence endpoint is separate from the radical-reduction reaction and does not establish a supplementation effect in people. exposure: Aqueous ascorbic acid described as physiological concentration in abstract (exact dose unavailable); bilayer alpha-tocopheroxyl radical detected at 10^-8–10^-7 M. cross_nutrient: true evidence_location: Primary abstract final result [c-reg-scarpa] Formation of alpha-tocopherol radical and recycling of alpha-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study. (1984). https://pubmed.ncbi.nlm.nih.gov/6089911/ DOI: 10.1016/0304-4165(84)90070-9
Complete structured claim and evidence
JLP-119 lymphoma cells died after extracellular ascorbate exposure even when previously loaded to about 3 mM intracellular ascorbate; matched loading through dehydroascorbic acid did not reproduce the extracellular-ascorbate death effect.
L-Ascorbate → Lymphoma cell death source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 2D–E
experimental_model
Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h
exposure
Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium.
limitations
Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. This conclusion is specific to this line and loading protocol.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The killing depended on vitamin C outside these lymphoma cells, not merely on having vitamin C inside them.
primary_references
[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
tissue_or_cell_type
Burkitt lymphoma cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1229–1241
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h · source_derived_draft · unverified_draft
### c-reg-lymphoma-extracellular-ascorbate JLP-119 lymphoma cells died after extracellular ascorbate exposure even when previously loaded to about 3 mM intracellular ascorbate; matched loading through dehydroascorbic acid did not reproduce the extracellular-ascorbate death effect. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The killing depended on vitamin C outside these lymphoma cells, not merely on having vitamin C inside them. organism: Homo sapiens tissue_or_cell_type: Burkitt lymphoma cells experimental_model: Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h limitations: Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. This conclusion is specific to this line and loading protocol. exposure: Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. cross_nutrient: false evidence_location: Figure 2D–E [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
Complete structured claim and evidence
Extracellular catalase prevented JLP-119 cell death after 2 mM ascorbate, supporting peroxide as a required mediator in this culture experiment.
Experimental catalase preparation → Lymphoma cell death source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 3A
experimental_model
Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h
exposure
Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Catalase 100 µg/mL preincubated 30 min.
limitations
Primary paper identifies catalase but does not specify species in the inspected Methods; the source species should not be inferred. Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens cells; experimental catalase preparation
plain_language
Breaking down peroxide outside the cells prevented the vitamin C-associated killing.
primary_references
[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
tissue_or_cell_type
Burkitt lymphoma cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1243–1255
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h · source_derived_draft · unverified_draft
### c-reg-catalase-protects-lymphoma Extracellular catalase prevented JLP-119 cell death after 2 mM ascorbate, supporting peroxide as a required mediator in this culture experiment. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Breaking down peroxide outside the cells prevented the vitamin C-associated killing. organism: Homo sapiens cells; experimental catalase preparation tissue_or_cell_type: Burkitt lymphoma cells experimental_model: Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h limitations: Primary paper identifies catalase but does not specify species in the inspected Methods; the source species should not be inferred. Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. exposure: Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Catalase 100 µg/mL preincubated 30 min. cross_nutrient: false evidence_location: Figure 3A [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
Complete structured claim and evidence
Ascorbate produced peroxide in cell culture medium without requiring cells; accumulation depended on ascorbate concentration, time and serum fraction, and tracked ascorbyl radical detected by EPR.
L-Ascorbate → Extracellular hydrogen peroxide accumulation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 4A–C
experimental_model
Cell-free medium; catalase-dependent oxygen-electrode peroxide assay and EPR
exposure
0.2–2 mM ascorbate over 1 h; 2 mM ascorbate with 0.5–10% FBS in serum-dependence experiment.
limitations
Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Net accumulation reflects both production and removal; ascorbate can interfere with routine peroxidase assays.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cell-free; bovine serum-containing medium
plain_language
The culture liquid itself could turn high-concentration vitamin C into peroxide.
primary_references
[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
tissue_or_cell_type
Extracellular assay medium
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1257–1269
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free medium; catalase-dependent oxygen-electrode peroxide assay and EPR · source_derived_draft · unverified_draft
### c-reg-medium-peroxide-generation Ascorbate produced peroxide in cell culture medium without requiring cells; accumulation depended on ascorbate concentration, time and serum fraction, and tracked ascorbyl radical detected by EPR. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The culture liquid itself could turn high-concentration vitamin C into peroxide. organism: Cell-free; bovine serum-containing medium tissue_or_cell_type: Extracellular assay medium experimental_model: Cell-free medium; catalase-dependent oxygen-electrode peroxide assay and EPR limitations: Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Net accumulation reflects both production and removal; ascorbate can interfere with routine peroxidase assays. exposure: 0.2–2 mM ascorbate over 1 h; 2 mM ascorbate with 0.5–10% FBS in serum-dependence experiment. cross_nutrient: false evidence_location: Figure 4A–C [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
Complete structured claim and evidence
Adding human erythrocytes at 25% or 50% hematocrit protected JLP-119 lymphoma cells from the 2 mM ascorbate challenge, demonstrating that blood-cell clearance can change an otherwise cytotoxic culture exposure.
Erythrocyte peroxide scavenging → Lymphoma cell death source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 5C; Methods RBC mixtures
experimental_model
Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h with added human red blood cells
exposure
Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Reconstituted 25% or 50% hematocrit; lymphoma cells recovered before later assessment.
limitations
Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Protective blood-cell mixture is not proof that all extravascular compartments are equally protected.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Red blood cells removed the damaging chemistry sufficiently to protect the lymphoma cells in this mixture.
primary_references
[c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
tissue_or_cell_type
Lymphoma/erythrocyte coculture
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1271–1283
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h with added human red blood cells · source_derived_draft · unverified_draft
### c-reg-erythrocytes-protect-lymphoma Adding human erythrocytes at 25% or 50% hematocrit protected JLP-119 lymphoma cells from the 2 mM ascorbate challenge, demonstrating that blood-cell clearance can change an otherwise cytotoxic culture exposure. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Red blood cells removed the damaging chemistry sufficiently to protect the lymphoma cells in this mixture. organism: Homo sapiens tissue_or_cell_type: Lymphoma/erythrocyte coculture experimental_model: Human JLP-119 Burkitt lymphoma culture; 1-h exposure, washing, Hoechst/propidium iodide cell-death assessment after 18–22 h with added human red blood cells limitations: Pharmacological in-vitro exposure; medium chemistry and peroxide clearance differ from intact tissues. No dietary or clinical anticancer inference. Protective blood-cell mixture is not proof that all extravascular compartments are equally protected. exposure: Fresh L-ascorbic acid neutralized to pH 7.0; 2 mM extracellular ascorbate for 1 h; cells 2.5 × 10^5/mL in serum-containing culture medium. Reconstituted 25% or 50% hematocrit; lymphoma cells recovered before later assessment. cross_nutrient: false evidence_location: Figure 5C; Methods RBC mixtures [c-reg-chen] Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. (2005). https://pubmed.ncbi.nlm.nih.gov/16157892/ DOI: 10.1073/pnas.0506390102
Complete structured claim and evidence
Supplementing RPMI/FCS with as little as 5 µM iron as FAC prevented the marked viability loss caused by 5–10 mM ascorbate in LNCaP and PC-3 cultures; protection also occurred at higher tested iron additions.
Ferric ammonium citrate → Prostate cancer-cell viability source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 1a–b; treatment Methods
experimental_model
Human LNCaP and PC-3 monolayers in RPMI-1640 +10% FCS; MTT and crystal-violet viability assays
exposure
5 or 10 mM freshly neutralized ascorbic acid, 2 h, then wash/recovery; FAC adds 5–30 µM iron to medium containing 5.6 ±1.3 µM total iron.
limitations
FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
In this medium, extra iron protected the prostate cancer cells from high-concentration vitamin C.
primary_references
[c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955
tissue_or_cell_type
Prostate carcinoma cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1285–1297
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human LNCaP and PC-3 monolayers in RPMI-1640 +10% FCS; MTT and crystal-violet viability assays · source_derived_draft · unverified_draft
### c-reg-extracellular-iron-cytoprotection Supplementing RPMI/FCS with as little as 5 µM iron as FAC prevented the marked viability loss caused by 5–10 mM ascorbate in LNCaP and PC-3 cultures; protection also occurred at higher tested iron additions. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this medium, extra iron protected the prostate cancer cells from high-concentration vitamin C. organism: Homo sapiens tissue_or_cell_type: Prostate carcinoma cells experimental_model: Human LNCaP and PC-3 monolayers in RPMI-1640 +10% FCS; MTT and crystal-violet viability assays limitations: FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion. exposure: 5 or 10 mM freshly neutralized ascorbic acid, 2 h, then wash/recovery; FAC adds 5–30 µM iron to medium containing 5.6 ±1.3 µM total iron. cross_nutrient: true evidence_location: Figure 1a–b; treatment Methods [c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955
Complete structured claim and evidence
In RPMI/FCS exposed to 5 mM ascorbate, added 5 µM FAC iron accelerated oxygen consumption/ascorbate oxidation but reduced detectable peroxide accumulation, showing that faster oxidation need not yield a larger steady peroxide pool.
Ferric ammonium citrate → Extracellular hydrogen peroxide accumulation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 2a–b; Oximetry Methods
experimental_model
Cell-free medium oximetry; peroxide inferred from catalase-triggered oxygen release
exposure
5 mM ascorbate ±5 µM FAC iron; oxygen trace and 600 U catalase addition after about 15 min.
limitations
FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion. The endpoint measures net peroxide and does not separately determine every elementary redox rate.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Cell-free bovine-serum-containing medium
plain_language
Iron sped up vitamin C oxidation while also helping remove the peroxide produced.
primary_references
[c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955
tissue_or_cell_type
RPMI-1640 +10% FCS
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1299–1311
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free medium oximetry; peroxide inferred from catalase-triggered oxygen release · source_derived_draft · unverified_draft
### c-reg-extracellular-iron-peroxide-removal In RPMI/FCS exposed to 5 mM ascorbate, added 5 µM FAC iron accelerated oxygen consumption/ascorbate oxidation but reduced detectable peroxide accumulation, showing that faster oxidation need not yield a larger steady peroxide pool. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron sped up vitamin C oxidation while also helping remove the peroxide produced. organism: Cell-free bovine-serum-containing medium tissue_or_cell_type: RPMI-1640 +10% FCS experimental_model: Cell-free medium oximetry; peroxide inferred from catalase-triggered oxygen release limitations: FAC supplementation changes iron speciation as well as concentration; matching plasma total iron does not reconstruct transferrin binding or tissue interstitial chemistry. No clinical efficacy conclusion. The endpoint measures net peroxide and does not separately determine every elementary redox rate. exposure: 5 mM ascorbate ±5 µM FAC iron; oxygen trace and 600 U catalase addition after about 15 min. cross_nutrient: true evidence_location: Figure 2a–b; Oximetry Methods [c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955
Complete structured claim and evidence
Adding iron to pharmacological ascorbate increased measured extracellular protein oxidation about threefold in the RPMI/FCS experiment while preserving intracellular thiols. The authors interpreted this as extracellular interception of Fenton-derived oxidants; direct hydroxyl-radical spin trapping was unsuccessful because ascorbate reduced the spin adducts.
Ferric ammonium citrate → Extracellular protein oxidation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 3a–c; Results discussing failed EPR spin trapping
experimental_model
Biochemical extracellular protein-oxidation assay and intracellular thiol-sensitive RSSR EPR assay
exposure
5 mM ascorbate ±5 µM FAC iron for 2 h in RPMI-1640 +10% FCS; additional 30 µM iron experiment gave similar results. Thiols assayed using 100 µM RSSR probe.
limitations
Observed protein oxidation supports but does not directly prove the proposed hydroxyl-radical buffering mechanism. FAC speciation and medium composition limit tissue extrapolation.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens LNCaP/PC-3 cells; bovine-serum-containing extracellular medium
plain_language
Extra iron shifted more oxidation onto proteins in the culture liquid while protecting the cells. The proposed short-lived radical intermediate could not be directly measured.
primary_references
[c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955
tissue_or_cell_type
Prostate cancer-cell cultures and their extracellular RPMI/FCS medium
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1313–1325
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical extracellular protein-oxidation assay and intracellular thiol-sensitive RSSR EPR assay · source_derived_draft · unverified_draft
### c-reg-extracellular-protein-oxidation Adding iron to pharmacological ascorbate increased measured extracellular protein oxidation about threefold in the RPMI/FCS experiment while preserving intracellular thiols. The authors interpreted this as extracellular interception of Fenton-derived oxidants; direct hydroxyl-radical spin trapping was unsuccessful because ascorbate reduced the spin adducts. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra iron shifted more oxidation onto proteins in the culture liquid while protecting the cells. The proposed short-lived radical intermediate could not be directly measured. organism: Homo sapiens LNCaP/PC-3 cells; bovine-serum-containing extracellular medium tissue_or_cell_type: Prostate cancer-cell cultures and their extracellular RPMI/FCS medium experimental_model: Biochemical extracellular protein-oxidation assay and intracellular thiol-sensitive RSSR EPR assay limitations: Observed protein oxidation supports but does not directly prove the proposed hydroxyl-radical buffering mechanism. FAC speciation and medium composition limit tissue extrapolation. exposure: 5 mM ascorbate ±5 µM FAC iron for 2 h in RPMI-1640 +10% FCS; additional 30 µM iron experiment gave similar results. Thiols assayed using 100 µM RSSR probe. cross_nutrient: true evidence_location: Figure 3a–c; Results discussing failed EPR spin trapping [c-reg-mojic] Extracellular iron diminishes anticancer effects of vitamin C: an in vitro study. (2014). https://pubmed.ncbi.nlm.nih.gov/25092529/ DOI: 10.1038/srep05955
Complete structured claim and evidence
Pharmacological ascorbate decreased total cellular aconitase activity in NSCLC cultures; catalase overexpression prevented this activity loss, implicating peroxide-dependent injury to the Fe-S enzyme system.
L-Ascorbate → Total cellular aconitase activity source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 6C
experimental_model
Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; total-cell aconitase activity assay and adenoviral catalase rescue
exposure
15 pmol ascorbate/cell (approximately 8 mM), 1 h; catalase rescue 50-MOI vector transduction 36 h before treatment.
limitations
Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. Total assay does not resolve cytosolic ACO1 from mitochondrial ACO2.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
High-concentration vitamin C impaired an iron-sulfur enzyme in these cancer cells, and removing peroxide protected its activity.
primary_references
[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
tissue_or_cell_type
NSCLC cell cultures
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1327–1339
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; total-cell aconitase activity assay and adenoviral catalase rescue · source_derived_draft · unverified_draft
### c-reg-aconitase-inactivation Pharmacological ascorbate decreased total cellular aconitase activity in NSCLC cultures; catalase overexpression prevented this activity loss, implicating peroxide-dependent injury to the Fe-S enzyme system. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: High-concentration vitamin C impaired an iron-sulfur enzyme in these cancer cells, and removing peroxide protected its activity. organism: Homo sapiens tissue_or_cell_type: NSCLC cell cultures experimental_model: Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; total-cell aconitase activity assay and adenoviral catalase rescue limitations: Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. Total assay does not resolve cytosolic ACO1 from mitochondrial ACO2. exposure: 15 pmol ascorbate/cell (approximately 8 mM), 1 h; catalase rescue 50-MOI vector transduction 36 h before treatment. cross_nutrient: true evidence_location: Figure 6C [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
Complete structured claim and evidence
After 15 pmol/cell (approximately 8 mM) ascorbate for 1 h, NSCLC lysates showed reduced respiratory-complex I activity while the separately assayed complex IV activity was retained, consistent with vulnerability of Fe-S-containing machinery.
L-Ascorbate → Mitochondrial respiratory complex I source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 6D
experimental_model
Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays
exposure
15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays.
limitations
Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
This high-concentration exposure impaired respiratory complex I in the studied cancer cells.
primary_references
[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
tissue_or_cell_type
NSCLC cell cultures
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1341–1353
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays · source_derived_draft · unverified_draft
### c-reg-complex-i-inactivation After 15 pmol/cell (approximately 8 mM) ascorbate for 1 h, NSCLC lysates showed reduced respiratory-complex I activity while the separately assayed complex IV activity was retained, consistent with vulnerability of Fe-S-containing machinery. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This high-concentration exposure impaired respiratory complex I in the studied cancer cells. organism: Homo sapiens tissue_or_cell_type: NSCLC cell cultures experimental_model: Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays limitations: Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed. exposure: 15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays. cross_nutrient: true evidence_location: Figure 6D [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
Complete structured claim and evidence
SOD2 knockout A549 cells had higher basal labile iron and greater clonogenic killing by ascorbate than parental cells, linking antioxidant machinery impairment to sensitivity in this model.
SOD2 gene → Cancer-cell clonogenic survival source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Figure 5C–E
experimental_model
SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival
exposure
10 pmol/cell (2 mM) ascorbate for 1 h; LIP measured with 500 nM calcein-AM and 100 µM 2,2′-bipyridyl dequenching.
limitations
SOD2 genotype is not dietary manganese deficiency; DHE oxidation alone is not chemically specific proof of superoxide. Study does not identify a universal cancer-selectivity mechanism.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Removing a mitochondrial antioxidant enzyme made these lung cancer cells more vulnerable to the high-dose exposure.
primary_references
[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
tissue_or_cell_type
Lung adenocarcinoma cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1355–1367
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival · source_derived_draft · unverified_draft
### c-reg-sod2-loss-sensitizes SOD2 knockout A549 cells had higher basal labile iron and greater clonogenic killing by ascorbate than parental cells, linking antioxidant machinery impairment to sensitivity in this model. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing a mitochondrial antioxidant enzyme made these lung cancer cells more vulnerable to the high-dose exposure. organism: Homo sapiens tissue_or_cell_type: Lung adenocarcinoma cells experimental_model: SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival limitations: SOD2 genotype is not dietary manganese deficiency; DHE oxidation alone is not chemically specific proof of superoxide. Study does not identify a universal cancer-selectivity mechanism. exposure: 10 pmol/cell (2 mM) ascorbate for 1 h; LIP measured with 500 nM calcein-AM and 100 µM 2,2′-bipyridyl dequenching. cross_nutrient: true evidence_location: Figure 5C–E [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
Complete structured claim and evidence
Ferritin-heavy-chain overexpression in H1299 cells lowered labile iron and increased clonogenic survival after pharmacological ascorbate, supporting a protective role of intracellular iron sequestration in this setting.
Ferritin heavy chain → Cancer-cell clonogenic survival source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 6I–L
experimental_model
H1299 adenoviral ferritin-heavy-chain versus empty-vector cultures; calcein/BIP and clonogenic assays
exposure
20-MOI ferritin-heavy-chain expression 36 h before experiment; 5 pmol/cell (approximately 2–3 mM) ascorbate for 1 h.
limitations
Engineered overexpression is not dietary iron deficiency or ordinary ferritin concentration; serum ferritin does not measure this intracellular intervention.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Locking more iron into ferritin protected these lung cancer cells from the exposure.
primary_references
[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
tissue_or_cell_type
NSCLC cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1369–1381
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · H1299 adenoviral ferritin-heavy-chain versus empty-vector cultures; calcein/BIP and clonogenic assays · source_derived_draft · unverified_draft
### c-reg-ferritin-heavy-protects Ferritin-heavy-chain overexpression in H1299 cells lowered labile iron and increased clonogenic survival after pharmacological ascorbate, supporting a protective role of intracellular iron sequestration in this setting. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Locking more iron into ferritin protected these lung cancer cells from the exposure. organism: Homo sapiens tissue_or_cell_type: NSCLC cells experimental_model: H1299 adenoviral ferritin-heavy-chain versus empty-vector cultures; calcein/BIP and clonogenic assays limitations: Engineered overexpression is not dietary iron deficiency or ordinary ferritin concentration; serum ferritin does not measure this intracellular intervention. exposure: 20-MOI ferritin-heavy-chain expression 36 h before experiment; 5 pmol/cell (approximately 2–3 mM) ascorbate for 1 h. cross_nutrient: true evidence_location: Figure 6I–L [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
Complete structured claim and evidence
The same pharmacological ascorbate exposure reduced NSCLC respiratory-complex II activity, extending the observed impairment to a second Fe-S-containing respiratory complex; complex IV activity was retained.
L-Ascorbate → Respiratory complex II source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 6D
experimental_model
Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays
exposure
15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays.
limitations
Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The exposure also impaired respiratory complex II, which participates in respiration and the citric acid cycle.
primary_references
[c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
tissue_or_cell_type
NSCLC cell cultures
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1383–1395
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays · source_derived_draft · unverified_draft
### c-reg-complex-ii-inactivation The same pharmacological ascorbate exposure reduced NSCLC respiratory-complex II activity, extending the observed impairment to a second Fe-S-containing respiratory complex; complex IV activity was retained. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The exposure also impaired respiratory complex II, which participates in respiration and the citric acid cycle. organism: Homo sapiens tissue_or_cell_type: NSCLC cell cultures experimental_model: Human NSCLC cells cultured in RPMI-1640 +10% FBS; L-ascorbic acid stocks neutralized to pH 7.0; isolated lysate respiratory-enzyme activity assays limitations: Short pharmacological culture exposure; dose per cell, medium and density alter toxicity. Enzyme activity loss is consistent with Fe-S damage but does not directly trace individual iron atoms leaving a cluster. This pattern supports but does not by itself prove direct cluster oxidation; no organism-level mitochondrial benefit or harm claimed. exposure: 15 pmol/cell (approximately 8 mM) ascorbate for 1 h before activity assays. cross_nutrient: true evidence_location: Figure 6D [c-reg-schoenfeld] O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. (2017). https://pubmed.ncbi.nlm.nih.gov/28366679/ DOI: 10.1016/j.ccell.2017.02.018
Complete structured claim and evidence
Steady-state plasma vitamin C followed a sigmoid dose-response: steepest at 30–100 mg/day, beyond the sigmoid region at 200 mg/day, with complete saturation reported at 1000 mg/day in this cohort.
L-Ascorbic acid → Plasma ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study.
exposure
Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments.
limitations
Small controlled cohort; saturation is assay- and endpoint-specific. Historical authors’ RDA and safety proposals are not presented as current universal guidance.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Taking more changed the blood level much less once the curve flattened.
primary_references
[c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1397–1407
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. · source_derived_draft · unverified_draft
### c-plasma-dose-sigmoid Steady-state plasma vitamin C followed a sigmoid dose-response: steepest at 30–100 mg/day, beyond the sigmoid region at 200 mg/day, with complete saturation reported at 1000 mg/day in this cohort. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Taking more changed the blood level much less once the curve flattened. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. limitations: Small controlled cohort; saturation is assay- and endpoint-specific. Historical authors’ RDA and safety proposals are not presented as current universal guidance. exposure: Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments. [c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
Complete structured claim and evidence
Neutrophils, monocytes and lymphocytes saturated at 100 mg/day and held vitamin C concentrations at least 14 times those in plasma.
L-Ascorbic acid → Circulating leukocyte ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study.
exposure
Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments.
limitations
Concentration is not an immune-function or infection-prevention endpoint.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Blood cells can concentrate vitamin C; the surrounding plasma does not give the same number.
primary_references
[c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
tissue_or_cell_type
Human circulating neutrophils, monocytes and lymphocytes
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1409–1419
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. · source_derived_draft · unverified_draft
### c-leukocyte-concentration-saturation Neutrophils, monocytes and lymphocytes saturated at 100 mg/day and held vitamin C concentrations at least 14 times those in plasma. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blood cells can concentrate vitamin C; the surrounding plasma does not give the same number. organism: Homo sapiens tissue_or_cell_type: Human circulating neutrophils, monocytes and lymphocytes experimental_model: Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. limitations: Concentration is not an immune-function or infection-prevention endpoint. exposure: Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments. [c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
Complete structured claim and evidence
A 200-mg single dose had complete bioavailability; fractional bioavailability declined at single doses of 500 mg and above.
L-Ascorbic acid → Oral vitamin C bioavailability source_derived_draftungraded
Experimental context and source evidence
experimental_model
Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study.
exposure
Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments.
limitations
Distinguish fraction absorbed from absolute amount and single-dose results from daily steady-state dosing.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
A larger swallowed dose did not mean the same fraction entered circulation.
primary_references
[c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1421–1431
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. · source_derived_draft · unverified_draft
### c-bioavailability-dose-dependence A 200-mg single dose had complete bioavailability; fractional bioavailability declined at single doses of 500 mg and above. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A larger swallowed dose did not mean the same fraction entered circulation. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. limitations: Distinguish fraction absorbed from absolute amount and single-dose results from daily steady-state dosing. exposure: Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments. [c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
Complete structured claim and evidence
Six of seven volunteers had no detectable urinary vitamin C until the 100-mg dose; higher exposure produced urinary loss.
L-Ascorbic acid → Urinary ascorbate excretion source_derived_draftungraded
Experimental context and source evidence
experimental_model
Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study.
exposure
Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments.
limitations
Detection limits and individual variation apply; not a universal kidney threshold.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The kidney conserved more at low supply and excreted more as supply rose.
primary_references
[c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1433–1443
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. · source_derived_draft · unverified_draft
### c-urinary-retention-dose Six of seven volunteers had no detectable urinary vitamin C until the 100-mg dose; higher exposure produced urinary loss. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The kidney conserved more at low supply and excreted more as supply rose. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Seven healthy volunteers hospitalized for 4–6 months in a controlled depletion/repletion study. limitations: Detection limits and individual variation apply; not a universal kidney threshold. exposure: Diet below 5 mg vitamin C/day, followed by seven daily doses spanning 30–2500 mg; separate single-dose bioavailability assessments. [c-levine1996] Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance (1996). https://pubmed.ncbi.nlm.nih.gov/8623000/ DOI: 10.1073/pnas.93.8.3704
Complete structured claim and evidence
In the young-women study, plasma and circulating cells saturated at 400 mg/day, with higher doses eliminated in urine.
L-Ascorbic acid → Plasma ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
Healthy young women hospitalized for 186 ± 28 days in a depletion/repletion study.
exposure
Vitamin C 30–2500 mg/day at sequential steady states. Participant count is not extracted from the inspected abstract.
limitations
Study differences do not establish a fixed sex-specific requirement; these are historical experimental endpoints.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The measured pools reached a plateau in this separate cohort.
primary_references
[c-levine2001] A new recommended dietary allowance of vitamin C for healthy young women (2001). https://pubmed.ncbi.nlm.nih.gov/11504949/ DOI: 10.1073/pnas.171318198
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1445–1455
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Healthy young women hospitalized for 186 ± 28 days in a depletion/repletion study. · source_derived_draft · unverified_draft
### c-women-plasma-saturation In the young-women study, plasma and circulating cells saturated at 400 mg/day, with higher doses eliminated in urine. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured pools reached a plateau in this separate cohort. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Healthy young women hospitalized for 186 ± 28 days in a depletion/repletion study. limitations: Study differences do not establish a fixed sex-specific requirement; these are historical experimental endpoints. exposure: Vitamin C 30–2500 mg/day at sequential steady states. Participant count is not extracted from the inspected abstract. [c-levine2001] A new recommended dietary allowance of vitamin C for healthy young women (2001). https://pubmed.ncbi.nlm.nih.gov/11504949/ DOI: 10.1073/pnas.171318198
Complete structured claim and evidence
Plasma and urinary F2-isoprostanes and a major urinary metabolite did not change across the studied vitamin C doses.
L-Ascorbic acid → F2-isoprostane measurements source_derived_draftungraded
Experimental context and source evidence
experimental_model
Healthy young women hospitalized for 186 ± 28 days in a depletion/repletion study.
exposure
Vitamin C 30–2500 mg/day at sequential steady states. Participant count is not extracted from the inspected abstract.
limitations
Does not negate ascorbate chemistry or establish no effect on every oxidant, tissue or disease state.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Increasing supply did not change these particular oxidative-damage markers in healthy women.
primary_references
[c-levine2001] A new recommended dietary allowance of vitamin C for healthy young women (2001). https://pubmed.ncbi.nlm.nih.gov/11504949/ DOI: 10.1073/pnas.171318198
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1457–1467
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Healthy young women hospitalized for 186 ± 28 days in a depletion/repletion study. · source_derived_draft · unverified_draft
### c-women-isoprostane-null Plasma and urinary F2-isoprostanes and a major urinary metabolite did not change across the studied vitamin C doses. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Increasing supply did not change these particular oxidative-damage markers in healthy women. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Healthy young women hospitalized for 186 ± 28 days in a depletion/repletion study. limitations: Does not negate ascorbate chemistry or establish no effect on every oxidant, tissue or disease state. exposure: Vitamin C 30–2500 mg/day at sequential steady states. Participant count is not extracted from the inspected abstract. [c-levine2001] A new recommended dietary allowance of vitamin C for healthy young women (2001). https://pubmed.ncbi.nlm.nih.gov/11504949/ DOI: 10.1073/pnas.171318198
Complete structured claim and evidence
At the same measured 1.25-g dose, mean peak plasma vitamin C was 134.8 ± 20.6 micromol/L orally versus 885 ± 201.2 micromol/L intravenously.
L-Ascorbic acid → Plasma ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
Seventeen healthy hospitalized volunteers; measured dose/concentration experiments plus pharmacokinetic modeling.
exposure
Measured oral/IV doses 0.015–1.25 g; modeled doses 1–100 g. Larger modeled exposures were not validated in cancer patients.
limitations
Healthy-volunteer pharmacokinetics, not evidence of cancer efficacy.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Bypassing the gut produced a much larger blood peak for the same administered amount.
primary_references
[c-padayatty2004] Vitamin C pharmacokinetics: implications for oral and intravenous use (2004). https://pubmed.ncbi.nlm.nih.gov/15068981/ DOI: 10.7326/0003-4819-140-7-200404060-00010
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1469–1479
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seventeen healthy hospitalized volunteers; measured dose/concentration experiments plus pharmacokinetic modeling. · source_derived_draft · unverified_draft
### c-oral-iv-measured-peaks At the same measured 1.25-g dose, mean peak plasma vitamin C was 134.8 ± 20.6 micromol/L orally versus 885 ± 201.2 micromol/L intravenously. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bypassing the gut produced a much larger blood peak for the same administered amount. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Seventeen healthy hospitalized volunteers; measured dose/concentration experiments plus pharmacokinetic modeling. limitations: Healthy-volunteer pharmacokinetics, not evidence of cancer efficacy. exposure: Measured oral/IV doses 0.015–1.25 g; modeled doses 1–100 g. Larger modeled exposures were not validated in cancer patients. [c-padayatty2004] Vitamin C pharmacokinetics: implications for oral and intravenous use (2004). https://pubmed.ncbi.nlm.nih.gov/15068981/ DOI: 10.7326/0003-4819-140-7-200404060-00010
Complete structured claim and evidence
The model predicted peaks of 220 micromol/L for oral 3 g every four hours and 13400 micromol/L for 50 g IV.
L-Ascorbic acid → Plasma ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
Seventeen healthy hospitalized volunteers; measured dose/concentration experiments plus pharmacokinetic modeling.
exposure
Measured oral/IV doses 0.015–1.25 g; modeled doses 1–100 g. Larger modeled exposures were not validated in cancer patients.
limitations
These high-dose values were calculated, not measured in this study; no patient recommendation or proof of benefit.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The model illustrates why oral and intravenous experiments cannot be treated as equivalent exposures.
primary_references
[c-padayatty2004] Vitamin C pharmacokinetics: implications for oral and intravenous use (2004). https://pubmed.ncbi.nlm.nih.gov/15068981/ DOI: 10.7326/0003-4819-140-7-200404060-00010
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1481–1491
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seventeen healthy hospitalized volunteers; measured dose/concentration experiments plus pharmacokinetic modeling. · source_derived_draft · unverified_draft
### c-oral-iv-modeled-peaks The model predicted peaks of 220 micromol/L for oral 3 g every four hours and 13400 micromol/L for 50 g IV. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The model illustrates why oral and intravenous experiments cannot be treated as equivalent exposures. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Seventeen healthy hospitalized volunteers; measured dose/concentration experiments plus pharmacokinetic modeling. limitations: These high-dose values were calculated, not measured in this study; no patient recommendation or proof of benefit. exposure: Measured oral/IV doses 0.015–1.25 g; modeled doses 1–100 g. Larger modeled exposures were not validated in cancer patients. [c-padayatty2004] Vitamin C pharmacokinetics: implications for oral and intravenous use (2004). https://pubmed.ncbi.nlm.nih.gov/15068981/ DOI: 10.7326/0003-4819-140-7-200404060-00010
Complete structured claim and evidence
The four completers developed scurvy; recorded signs included follicular hyperkeratosis, swollen bleeding gums and perifollicular or conjunctival hemorrhage.
Vitamin C → Scurvy skin, gum and hemorrhagic signs source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy.
exposure
Diet devoid of vitamin C but adequate in other essential nutrients.
limitations
The human study measured signs, not the contribution of each specific collagen enzyme.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Severe shortage became visible in skin, gums and small-vessel bleeding.
primary_references
[c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1493–1503
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. · source_derived_draft · unverified_draft
### c-scurvy-mucocutaneous-signs The four completers developed scurvy; recorded signs included follicular hyperkeratosis, swollen bleeding gums and perifollicular or conjunctival hemorrhage. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Severe shortage became visible in skin, gums and small-vessel bleeding. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. limitations: The human study measured signs, not the contribution of each specific collagen enzyme. exposure: Diet devoid of vitamin C but adequate in other essential nutrients. [c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535
Complete structured claim and evidence
The publisher summary reports near disappearance of ascorbic acid from blood and urine, with erratic low-level readings attributed to an interfering substance.
Vitamin C → Plasma ascorbate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy.
exposure
Diet devoid of vitamin C but adequate in other essential nutrients.
limitations
Blood and urine findings are not measurements of every tissue pool.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Very low readings accompanied scurvy, but the historical assay became unreliable near depletion.
primary_references
[c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1505–1515
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. · source_derived_draft · unverified_draft
### c-scurvy-circulating-depletion The publisher summary reports near disappearance of ascorbic acid from blood and urine, with erratic low-level readings attributed to an interfering substance. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Very low readings accompanied scurvy, but the historical assay became unreliable near depletion. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. limitations: Blood and urine findings are not measurements of every tissue pool. exposure: Diet devoid of vitamin C but adequate in other essential nutrients. [c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535
Complete structured claim and evidence
Despite the clinical scurvy signs, the report found no abnormality in the measured wound-healing rate, blood counts or coagulation tests.
Vitamin C → Experimental wound healing rate source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy.
exposure
Diet devoid of vitamin C but adequate in other essential nutrients.
limitations
Wound closure rate is not scar breaking strength; the inspected summary does not establish preserved collagen quality or contradict all wound-healing studies.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Not every commonly expected scurvy endpoint changed in this particular experiment.
primary_references
[c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1517–1527
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. · source_derived_draft · unverified_draft
### c-scurvy-wound-rate-boundary Despite the clinical scurvy signs, the report found no abnormality in the measured wound-healing rate, blood counts or coagulation tests. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Not every commonly expected scurvy endpoint changed in this particular experiment. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Historical metabolic-ward study: six apparently healthy male prisoners enrolled, four completed vitamin C deprivation and developed scurvy. limitations: Wound closure rate is not scar breaking strength; the inspected summary does not establish preserved collagen quality or contradict all wound-healing studies. exposure: Diet devoid of vitamin C but adequate in other essential nutrients. [c-hodges1969] Experimental scurvy in man (1969). https://pubmed.ncbi.nlm.nih.gov/4977512/ DOI: 10.1093/ajcn/22.5.535
Complete structured claim and evidence
Forearm vasoconstriction to intra-arterial norepinephrine and tyramine was greater after repletion; four subjects also had lower resistance-vessel responsiveness to lower-body negative pressure during deficiency.
Vitamin C → Forearm vasoconstriction to adrenergic stimuli source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion.
exposure
Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine.
limitations
Does not isolate endothelial, smooth-muscle or collagen mechanisms.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The blood vessels responded less strongly to some constricting signals during shortage.
primary_references
[c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1529–1539
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. · source_derived_draft · unverified_draft
### c-scurvy-vascular-responsiveness Forearm vasoconstriction to intra-arterial norepinephrine and tyramine was greater after repletion; four subjects also had lower resistance-vessel responsiveness to lower-body negative pressure during deficiency. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The blood vessels responded less strongly to some constricting signals during shortage. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. limitations: Does not isolate endothelial, smooth-muscle or collagen mechanisms. exposure: Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine. [c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239
Complete structured claim and evidence
Resting plasma catecholamines and hemodynamic measurements did not change significantly after correction; reflex tachycardia and bradycardia were similar in the deficient and repleted studies.
Vitamin C → Plasma catecholamine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Clinical boundary for the copper/ascorbate-dependent dopamine beta-hydroxylase pathway.
experimental_model
Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion.
exposure
Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine.
limitations
Plasma catecholamines do not measure all neuronal stores or DBH flux; limited power in five participants.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
An enzyme’s vitamin C requirement did not translate into complete failure of the human stress-signal system.
primary_references
[c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1541–1552
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. · source_derived_draft · unverified_draft
### c-scurvy-catecholamine-reflex-boundary Resting plasma catecholamines and hemodynamic measurements did not change significantly after correction; reflex tachycardia and bradycardia were similar in the deficient and repleted studies. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme’s vitamin C requirement did not translate into complete failure of the human stress-signal system. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Five volunteers studied after three months of vitamin C deprivation and again after four months of repletion. limitations: Plasma catecholamines do not measure all neuronal stores or DBH flux; limited power in five participants. exposure: Clinical scurvy; forearm blood flow, pressure, catecholamines and responses to lower-body negative pressure, norepinephrine and tyramine. cross_nutrient: Clinical boundary for the copper/ascorbate-dependent dopamine beta-hydroxylase pathway. [c-abboud1970] Autonomic reflexes and vascular reactivity in experimental scurvy in man (1970). https://pubmed.ncbi.nlm.nih.gov/5411783/ DOI: 10.1172/jci106239
Complete structured claim and evidence
Ascorbate enhanced ferric-NTA iron uptake; ascorbate oxidase and Fe(II) chelators inhibited the enhancement, supporting a required Fe(III)-to-Fe(II) reduction step in this cell model.
L-Ascorbate → Caco-2 apical iron uptake source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin C changes availability of iron for uptake; not proof that all iron absorption requires added vitamin C.
experimental_model
Differentiated human Caco-2 monolayers; apical ferric nitrilotriacetate and transepithelial transport assays.
exposure
Apical 10 micromolar Fe(III) as 1 Fe:2 NTA, varied ascorbic acid, ascorbate oxidase and Fe(II) chelators.
limitations
Chelator/oxidase interventions support redox dependence; the experiment does not identify every human intestinal transport step.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Changing iron’s chemical state helped the intestinal-model cells acquire it.
primary_references
[c-han1995] Reduction of Fe(III) is required for uptake of nonheme iron by Caco-2 cells (1995). https://pubmed.ncbi.nlm.nih.gov/7738689/ DOI: 10.1093/jn/125.5.1291
tissue_or_cell_type
Human Caco-2 apical cell surface and culture medium
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1554–1565
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated human Caco-2 monolayers; apical ferric nitrilotriacetate and transepithelial transport assays. · source_derived_draft · unverified_draft
### c-iron-ferric-reduction-uptake Ascorbate enhanced ferric-NTA iron uptake; ascorbate oxidase and Fe(II) chelators inhibited the enhancement, supporting a required Fe(III)-to-Fe(II) reduction step in this cell model. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing iron’s chemical state helped the intestinal-model cells acquire it. organism: Homo sapiens tissue_or_cell_type: Human Caco-2 apical cell surface and culture medium experimental_model: Differentiated human Caco-2 monolayers; apical ferric nitrilotriacetate and transepithelial transport assays. limitations: Chelator/oxidase interventions support redox dependence; the experiment does not identify every human intestinal transport step. exposure: Apical 10 micromolar Fe(III) as 1 Fe:2 NTA, varied ascorbic acid, ascorbate oxidase and Fe(II) chelators. cross_nutrient: Vitamin C changes availability of iron for uptake; not proof that all iron absorption requires added vitamin C. [c-han1995] Reduction of Fe(III) is required for uptake of nonheme iron by Caco-2 cells (1995). https://pubmed.ncbi.nlm.nih.gov/7738689/ DOI: 10.1093/jn/125.5.1291
Complete structured claim and evidence
Apical ascorbic acid at 100 and 1000 micromolar increased apical-to-basolateral iron transport 5.6-fold and 30-fold, respectively, in the ferric-NTA system.
L-Ascorbic acid → Caco-2 transepithelial iron flux source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Direct vitamin C/iron transport experiment.
experimental_model
Differentiated human Caco-2 monolayers; apical ferric nitrilotriacetate and transepithelial transport assays.
exposure
Apical 10 micromolar Fe(III) as 1 Fe:2 NTA, varied ascorbic acid, ascorbate oxidase and Fe(II) chelators.
limitations
Culture concentrations and ligand system cannot be converted into a human absorption percentage.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
More iron crossed the model cell layer under those experimental conditions.
primary_references
[c-han1995] Reduction of Fe(III) is required for uptake of nonheme iron by Caco-2 cells (1995). https://pubmed.ncbi.nlm.nih.gov/7738689/ DOI: 10.1093/jn/125.5.1291
tissue_or_cell_type
Human Caco-2 monolayers
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1567–1578
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated human Caco-2 monolayers; apical ferric nitrilotriacetate and transepithelial transport assays. · source_derived_draft · unverified_draft
### c-iron-transepithelial-flux Apical ascorbic acid at 100 and 1000 micromolar increased apical-to-basolateral iron transport 5.6-fold and 30-fold, respectively, in the ferric-NTA system. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: More iron crossed the model cell layer under those experimental conditions. organism: Homo sapiens tissue_or_cell_type: Human Caco-2 monolayers experimental_model: Differentiated human Caco-2 monolayers; apical ferric nitrilotriacetate and transepithelial transport assays. limitations: Culture concentrations and ligand system cannot be converted into a human absorption percentage. exposure: Apical 10 micromolar Fe(III) as 1 Fe:2 NTA, varied ascorbic acid, ascorbate oxidase and Fe(II) chelators. cross_nutrient: Direct vitamin C/iron transport experiment. [c-han1995] Reduction of Fe(III) is required for uptake of nonheme iron by Caco-2 cells (1995). https://pubmed.ncbi.nlm.nih.gov/7738689/ DOI: 10.1093/jn/125.5.1291
Complete structured claim and evidence
Added ascorbic acid significantly counteracted the inhibition of radiolabeled nonheme iron absorption caused by sodium phytate in wheat-roll meals.
L-Ascorbic acid → Nonheme iron absorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Meal composition modifies the vitamin C/iron interaction.
experimental_model
Human alternate-day paired radiolabeled wheat-roll experiments.
exposure
Seven sodium phytate levels spanning 2–250 mg expressed as phytate phosphorus, with and without ascorbic acid; 55Fe/59Fe labels. Exact C dose and participant count are not extracted from the abstract.
limitations
Single-meal tracer result; does not prove full cancellation of inhibition or long-term correction of anemia.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Vitamin C helped offset an iron-absorption inhibitor in the tested meals.
primary_references
[c-hallberg1989] Iron absorption in man: ascorbic acid and dose-dependent inhibition by phytate (1989). https://pubmed.ncbi.nlm.nih.gov/2911999/ DOI: 10.1093/ajcn/49.1.140
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1580–1591
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human alternate-day paired radiolabeled wheat-roll experiments. · source_derived_draft · unverified_draft
### c-phytate-iron-inhibition-counteraction Added ascorbic acid significantly counteracted the inhibition of radiolabeled nonheme iron absorption caused by sodium phytate in wheat-roll meals. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C helped offset an iron-absorption inhibitor in the tested meals. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Human alternate-day paired radiolabeled wheat-roll experiments. limitations: Single-meal tracer result; does not prove full cancellation of inhibition or long-term correction of anemia. exposure: Seven sodium phytate levels spanning 2–250 mg expressed as phytate phosphorus, with and without ascorbic acid; 55Fe/59Fe labels. Exact C dose and participant count are not extracted from the abstract. cross_nutrient: Meal composition modifies the vitamin C/iron interaction. [c-hallberg1989] Iron absorption in man: ascorbic acid and dose-dependent inhibition by phytate (1989). https://pubmed.ncbi.nlm.nih.gov/2911999/ DOI: 10.1093/ajcn/49.1.140
Complete structured claim and evidence
Mean iron absorption did not differ significantly across the three complete-diet periods despite mean vitamin C intakes spanning 51–247 mg/day.
L-Ascorbic acid → Nonheme iron absorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Human total-diet boundary on the single-meal interaction.
experimental_model
Twelve subjects completing three dietary periods; labeled wheat rolls with every meal for five days per period.
exposure
Self-selected, low-C and high-C complete diets; mean vitamin C intakes spanned 51–247 mg/day.
limitations
Only twelve participants; meals and iron status also varied. Different design from the phytate challenge, not a draft correction or an unexplained contradiction.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
An effect visible in a single meal can be much smaller across a complete diet.
primary_references
[c-cook2001] Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet (2001). https://pubmed.ncbi.nlm.nih.gov/11124756/ DOI: 10.1093/ajcn/73.1.93
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1593–1604
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twelve subjects completing three dietary periods; labeled wheat rolls with every meal for five days per period. · source_derived_draft · unverified_draft
### c-whole-diet-iron-absorption-null Mean iron absorption did not differ significantly across the three complete-diet periods despite mean vitamin C intakes spanning 51–247 mg/day. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: An effect visible in a single meal can be much smaller across a complete diet. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Twelve subjects completing three dietary periods; labeled wheat rolls with every meal for five days per period. limitations: Only twelve participants; meals and iron status also varied. Different design from the phytate challenge, not a draft correction or an unexplained contradiction. exposure: Self-selected, low-C and high-C complete diets; mean vitamin C intakes spanned 51–247 mg/day. cross_nutrient: Human total-diet boundary on the single-meal interaction. [c-cook2001] Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet (2001). https://pubmed.ncbi.nlm.nih.gov/11124756/ DOI: 10.1093/ajcn/73.1.93
Complete structured claim and evidence
Pooled regression adjusted for iron status found a positive association between ascorbic acid intake and absorption (P=0.0069), alongside associations with animal tissue and phosphate.
L-Ascorbic acid → Nonheme iron absorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Iron status and dietary matrix affect the observed relationship.
experimental_model
Twelve subjects completing three dietary periods; labeled wheat rolls with every meal for five days per period.
exposure
Self-selected, low-C and high-C complete diets; mean vitamin C intakes spanned 51–247 mg/day.
limitations
Regression within a small dietary experiment is not an isolated randomized causal estimate.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The vitamin C association remained visible in an adjusted analysis, even though the period means did not differ significantly.
primary_references
[c-cook2001] Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet (2001). https://pubmed.ncbi.nlm.nih.gov/11124756/ DOI: 10.1093/ajcn/73.1.93
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1606–1617
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twelve subjects completing three dietary periods; labeled wheat rolls with every meal for five days per period. · source_derived_draft · unverified_draft
### c-whole-diet-adjusted-iron-association Pooled regression adjusted for iron status found a positive association between ascorbic acid intake and absorption (P=0.0069), alongside associations with animal tissue and phosphate. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The vitamin C association remained visible in an adjusted analysis, even though the period means did not differ significantly. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Twelve subjects completing three dietary periods; labeled wheat rolls with every meal for five days per period. limitations: Regression within a small dietary experiment is not an isolated randomized causal estimate. exposure: Self-selected, low-C and high-C complete diets; mean vitamin C intakes spanned 51–247 mg/day. cross_nutrient: Iron status and dietary matrix affect the observed relationship. [c-cook2001] Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet (2001). https://pubmed.ncbi.nlm.nih.gov/11124756/ DOI: 10.1093/ajcn/73.1.93
Complete structured claim and evidence
Hemoglobin increased 2.00 g/dL with iron plus C versus 1.84 with iron alone at two weeks; difference 0.16 (95% CI -0.03 to 0.35), within the prespecified 1-g/dL equivalence margin.
L-Ascorbic acid → Blood hemoglobin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Separates chemical absorption support from added clinical benefit during iron replacement.
experimental_model
Single-center open-label randomized equivalence trial: 440 adults with iron-deficiency anemia, 426 women.
exposure
Ferrous succinate 100 mg/tablet with or without vitamin C 200 mg every eight hours, three months; taken half an hour after meals. Tablet mass is not relabeled as elemental iron.
limitations
Equivalence is margin-dependent and does not mean numerical identity; no direct isotope absorption or intracellular mechanism was measured.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Adding vitamin C did not provide a clinically distinct early hemoglobin response under the trial’s equivalence definition.
primary_references
[c-li2020] The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial (2020). https://pubmed.ncbi.nlm.nih.gov/33136134/ DOI: 10.1001/jamanetworkopen.2020.23644
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1619–1630
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-center open-label randomized equivalence trial: 440 adults with iron-deficiency anemia, 426 women. · source_derived_draft · unverified_draft
### c-iron-treatment-hemoglobin-equivalence Hemoglobin increased 2.00 g/dL with iron plus C versus 1.84 with iron alone at two weeks; difference 0.16 (95% CI -0.03 to 0.35), within the prespecified 1-g/dL equivalence margin. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding vitamin C did not provide a clinically distinct early hemoglobin response under the trial’s equivalence definition. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Single-center open-label randomized equivalence trial: 440 adults with iron-deficiency anemia, 426 women. limitations: Equivalence is margin-dependent and does not mean numerical identity; no direct isotope absorption or intracellular mechanism was measured. exposure: Ferrous succinate 100 mg/tablet with or without vitamin C 200 mg every eight hours, three months; taken half an hour after meals. Tablet mass is not relabeled as elemental iron. cross_nutrient: Separates chemical absorption support from added clinical benefit during iron replacement. [c-li2020] The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial (2020). https://pubmed.ncbi.nlm.nih.gov/33136134/ DOI: 10.1001/jamanetworkopen.2020.23644
Complete structured claim and evidence
Eight-week ferritin increases were 35.75 versus 34.48 ng/mL; between-group difference 1.27 (95% CI -0.70 to 3.24; P=0.21).
L-Ascorbic acid → Serum ferritin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin C/iron clinical outcome recorded separately from the uptake reaction.
experimental_model
Single-center open-label randomized equivalence trial: 440 adults with iron-deficiency anemia, 426 women.
exposure
Ferrous succinate 100 mg/tablet with or without vitamin C 200 mg every eight hours, three months; taken half an hour after meals. Tablet mass is not relabeled as elemental iron.
limitations
Ferritin is a biomarker; no proof that iron absorption was identical at every meal.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The added vitamin C did not significantly improve the measured iron-storage response.
primary_references
[c-li2020] The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial (2020). https://pubmed.ncbi.nlm.nih.gov/33136134/ DOI: 10.1001/jamanetworkopen.2020.23644
tissue_or_cell_type
Human blood or whole-person endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1632–1643
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-center open-label randomized equivalence trial: 440 adults with iron-deficiency anemia, 426 women. · source_derived_draft · unverified_draft
### c-iron-treatment-ferritin-null Eight-week ferritin increases were 35.75 versus 34.48 ng/mL; between-group difference 1.27 (95% CI -0.70 to 3.24; P=0.21). Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The added vitamin C did not significantly improve the measured iron-storage response. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Single-center open-label randomized equivalence trial: 440 adults with iron-deficiency anemia, 426 women. limitations: Ferritin is a biomarker; no proof that iron absorption was identical at every meal. exposure: Ferrous succinate 100 mg/tablet with or without vitamin C 200 mg every eight hours, three months; taken half an hour after meals. Tablet mass is not relabeled as elemental iron. cross_nutrient: Vitamin C/iron clinical outcome recorded separately from the uptake reaction. [c-li2020] The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial (2020). https://pubmed.ncbi.nlm.nih.gov/33136134/ DOI: 10.1001/jamanetworkopen.2020.23644
Complete structured claim and evidence
Nineteen of 48 participants, including 12 stone formers and seven non-stone formers, had more than 10% greater 24-hour oxalate excretion with 2 g/day vitamin C.
L-Ascorbic acid → Urinary oxalate excretion source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Oxalate is relevant to calcium oxalate stone chemistry.
experimental_model
Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers.
exposure
Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation.
limitations
Responders were defined by the observed rise; no incident-stone endpoint and no extrapolation to ordinary food intake.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Some people excreted more oxalate after the high oral exposure.
primary_references
[c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1645–1656
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. · source_derived_draft · unverified_draft
### c-high-oral-dose-oxaluria Nineteen of 48 participants, including 12 stone formers and seven non-stone formers, had more than 10% greater 24-hour oxalate excretion with 2 g/day vitamin C. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some people excreted more oxalate after the high oral exposure. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. limitations: Responders were defined by the observed rise; no incident-stone endpoint and no extrapolation to ordinary food intake. exposure: Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation. cross_nutrient: Oxalate is relevant to calcium oxalate stone chemistry. [c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
Complete structured claim and evidence
Within the responder subset, estimated endogenous oxalate synthesis was 544 versus 391 micromol/day with versus without supplementation.
L-Ascorbic acid → Endogenous oxalate synthesis source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers.
exposure
Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation.
limitations
Selected subgroup and short exposure; does not identify every enzymatic or nonenzymatic conversion step.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The tracer-based analysis separated oxalate made within the body from oxalate absorbed from the test diet.
primary_references
[c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1658–1668
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. · source_derived_draft · unverified_draft
### c-high-oral-dose-oxalate-synthesis Within the responder subset, estimated endogenous oxalate synthesis was 544 versus 391 micromol/day with versus without supplementation. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tracer-based analysis separated oxalate made within the body from oxalate absorbed from the test diet. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. limitations: Selected subgroup and short exposure; does not identify every enzymatic or nonenzymatic conversion step. exposure: Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation. [c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
Complete structured claim and evidence
Responder-subset dietary oxalate absorption was 10.5% versus 8.0% with versus without vitamin C.
L-Ascorbic acid → Dietary oxalate absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers.
exposure
Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation.
limitations
Not a universal effect in all 48 participants; intestinal mediator was not identified.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The additional urinary oxalate was not attributed solely to vitamin C breakdown.
primary_references
[c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1670–1680
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. · source_derived_draft · unverified_draft
### c-high-oral-dose-oxalate-absorption Responder-subset dietary oxalate absorption was 10.5% versus 8.0% with versus without vitamin C. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The additional urinary oxalate was not attributed solely to vitamin C breakdown. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. limitations: Not a universal effect in all 48 participants; intestinal mediator was not identified. exposure: Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation. [c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
Complete structured claim and evidence
The responder subset had a Tiselius Risk Index of 1.10 with versus 0.76 without supplementation.
L-Ascorbic acid → Tiselius calcium oxalate risk index source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Calcium/oxalate urinary chemistry connects a vitamin metabolite to mineral precipitation risk.
experimental_model
Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers.
exposure
Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation.
limitations
Calculated risk is not observed stone formation; this is distinct from a directly measured calcium oxalate activity product.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Their urine measurements shifted toward a higher calculated calcium oxalate stone risk.
primary_references
[c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1682–1693
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. · source_derived_draft · unverified_draft
### c-high-oral-dose-calcium-oxalate-index The responder subset had a Tiselius Risk Index of 1.10 with versus 0.76 without supplementation. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Their urine measurements shifted toward a higher calculated calcium oxalate stone risk. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized controlled-diet crossover study: 29 calcium stone formers and 19 non-stone formers. limitations: Calculated risk is not observed stone formation; this is distinct from a directly measured calcium oxalate activity product. exposure: Ascorbic acid 1000 mg twice daily for six days versus no supplement for six days; 13C2 oxalate challenge after adaptation. cross_nutrient: Calcium/oxalate urinary chemistry connects a vitamin metabolite to mineral precipitation risk. [c-massey2005] Ascorbate increases human oxaluria and kidney stone risk (2005). https://pubmed.ncbi.nlm.nih.gov/15987848/ DOI: 10.1093/jn/135.7.1673
Complete structured claim and evidence
The primary composite occurred in 44.5% with IV C versus 38.5% with placebo (RR 1.21, 95% CI 1.04–1.40; P=0.01).
L-Ascorbic acid → Sepsis death or persistent organ dysfunction at day 28 source_derived_draftungraded
Experimental context and source evidence
experimental_model
LOVIT: multicenter placebo-controlled randomized ICU trial; 872 randomized, 863 in primary analysis, with sepsis and vasopressor use.
exposure
IV vitamin C 50 mg/kg every six hours for up to 96 hours versus matched placebo.
limitations
The trial did not identify the molecular cause; pharmacologic IV exposure cannot be generalized to food vitamin C or correction of scurvy.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
In this sepsis population, the tested infusion increased the combined risk of death or ongoing organ-support needs.
primary_references
[c-lamontagne2022] Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit (2022). https://pubmed.ncbi.nlm.nih.gov/35704292/ DOI: 10.1056/nejmoa2200644
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1695–1705
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · LOVIT: multicenter placebo-controlled randomized ICU trial; 872 randomized, 863 in primary analysis, with sepsis and vasopressor use. · source_derived_draft · unverified_draft
### c-lovit-primary-composite The primary composite occurred in 44.5% with IV C versus 38.5% with placebo (RR 1.21, 95% CI 1.04–1.40; P=0.01). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this sepsis population, the tested infusion increased the combined risk of death or ongoing organ-support needs. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: LOVIT: multicenter placebo-controlled randomized ICU trial; 872 randomized, 863 in primary analysis, with sepsis and vasopressor use. limitations: The trial did not identify the molecular cause; pharmacologic IV exposure cannot be generalized to food vitamin C or correction of scurvy. exposure: IV vitamin C 50 mg/kg every six hours for up to 96 hours versus matched placebo. [c-lamontagne2022] Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit (2022). https://pubmed.ncbi.nlm.nih.gov/35704292/ DOI: 10.1056/nejmoa2200644
Complete structured claim and evidence
Day-28 mortality was 35.4% versus 31.6% (RR 1.17, 95% CI 0.98–1.40), while the combined primary endpoint was significant.
L-Ascorbic acid → Sepsis mortality at day 28 source_derived_draftungraded
Experimental context and source evidence
experimental_model
LOVIT: multicenter placebo-controlled randomized ICU trial; 872 randomized, 863 in primary analysis, with sepsis and vasopressor use.
exposure
IV vitamin C 50 mg/kg every six hours for up to 96 hours versus matched placebo.
limitations
Confidence interval includes no difference; neither a proven mortality increase alone nor evidence of identical mortality.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The combined endpoint and mortality alone had different statistical results.
primary_references
[c-lamontagne2022] Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit (2022). https://pubmed.ncbi.nlm.nih.gov/35704292/ DOI: 10.1056/nejmoa2200644
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1707–1717
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · LOVIT: multicenter placebo-controlled randomized ICU trial; 872 randomized, 863 in primary analysis, with sepsis and vasopressor use. · source_derived_draft · unverified_draft
### c-lovit-mortality-component Day-28 mortality was 35.4% versus 31.6% (RR 1.17, 95% CI 0.98–1.40), while the combined primary endpoint was significant. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The combined endpoint and mortality alone had different statistical results. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: LOVIT: multicenter placebo-controlled randomized ICU trial; 872 randomized, 863 in primary analysis, with sepsis and vasopressor use. limitations: Confidence interval includes no difference; neither a proven mortality increase alone nor evidence of identical mortality. exposure: IV vitamin C 50 mg/kg every six hours for up to 96 hours versus matched placebo. [c-lamontagne2022] Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit (2022). https://pubmed.ncbi.nlm.nih.gov/35704292/ DOI: 10.1056/nejmoa2200644
Complete structured claim and evidence
CITRIS-ALI found no significant difference in the primary modified SOFA change through 96 hours (P=0.86).
L-Ascorbic acid → Modified Sequential Organ Failure Assessment score source_derived_draftungraded
Experimental context and source evidence
experimental_model
CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo).
exposure
IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo.
limitations
This specific primary endpoint is not a summary of every secondary outcome.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The studied infusion did not improve the trial’s main organ-function score.
primary_references
[c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1719–1729
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). · source_derived_draft · unverified_draft
### c-citris-organ-score-null CITRIS-ALI found no significant difference in the primary modified SOFA change through 96 hours (P=0.86). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The studied infusion did not improve the trial’s main organ-function score. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). limitations: This specific primary endpoint is not a summary of every secondary outcome. exposure: IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo. [c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
Complete structured claim and evidence
At 168 hours, the prespecified CRP comparison was nonsignificant (P=0.33).
L-Ascorbic acid → Plasma C-reactive protein concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo).
exposure
IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo.
limitations
Marker results do not establish that every inflammatory pathway was unchanged.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
This inflammatory marker did not show the proposed benefit.
primary_references
[c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1731–1741
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). · source_derived_draft · unverified_draft
### c-citris-crp-null At 168 hours, the prespecified CRP comparison was nonsignificant (P=0.33). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This inflammatory marker did not show the proposed benefit. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). limitations: Marker results do not establish that every inflammatory pathway was unchanged. exposure: IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo. [c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
Complete structured claim and evidence
At 168 hours, the prespecified thrombomodulin comparison was nonsignificant (P=0.70).
L-Ascorbic acid → Plasma thrombomodulin concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo).
exposure
IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo.
limitations
The circulating marker is distinct from directly measuring endothelial repair.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
This vessel-injury marker did not show the proposed benefit.
primary_references
[c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1743–1753
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). · source_derived_draft · unverified_draft
### c-citris-thrombomodulin-null At 168 hours, the prespecified thrombomodulin comparison was nonsignificant (P=0.70). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This vessel-injury marker did not show the proposed benefit. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). limitations: The circulating marker is distinct from directly measuring endothelial repair. exposure: IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo. [c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
Complete structured claim and evidence
Day-28 mortality was 25/84 (29.8%) with C versus 38/82 (46.3%) with placebo (P=0.03), in an exploratory analysis without adjustment for multiple comparisons.
L-Ascorbic acid → Sepsis mortality at day 28 source_derived_draftungraded
Experimental context and source evidence
experimental_model
CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo).
exposure
IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo.
limitations
One of 46 secondary outcomes; 43 were nonsignificant. Different eligibility and endpoint hierarchy from LOVIT. The signal is hypothesis-generating, and no cellular mediator was proven.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
This smaller trial reported a possible survival benefit, although its main endpoints were negative.
primary_references
[c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1755–1765
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). · source_derived_draft · unverified_draft
### c-citris-exploratory-mortality-signal Day-28 mortality was 25/84 (29.8%) with C versus 38/82 (46.3%) with placebo (P=0.03), in an exploratory analysis without adjustment for multiple comparisons. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: This smaller trial reported a possible survival benefit, although its main endpoints were negative. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: CITRIS-ALI: double-blind multicenter randomized trial; 170 initially randomized, three subsequently excluded without receiving C, 167 in the reported analysis (84 C, 83 placebo). limitations: One of 46 secondary outcomes; 43 were nonsignificant. Different eligibility and endpoint hierarchy from LOVIT. The signal is hypothesis-generating, and no cellular mediator was proven. exposure: IV vitamin C 50 mg/kg in 5% dextrose every six hours for 96 hours versus dextrose placebo. [c-fowler2019] Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial (2019). https://pubmed.ncbi.nlm.nih.gov/31573637/ DOI: 10.1001/jama.2019.11825
Complete structured claim and evidence
Vitamin C showed no survival advantage over placebo in the advanced colorectal cancer trial.
L-Ascorbic acid → Overall survival in colorectal cancer source_derived_draftungraded
Experimental context and source evidence
experimental_model
Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy.
exposure
Oral vitamin C 10 g/day versus placebo. The 1985 abstract does not specify route; route is cross-checked in Chen2005 Introduction, which identifies the two oral randomized trials through references 5 and 6.
limitations
Different cancer, route and cointerventions from modern IV combination trials; not a direct test of their mechanism.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The historical randomized trial did not show longer survival for its regimen.
primary_references
[c-moertel1985] High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison (1985). https://pubmed.ncbi.nlm.nih.gov/3880867/ DOI: 10.1056/nejm198501173120301
route_provenance
Oral route cross-checked in Chen2005 Introduction and reference 6 (Moertel1985): https://pmc.ncbi.nlm.nih.gov/articles/PMC1224653/ . Clinical outcomes come from the Moertel abstract.
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1767–1778
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy. · source_derived_draft · unverified_draft
### c-oral-colorectal-survival-null Vitamin C showed no survival advantage over placebo in the advanced colorectal cancer trial. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The historical randomized trial did not show longer survival for its regimen. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy. limitations: Different cancer, route and cointerventions from modern IV combination trials; not a direct test of their mechanism. exposure: Oral vitamin C 10 g/day versus placebo. The 1985 abstract does not specify route; route is cross-checked in Chen2005 Introduction, which identifies the two oral randomized trials through references 5 and 6. route_provenance: Oral route cross-checked in Chen2005 Introduction and reference 6 (Moertel1985): https://pmc.ncbi.nlm.nih.gov/articles/PMC1224653/ . Clinical outcomes come from the Moertel abstract. [c-moertel1985] High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison (1985). https://pubmed.ncbi.nlm.nih.gov/3880867/ DOI: 10.1056/nejm198501173120301
Complete structured claim and evidence
The interval from starting treatment to disease progression did not improve with vitamin C versus placebo.
L-Ascorbic acid → Time to progression in colorectal cancer source_derived_draftungraded
Experimental context and source evidence
experimental_model
Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy.
exposure
Oral vitamin C 10 g/day versus placebo. The 1985 abstract does not specify route; route is cross-checked in Chen2005 Introduction, which identifies the two oral randomized trials through references 5 and 6.
limitations
This historical regimen does not test modern intravenous combination exposures.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Time to progression was measured separately from overall survival.
primary_references
[c-moertel1985] High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison (1985). https://pubmed.ncbi.nlm.nih.gov/3880867/ DOI: 10.1056/nejm198501173120301
route_provenance
Oral route cross-checked in Chen2005 Introduction and reference 6 (Moertel1985): https://pmc.ncbi.nlm.nih.gov/articles/PMC1224653/ . Clinical outcomes come from the Moertel abstract.
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1780–1791
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy. · source_derived_draft · unverified_draft
### c-oral-colorectal-progression-null The interval from starting treatment to disease progression did not improve with vitamin C versus placebo. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Time to progression was measured separately from overall survival. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy. limitations: This historical regimen does not test modern intravenous combination exposures. exposure: Oral vitamin C 10 g/day versus placebo. The 1985 abstract does not specify route; route is cross-checked in Chen2005 Introduction, which identifies the two oral randomized trials through references 5 and 6. route_provenance: Oral route cross-checked in Chen2005 Introduction and reference 6 (Moertel1985): https://pmc.ncbi.nlm.nih.gov/articles/PMC1224653/ . Clinical outcomes come from the Moertel abstract. [c-moertel1985] High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison (1985). https://pubmed.ncbi.nlm.nih.gov/3880867/ DOI: 10.1056/nejm198501173120301
Complete structured claim and evidence
No objective improvement occurred among the vitamin C trial participants with measurable disease.
L-Ascorbic acid → Objective response in colorectal cancer source_derived_draftungraded
Experimental context and source evidence
experimental_model
Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy.
exposure
Oral vitamin C 10 g/day versus placebo. The 1985 abstract does not specify route; route is cross-checked in Chen2005 Introduction, which identifies the two oral randomized trials through references 5 and 6.
limitations
Abstract does not provide the subgroup denominator; no extrapolation to every cancer or pharmacological regimen.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The trial did not report a measurable tumor response in that subgroup.
primary_references
[c-moertel1985] High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison (1985). https://pubmed.ncbi.nlm.nih.gov/3880867/ DOI: 10.1056/nejm198501173120301
route_provenance
Oral route cross-checked in Chen2005 Introduction and reference 6 (Moertel1985): https://pmc.ncbi.nlm.nih.gov/articles/PMC1224653/ . Clinical outcomes come from the Moertel abstract.
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1793–1804
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy. · source_derived_draft · unverified_draft
### c-oral-colorectal-objective-response-null No objective improvement occurred among the vitamin C trial participants with measurable disease. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The trial did not report a measurable tumor response in that subgroup. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 100 advanced colorectal cancer patients without previous cytotoxic chemotherapy. limitations: Abstract does not provide the subgroup denominator; no extrapolation to every cancer or pharmacological regimen. exposure: Oral vitamin C 10 g/day versus placebo. The 1985 abstract does not specify route; route is cross-checked in Chen2005 Introduction, which identifies the two oral randomized trials through references 5 and 6. route_provenance: Oral route cross-checked in Chen2005 Introduction and reference 6 (Moertel1985): https://pmc.ncbi.nlm.nih.gov/articles/PMC1224653/ . Clinical outcomes come from the Moertel abstract. [c-moertel1985] High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison (1985). https://pubmed.ncbi.nlm.nih.gov/3880867/ DOI: 10.1056/nejm198501173120301
Complete structured claim and evidence
Median overall survival was 16 versus 8.3 months with versus without added IV ascorbate (HR 0.46; 90% CI 0.23–0.92; P=0.030).
L-Ascorbate → Overall survival in pancreatic cancer source_derived_draftungraded
Experimental context and source evidence
experimental_model
Unblinded randomized phase II metastatic pancreatic cancer trial at two academic sites: 36 randomized, 34 received assigned therapy and entered analysis.
exposure
Gemcitabine and nab-paclitaxel with or without IV pharmacologic ascorbate 75 g three times weekly.
limitations
Small unblinded trial; a planned futility interim analysis was followed by efficacy-based closure supported by the monitoring committee, without a stated prespecified efficacy boundary. 34 treated/evaluable of 36 randomized, 90% rather than 95% intervals, one-sided design. Tumor redox mediators were not measured; requires confirmation and does not support replacing chemotherapy.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
Adding the infusions to the two-drug regimen produced a promising survival signal in this small study.
primary_references
[c-bodeker2024] A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer (2024). https://pubmed.ncbi.nlm.nih.gov/39369582/ DOI: 10.1016/j.redox.2024.103375
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1806–1816
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Unblinded randomized phase II metastatic pancreatic cancer trial at two academic sites: 36 randomized, 34 received assigned therapy and entered analysis. · source_derived_draft · unverified_draft
### c-iv-pancreas-survival-signal Median overall survival was 16 versus 8.3 months with versus without added IV ascorbate (HR 0.46; 90% CI 0.23–0.92; P=0.030). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding the infusions to the two-drug regimen produced a promising survival signal in this small study. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Unblinded randomized phase II metastatic pancreatic cancer trial at two academic sites: 36 randomized, 34 received assigned therapy and entered analysis. limitations: Small unblinded trial; a planned futility interim analysis was followed by efficacy-based closure supported by the monitoring committee, without a stated prespecified efficacy boundary. 34 treated/evaluable of 36 randomized, 90% rather than 95% intervals, one-sided design. Tumor redox mediators were not measured; requires confirmation and does not support replacing chemotherapy. exposure: Gemcitabine and nab-paclitaxel with or without IV pharmacologic ascorbate 75 g three times weekly. [c-bodeker2024] A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer (2024). https://pubmed.ncbi.nlm.nih.gov/39369582/ DOI: 10.1016/j.redox.2024.103375
Complete structured claim and evidence
Median progression-free survival was 6.2 versus 3.9 months (HR 0.43; 90% CI 0.20–0.92; P=0.029).
L-Ascorbate → Progression-free survival in pancreatic cancer source_derived_draftungraded
Experimental context and source evidence
experimental_model
Unblinded randomized phase II metastatic pancreatic cancer trial at two academic sites: 36 randomized, 34 received assigned therapy and entered analysis.
exposure
Gemcitabine and nab-paclitaxel with or without IV pharmacologic ascorbate 75 g three times weekly.
limitations
Small unblinded trial; a planned futility interim analysis was followed by efficacy-based closure supported by the monitoring committee, without a stated prespecified efficacy boundary. 34 treated/evaluable of 36 randomized, 90% rather than 95% intervals, one-sided design. Tumor redox mediators were not measured; requires confirmation and does not support replacing chemotherapy.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
The treated group also had a longer measured interval before progression or death.
primary_references
[c-bodeker2024] A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer (2024). https://pubmed.ncbi.nlm.nih.gov/39369582/ DOI: 10.1016/j.redox.2024.103375
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1818–1828
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Unblinded randomized phase II metastatic pancreatic cancer trial at two academic sites: 36 randomized, 34 received assigned therapy and entered analysis. · source_derived_draft · unverified_draft
### c-iv-pancreas-progression-signal Median progression-free survival was 6.2 versus 3.9 months (HR 0.43; 90% CI 0.20–0.92; P=0.029). Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The treated group also had a longer measured interval before progression or death. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Unblinded randomized phase II metastatic pancreatic cancer trial at two academic sites: 36 randomized, 34 received assigned therapy and entered analysis. limitations: Small unblinded trial; a planned futility interim analysis was followed by efficacy-based closure supported by the monitoring committee, without a stated prespecified efficacy boundary. 34 treated/evaluable of 36 randomized, 90% rather than 95% intervals, one-sided design. Tumor redox mediators were not measured; requires confirmation and does not support replacing chemotherapy. exposure: Gemcitabine and nab-paclitaxel with or without IV pharmacologic ascorbate 75 g three times weekly. [c-bodeker2024] A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer (2024). https://pubmed.ncbi.nlm.nih.gov/39369582/ DOI: 10.1016/j.redox.2024.103375
Complete structured claim and evidence
Vitamin C assignment did not reduce major cardiovascular events (HR 0.99; 95% CI 0.89–1.11; P=0.91) over mean eight-year follow-up.
L-Ascorbic acid → Major cardiovascular event incidence source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Clinical outcome boundary for extrapolation from vitamin C/vitamin E redox recycling.
experimental_model
Physicians Health Study II: placebo-controlled double-blind factorial trial, 14641 male physicians aged at least 50, mean eight-year follow-up.
exposure
Vitamin C 500 mg/day and separately randomized vitamin E 400 IU every other day; clinical CVD endpoints.
limitations
Older male physicians, not a selected scurvy cohort; separate vitamin E randomization is not proof of molecular synergy or antagonism.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Homo sapiens
plain_language
A long-term supplement trial did not turn the antioxidant rationale into fewer major cardiovascular events.
primary_references
[c-sesso2008] Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial (2008). https://pubmed.ncbi.nlm.nih.gov/18997197/ DOI: 10.1001/jama.2008.600
tissue_or_cell_type
Human blood or whole-person endpoints
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1830–1841
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Physicians Health Study II: placebo-controlled double-blind factorial trial, 14641 male physicians aged at least 50, mean eight-year follow-up. · source_derived_draft · unverified_draft
### c-cvd-prevention-null Vitamin C assignment did not reduce major cardiovascular events (HR 0.99; 95% CI 0.89–1.11; P=0.91) over mean eight-year follow-up. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A long-term supplement trial did not turn the antioxidant rationale into fewer major cardiovascular events. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Physicians Health Study II: placebo-controlled double-blind factorial trial, 14641 male physicians aged at least 50, mean eight-year follow-up. limitations: Older male physicians, not a selected scurvy cohort; separate vitamin E randomization is not proof of molecular synergy or antagonism. exposure: Vitamin C 500 mg/day and separately randomized vitamin E 400 IU every other day; clinical CVD endpoints. cross_nutrient: Clinical outcome boundary for extrapolation from vitamin C/vitamin E redox recycling. [c-sesso2008] Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial (2008). https://pubmed.ncbi.nlm.nih.gov/18997197/ DOI: 10.1001/jama.2008.600
Complete structured claim and evidence
Sequencing the TET2 coding region in 320 patients found somatic deletions or mutations in 19% of myelodysplastic syndromes (15 of 81), 12% of myeloproliferative disorders (24 of 198), 24% of secondary acute myeloid leukaemia (5 of 21) and 22% of chronic myelomonocytic leukaemia (2 of 9).
Human TET2 → TET2 mutation frequency across human myeloid neoplasms source_derived_draftungraded
Experimental context and source evidence
duration
Cross-sectional
experimental_model
320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses
exposure
No intervention; observational sequencing of patient material
limitations
A mutation frequency is an association, not a demonstration that TET2 loss caused any of these cancers. Ascertainment was partly enriched: six patients were selected for 4q24 rearrangements and five for a JAK2 V617F-positive dominant clone.
organism
Homo sapiens
plain_language
About one in seven patients with these blood cancers carried a damaged copy of TET2.
primary_references
[delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
tissue
Haematopoietic cells and bone marrow
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 13–21
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · 320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses · source_derived_draft · unverified_draft
## tet2-mutated-across-myeloid-neoplasms Sequencing the TET2 coding region in 320 patients found somatic deletions or mutations in 19% of myelodysplastic syndromes (15 of 81), 12% of myeloproliferative disorders (24 of 198), 24% of secondary acute myeloid leukaemia (5 of 21) and 22% of chronic myelomonocytic leukaemia (2 of 9). Model/species: 320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses Organism: Homo sapiens Tissue/system: Haematopoietic cells and bone marrow Exposure: No intervention; observational sequencing of patient material Duration: Cross-sectional Limits: A mutation frequency is an association, not a demonstration that TET2 loss caused any of these cancers. Ascertainment was partly enriched: six patients were selected for 4q24 rearrangements and five for a JAK2 V617F-positive dominant clone. Primary reference: [delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
Complete structured claim and evidence
TET2 defects were present in haematopoietic stem cells and preceded the JAK2 V617F mutation in the five analysed samples from patients with myeloproliferative disorders.
Human TET2 → Order of TET2 and JAK2 V617F acquisition in human myeloproliferative clones source_derived_draftungraded
Experimental context and source evidence
duration
Cross-sectional
experimental_model
Five myeloproliferative-disorder patient samples with clonal analysis of progenitors
exposure
No intervention; clonal ordering within patient samples
limitations
Five samples. Order of acquisition in a clone does not by itself establish which lesion drives the disease.
organism
Homo sapiens
plain_language
Where both were present, the TET2 damage came first.
primary_references
[delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
tissue
Haematopoietic stem and progenitor cells
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 23–31
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Five myeloproliferative-disorder patient samples with clonal analysis of progenitors · source_derived_draft · unverified_draft
## tet2-defect-precedes-jak2-v617f TET2 defects were present in haematopoietic stem cells and preceded the JAK2 V617F mutation in the five analysed samples from patients with myeloproliferative disorders. Model/species: Five myeloproliferative-disorder patient samples with clonal analysis of progenitors Organism: Homo sapiens Tissue/system: Haematopoietic stem and progenitor cells Exposure: No intervention; clonal ordering within patient samples Duration: Cross-sectional Limits: Five samples. Order of acquisition in a clone does not by itself establish which lesion drives the disease. Primary reference: [delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
Complete structured claim and evidence
Bone marrow from patients carrying TET2 mutations showed uniformly low 5-hydroxymethylcytosine in genomic DNA compared with bone marrow from healthy controls, and the mutations compromised catalytic activity in the same study.
Human TET2 → Bone-marrow genomic 5-hydroxymethylcytosine content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Cross-sectional
experimental_model
Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein
exposure
No intervention; naturally occurring mutations
limitations
Samples with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites, so the downstream methylation consequence is not a simple global gain.
organism
Homo sapiens
plain_language
Patients with a damaged TET2 had less of the chemical mark the enzyme makes.
primary_references
[ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
tissue
Bone marrow genomic DNA
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 33–41
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein · source_derived_draft · unverified_draft
## tet2-mutation-lowers-marrow-5hmc Bone marrow from patients carrying TET2 mutations showed uniformly low 5-hydroxymethylcytosine in genomic DNA compared with bone marrow from healthy controls, and the mutations compromised catalytic activity in the same study. Model/species: Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein Organism: Homo sapiens Tissue/system: Bone marrow genomic DNA Exposure: No intervention; naturally occurring mutations Duration: Cross-sectional Limits: Samples with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites, so the downstream methylation consequence is not a simple global gain. Primary reference: [ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
Complete structured claim and evidence
Short-hairpin-RNA depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte and macrophage lineages in culture.
Mouse Tet2 → Monocyte and macrophage lineage skewing of mouse haematopoietic precursors source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Culture experiment
experimental_model
Mouse haematopoietic precursors with shRNA knockdown, in culture
exposure
shRNA-mediated Tet2 depletion
limitations
A culture differentiation bias is not leukaemia, and knockdown is not the patient mutation.
organism
Mus musculus
plain_language
Removing Tet2 pushed young blood cells toward one lineage.
primary_references
[ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
tissue
Cultured haematopoietic precursors
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 43–51
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Mouse haematopoietic precursors with shRNA knockdown, in culture · source_derived_draft · unverified_draft
## tet2-depletion-skews-mouse-precursors Short-hairpin-RNA depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte and macrophage lineages in culture. Model/species: Mouse haematopoietic precursors with shRNA knockdown, in culture Organism: Mus musculus Tissue/system: Cultured haematopoietic precursors Exposure: shRNA-mediated Tet2 depletion Duration: Culture experiment Limits: A culture differentiation bias is not leukaemia, and knockdown is not the patient mutation. Primary reference: [ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
Complete structured claim and evidence
Conditional deletion of Tet2 in the mouse haematopoietic compartment increased stem-cell self-renewal in competitive transplant assays, and Tet2 heterozygous mice also showed increased self-renewal and extramedullary haematopoiesis.
Mouse Tet2 → Mouse haematopoietic stem and progenitor cell self-renewal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
In vivo, to the development of disease
experimental_model
Conditional Tet2-knockout mice; competitive transplantation
exposure
Conditional genetic deletion of Tet2; homozygous and heterozygous
limitations
Haploinsufficiency means one damaged copy already changes the phenotype; this is a genetic model, not a nutritional one.
organism
Mus musculus
plain_language
Losing Tet2 made blood stem cells renew themselves more than they should.
primary_references
[moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
tissue
Haematopoietic stem cell compartment
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 53–61
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Conditional Tet2-knockout mice; competitive transplantation · source_derived_draft · unverified_draft
## tet2-loss-increases-hspc-self-renewal Conditional deletion of Tet2 in the mouse haematopoietic compartment increased stem-cell self-renewal in competitive transplant assays, and Tet2 heterozygous mice also showed increased self-renewal and extramedullary haematopoiesis. Model/species: Conditional Tet2-knockout mice; competitive transplantation Organism: Mus musculus Tissue/system: Haematopoietic stem cell compartment Exposure: Conditional genetic deletion of Tet2; homozygous and heterozygous Duration: In vivo, to the development of disease Limits: Haploinsufficiency means one damaged copy already changes the phenotype; this is a genetic model, not a nutritional one. Primary reference: [moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
Complete structured claim and evidence
Conditional Tet2 loss produced progressive enlargement of the haematopoietic stem-cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis and extramedullary haematopoiesis.
Mouse Tet2 → Myeloproliferation in mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Progressive, in vivo
experimental_model
Conditional Tet2-knockout mice followed in vivo
exposure
Conditional genetic deletion of Tet2
limitations
Myeloproliferation in a conditional knockout mouse is not the same entity as a human myelodysplastic syndrome, and this model deletes the gene rather than reproducing a point mutation.
organism
Mus musculus
plain_language
Mice without Tet2 went on to develop a blood disorder of overgrowth.
primary_references
[moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
tissue
Bone marrow, spleen and peripheral blood
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 63–71
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Conditional Tet2-knockout mice followed in vivo · source_derived_draft · unverified_draft
## tet2-loss-causes-myeloproliferation Conditional Tet2 loss produced progressive enlargement of the haematopoietic stem-cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis and extramedullary haematopoiesis. Model/species: Conditional Tet2-knockout mice followed in vivo Organism: Mus musculus Tissue/system: Bone marrow, spleen and peripheral blood Exposure: Conditional genetic deletion of Tet2 Duration: Progressive, in vivo Limits: Myeloproliferation in a conditional knockout mouse is not the same entity as a human myelodysplastic syndrome, and this model deletes the gene rather than reproducing a point mutation. Primary reference: [moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
Complete structured claim and evidence
Inactivating Tet2 in mouse perturbed both early and late haematopoiesis in a cell-autonomous manner, gave the cells a competitive advantage, and eventually led to the development of haematological malignancies.
Mouse Tet2 → Haematological malignancy in mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
In vivo, to malignancy
experimental_model
Tet2-inactivated mice; competitive repopulation
exposure
Genetic inactivation of Tet2
limitations
A different group from the conditional-knockout study above, but the same group as the 2009 human mutation survey in this collection, so that survey and this mouse model are one line of evidence rather than two.
organism
Mus musculus
plain_language
A second group's mice also developed blood cancers after Tet2 was switched off.
primary_references
[quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
tissue
Myeloid and lymphoid compartments
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 73–81
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet2-inactivated mice; competitive repopulation · source_derived_draft · unverified_draft
## tet2-inactivation-causes-mouse-malignancy Inactivating Tet2 in mouse perturbed both early and late haematopoiesis in a cell-autonomous manner, gave the cells a competitive advantage, and eventually led to the development of haematological malignancies. Model/species: Tet2-inactivated mice; competitive repopulation Organism: Mus musculus Tissue/system: Myeloid and lymphoid compartments Exposure: Genetic inactivation of Tet2 Duration: In vivo, to malignancy Limits: A different group from the conditional-knockout study above, but the same group as the 2009 human mutation survey in this collection, so that survey and this mouse model are one line of evidence rather than two. Primary reference: [quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
Complete structured claim and evidence
TET2 mutations were observed in human lymphoid disorders and could be detected in immature progenitors that retained myeloid colony-forming potential.
Human TET2 → TET2 mutation in human lymphoid neoplasms source_derived_draftungraded
Experimental context and source evidence
duration
Cross-sectional
experimental_model
Human lymphoid disorder samples with progenitor colony assays
exposure
No intervention; observational sequencing
limitations
Detection in a progenitor shows where the mutation sits in the hierarchy, not that it caused the lymphoid tumour.
organism
Homo sapiens
plain_language
The same damaged gene also turns up in lymphoid cancers, not only myeloid ones.
primary_references
[quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
tissue
Lymphoid tumour cells and immature progenitors
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 83–91
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human lymphoid disorder samples with progenitor colony assays · source_derived_draft · unverified_draft
## tet2-mutation-in-lymphoid-disorders TET2 mutations were observed in human lymphoid disorders and could be detected in immature progenitors that retained myeloid colony-forming potential. Model/species: Human lymphoid disorder samples with progenitor colony assays Organism: Homo sapiens Tissue/system: Lymphoid tumour cells and immature progenitors Exposure: No intervention; observational sequencing Duration: Cross-sectional Limits: Detection in a progenitor shows where the mutation sits in the hierarchy, not that it caused the lymphoid tumour. Primary reference: [quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
Complete structured claim and evidence
Restoring endogenous Tet2 expression in a reversible transgenic RNAi mouse reversed aberrant haematopoietic stem and progenitor cell self-renewal both in vitro and in vivo.
Mouse Tet2 → Mouse haematopoietic stem and progenitor cell self-renewal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
In vitro and in vivo after restoration
experimental_model
Reversible transgenic RNAi mouse permitting Tet2 knockdown and restoration
exposure
Genetic restoration of endogenous Tet2 expression after knockdown
limitations
Restoring a knockdown is not the same as correcting a mutated allele in a patient, and the reversal was measured as self-renewal rather than as cure of an established leukaemia.
organism
Mus musculus
plain_language
Switching Tet2 back on undid the abnormal renewal, which is the strongest sign the enzyme itself was responsible.
primary_references
[cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
tissue
Haematopoietic stem and progenitor cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 93–101
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Reversible transgenic RNAi mouse permitting Tet2 knockdown and restoration · source_derived_draft · unverified_draft
## tet2-restoration-reverses-self-renewal Restoring endogenous Tet2 expression in a reversible transgenic RNAi mouse reversed aberrant haematopoietic stem and progenitor cell self-renewal both in vitro and in vivo. Model/species: Reversible transgenic RNAi mouse permitting Tet2 knockdown and restoration Organism: Mus musculus Tissue/system: Haematopoietic stem and progenitor cells Exposure: Genetic restoration of endogenous Tet2 expression after knockdown Duration: In vitro and in vivo after restoration Limits: Restoring a knockdown is not the same as correcting a mutated allele in a patient, and the reversal was measured as self-renewal rather than as cure of an established leukaemia. Primary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
Complete structured claim and evidence
Vitamin C treatment enhanced 5-hydroxymethylcytosine formation in Tet2-deficient mouse haematopoietic stem and progenitor cells, mimicking genetic Tet2 restoration.
L-Ascorbate → DNA 5-hydroxymethylcytosine residues source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Treatment in culture and in vivo
experimental_model
Tet2-deficient mouse haematopoietic stem and progenitor cells
exposure
Vitamin C as a cofactor of Fe(II)- and 2-oxoglutarate-dependent dioxygenases
limitations
Vitamin C is a cofactor for the whole family of Fe(II)- and 2-oxoglutarate-dependent dioxygenases, so raised 5hmC in a Tet2-deficient cell does not establish that TET2 itself was reactivated.
organism
Mus musculus
plain_language
Vitamin C raised the same chemical mark that restoring the enzyme raises.
primary_references
[cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
tissue
Haematopoietic stem and progenitor cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 103–111
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet2-deficient mouse haematopoietic stem and progenitor cells · source_derived_draft · unverified_draft
## ascorbate-raises-5hmc-in-tet2-deficient-hspc Vitamin C treatment enhanced 5-hydroxymethylcytosine formation in Tet2-deficient mouse haematopoietic stem and progenitor cells, mimicking genetic Tet2 restoration. Model/species: Tet2-deficient mouse haematopoietic stem and progenitor cells Organism: Mus musculus Tissue/system: Haematopoietic stem and progenitor cells Exposure: Vitamin C as a cofactor of Fe(II)- and 2-oxoglutarate-dependent dioxygenases Duration: Treatment in culture and in vivo Limits: Vitamin C is a cofactor for the whole family of Fe(II)- and 2-oxoglutarate-dependent dioxygenases, so raised 5hmC in a Tet2-deficient cell does not establish that TET2 itself was reactivated. Primary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
Complete structured claim and evidence
Vitamin C treatment suppressed leukaemic colony formation by human leukaemia cells and slowed leukaemia progression in primary human acute-myeloid-leukaemia patient-derived xenografts.
L-Ascorbate → Human acute myeloid leukaemia colony formation and xenograft progression source_derived_draftungraded
Experimental context and source evidence
duration
Colony assays and xenograft progression
experimental_model
Human leukaemia cell lines and primary human AML patient-derived xenografts
exposure
Pharmacological vitamin C
limitations
Pharmacological vitamin C in a xenograft is not dietary intake, and a xenograft host lacks an intact immune system.
organism
Homo sapiens cells in mouse xenograft hosts
plain_language
Vitamin C slowed human leukaemia cells in a dish and in mice carrying them.
primary_references
[cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
tissue
Leukaemic blasts
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 113–121
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human leukaemia cell lines and primary human AML patient-derived xenografts · source_derived_draft · unverified_draft
## ascorbate-suppresses-aml-colony-formation Vitamin C treatment suppressed leukaemic colony formation by human leukaemia cells and slowed leukaemia progression in primary human acute-myeloid-leukaemia patient-derived xenografts. Model/species: Human leukaemia cell lines and primary human AML patient-derived xenografts Organism: Homo sapiens cells in mouse xenograft hosts Tissue/system: Leukaemic blasts Exposure: Pharmacological vitamin C Duration: Colony assays and xenograft progression Limits: Pharmacological vitamin C in a xenograft is not dietary intake, and a xenograft host lacks an intact immune system. Primary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
Complete structured claim and evidence
Systemic ascorbate depletion in mice increased haematopoietic stem cell frequency and function, in part by reducing the function of Tet2, and haematopoietic stem cells were shown to hold unusually high ascorbate that falls with differentiation.
L-Ascorbate → Mouse haematopoietic stem cell frequency source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
duration
Systemic depletion in vivo
experimental_model
Mice under systemic ascorbate depletion; metabolomics of rare cell populations isolated directly from tissues
exposure
Systemic ascorbate depletion; the retrieved abstract does not state the strain or the depletion protocol
limitations
The retrieved abstract does not state the strain or protocol used to deplete ascorbate. Mice ordinarily synthesise their own ascorbate, so a mouse depletion model is not equivalent to human dietary deficiency, and more stem cells is not by itself a disease.
organism
Mus musculus
plain_language
Taking vitamin C away made blood stem cells multiply more, partly by slowing the enzyme.
primary_references
[agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
tissue
Haematopoietic stem cells
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 123–131
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Mice under systemic ascorbate depletion; metabolomics of rare cell populations isolated directly from tissues · source_derived_draft · unverified_draft
## ascorbate-depletion-raises-hsc-frequency Systemic ascorbate depletion in mice increased haematopoietic stem cell frequency and function, in part by reducing the function of Tet2, and haematopoietic stem cells were shown to hold unusually high ascorbate that falls with differentiation. Model/species: Mice under systemic ascorbate depletion; metabolomics of rare cell populations isolated directly from tissues Organism: Mus musculus Tissue/system: Haematopoietic stem cells Exposure: Systemic ascorbate depletion; the retrieved abstract does not state the strain or the depletion protocol Duration: Systemic depletion in vivo Limits: The retrieved abstract does not state the strain or protocol used to deplete ascorbate. Mice ordinarily synthesise their own ascorbate, so a mouse depletion model is not equivalent to human dietary deficiency, and more stem cells is not by itself a disease. Primary reference: [agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
Complete structured claim and evidence
Systemic ascorbate depletion cooperated with Flt3 internal tandem duplication to accelerate leukaemogenesis in mice, and restoring dietary ascorbate reversed that acceleration.
L-Ascorbate → Leukaemogenesis in Flt3-internal-tandem-duplication mice source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
duration
To leukaemia onset
experimental_model
Ascorbate-depleted mice carrying Flt3 internal tandem duplication
exposure
Dietary ascorbate depletion, with dietary ascorbate restoration as the reversal arm
limitations
Depletion acted together with a leukaemic driver mutation; this is not evidence that ascorbate shortage alone causes leukaemia. The authors note possible non-cell-autonomous mechanisms.
organism
Mus musculus
plain_language
In mice already carrying a leukaemia mutation, vitamin C shortage made the disease come faster, and feeding it back undid that.
primary_references
[agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
tissue
Haematopoietic system
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 133–141
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Ascorbate-depleted mice carrying Flt3 internal tandem duplication · source_derived_draft · unverified_draft
## ascorbate-depletion-accelerates-leukaemogenesis Systemic ascorbate depletion cooperated with Flt3 internal tandem duplication to accelerate leukaemogenesis in mice, and restoring dietary ascorbate reversed that acceleration. Model/species: Ascorbate-depleted mice carrying Flt3 internal tandem duplication Organism: Mus musculus Tissue/system: Haematopoietic system Exposure: Dietary ascorbate depletion, with dietary ascorbate restoration as the reversal arm Duration: To leukaemia onset Limits: Depletion acted together with a leukaemic driver mutation; this is not evidence that ascorbate shortage alone causes leukaemia. The authors note possible non-cell-autonomous mechanisms. Primary reference: [agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
Complete structured claim and evidence
All-trans retinoic acid induced retinoic-acid-receptor-alpha-mediated TET2 transcription in myeloid leukaemia cells.
All-trans-retinoic acid → Human TET2 source_derived_draftungraded
Experimental context and source evidence
duration
Culture treatment
experimental_model
Myeloid leukaemia cell lines and primary human AML models
exposure
All-trans retinoic acid
limitations
A transcript rise is not a measured rise in enzyme activity, and pharmacological ATRA is not dietary vitamin A.
organism
Homo sapiens
plain_language
Retinoic acid made leukaemia cells produce more of the TET2 enzyme.
primary_references
[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
tissue
Myeloid leukaemia cells
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 143–151
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Myeloid leukaemia cell lines and primary human AML models · source_derived_draft · unverified_draft
## atra-induces-tet2-transcription All-trans retinoic acid induced retinoic-acid-receptor-alpha-mediated TET2 transcription in myeloid leukaemia cells. Model/species: Myeloid leukaemia cell lines and primary human AML models Organism: Homo sapiens Tissue/system: Myeloid leukaemia cells Exposure: All-trans retinoic acid Duration: Culture treatment Limits: A transcript rise is not a measured rise in enzyme activity, and pharmacological ATRA is not dietary vitamin A. Primary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
Complete structured claim and evidence
All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival.
All-trans-retinoic acid → Leukaemia stem cell self-renewal in human acute myeloid leukaemia models source_derived_draftungraded
Experimental context and source evidence
duration
In vivo to survival
experimental_condition
Untreated or single-agent primary human AML models All-trans retinoic acid administered · All-trans-retinoic acid Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Untreated or single-agent primary human AML models Ascorbate administered · L-Ascorbate Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "All-trans retinoic acid plus ascorbate", "comparator": "Untreated or single-agent primary human AML models", "endpoint": "Leukaemia stem cell self-renewal and survival", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "all-trans-retinoic-acid", "state": "All-trans retinoic acid administered"}, {"entity_slug": "ascorbate", "state": "Ascorbate administered"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Tet1/2/3-deficient mice and primary human AML models
exposure
All-trans retinoic acid combined with ascorbate
limitations
A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone.
organism
Mus musculus and Homo sapiens
plain_language
Retinoic acid and vitamin C together worked better than either was expected to alone.
primary_references
[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
tissue
Leukaemia stem cells
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 153–161
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet1/2/3-deficient mice and primary human AML models · source_derived_draft · unverified_draft
## atra-with-ascorbate-reduces-lsc-self-renewal All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival. Model/species: Tet1/2/3-deficient mice and primary human AML models Organism: Mus musculus and Homo sapiens Tissue/system: Leukaemia stem cells Exposure: All-trans retinoic acid combined with ascorbate Duration: In vivo to survival Limits: A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone. Primary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
Complete structured claim and evidence
In patient-derived primary acute-myeloid-leukaemia cells, vitamin C restored TET2 activity only when SLC2A3 was expressed, and SLC2A3 knockdown in the KG-1 cell line decreased the response to vitamin C.
Human GLUT3 / SLC2A3 → Cellular ascorbate uptake source_derived_draftungraded
Experimental context and source evidence
duration
Culture experiments
experimental_model
AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis
exposure
Vitamin C, with and without SLC2A3 knockdown
limitations
Below-median SLC2A3 expression was associated with poorer overall survival, which is an association within a database cohort and not an experimental outcome.
organism
Homo sapiens
plain_language
If the cell cannot take vitamin C in, the vitamin cannot restore the enzyme.
primary_references
[liu-2020] Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration (2020). https://pubmed.ncbi.nlm.nih.gov/32203209/ DOI: 10.1038/s41416-020-0788-8
tissue
Leukaemic blasts
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 163–171
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis · source_derived_draft · unverified_draft
## slc2a3-gates-vitamin-c-tet2-restoration In patient-derived primary acute-myeloid-leukaemia cells, vitamin C restored TET2 activity only when SLC2A3 was expressed, and SLC2A3 knockdown in the KG-1 cell line decreased the response to vitamin C. Model/species: AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis Organism: Homo sapiens Tissue/system: Leukaemic blasts Exposure: Vitamin C, with and without SLC2A3 knockdown Duration: Culture experiments Limits: Below-median SLC2A3 expression was associated with poorer overall survival, which is an association within a database cohort and not an experimental outcome. Primary reference: [liu-2020] Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration (2020). https://pubmed.ncbi.nlm.nih.gov/32203209/ DOI: 10.1038/s41416-020-0788-8
Complete structured claim and evidence
The ability of ascorbic acid to restore TET2 activity in cells depended on N-terminal and C-terminal lysine acetylation and on the nature of the TET2 mutation.
L-Ascorbate → Human TET2 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Culture experiments
experimental_model
TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation
exposure
Ascorbic acid, with pharmacological modulation of acetyltransferases and histone deacetylases
limitations
Which mutations respond is not resolved here; the study proposes combinations rather than demonstrating clinical benefit.
organism
Homo sapiens
plain_language
Whether vitamin C can revive the enzyme depends on which mutation the patient has.
primary_references
[mustafi-2020] Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia (2020). https://pubmed.ncbi.nlm.nih.gov/32895473/ DOI: 10.1038/s42003-020-01220-9
tissue
Myeloid neoplasia cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 173–181
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation · source_derived_draft · unverified_draft
## ascorbate-restoration-depends-on-mutation-and-acetylation The ability of ascorbic acid to restore TET2 activity in cells depended on N-terminal and C-terminal lysine acetylation and on the nature of the TET2 mutation. Model/species: TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation Organism: Homo sapiens Tissue/system: Myeloid neoplasia cells Exposure: Ascorbic acid, with pharmacological modulation of acetyltransferases and histone deacetylases Duration: Culture experiments Limits: Which mutations respond is not resolved here; the study proposes combinations rather than demonstrating clinical benefit. Primary reference: [mustafi-2020] Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia (2020). https://pubmed.ncbi.nlm.nih.gov/32895473/ DOI: 10.1038/s42003-020-01220-9
Complete structured claim and evidence
TET2 knockout in human HAP1 cells lowered 5-hydroxymethylcytosine and 5-formylcytosine measured by 2D-UPLC-MS/MS, and vitamin C treatment did not restore them to the levels seen in treated wild-type cells, so loss of one TET paralog was not compensated by the remaining ones.
Human TET2 → Cytosine oxidation products in human HAP1 TET-knockout cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Culture experiments
experimental_model
Human HAP1 cells with single and double TET knockouts
exposure
Vitamin C treatment of wild-type and TET-knockout cells
limitations
A near-haploid cell line, not a haematopoietic cell; a knockout is not a patient's point mutation.
organism
Homo sapiens
plain_language
Vitamin C cannot fully substitute for a TET2 that is missing.
primary_references
[kusmierek-2025] Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells (2025). https://pubmed.ncbi.nlm.nih.gov/41287077/ DOI: 10.1186/s13072-025-00634-1
tissue
HAP1 cell line
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 183–191
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human HAP1 cells with single and double TET knockouts · source_derived_draft · unverified_draft
## vitamin-c-cannot-replace-lost-tet2 TET2 knockout in human HAP1 cells lowered 5-hydroxymethylcytosine and 5-formylcytosine measured by 2D-UPLC-MS/MS, and vitamin C treatment did not restore them to the levels seen in treated wild-type cells, so loss of one TET paralog was not compensated by the remaining ones. Model/species: Human HAP1 cells with single and double TET knockouts Organism: Homo sapiens Tissue/system: HAP1 cell line Exposure: Vitamin C treatment of wild-type and TET-knockout cells Duration: Culture experiments Limits: A near-haploid cell line, not a haematopoietic cell; a knockout is not a patient's point mutation. Primary reference: [kusmierek-2025] Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells (2025). https://pubmed.ncbi.nlm.nih.gov/41287077/ DOI: 10.1186/s13072-025-00634-1
Complete structured claim and evidence
One year of oral vitamin C at 1 g/day in members of a family carrying a heterozygous truncating germline TET2 mutation reduced the proportion of hypermethylated loci and diminished gene-expression differences between carriers and non-carrier relatives.
L-Ascorbate → DNA hypermethylation in TET2 germline mutation carriers source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
One year
experimental_model
Clinical trial of one year in a single lymphoma-predisposition family; genome-wide methylation and expression
exposure
Oral vitamin C 1 g/day
limitations
One family, no disease endpoint measured. A methylation change is a biomarker, not a demonstration that lymphoma risk fell. Registered as EudraCT 2018-000155-41.
organism
Homo sapiens
plain_language
A year of vitamin C shifted the DNA marks in people born with a damaged TET2, but no cancer outcome was measured.
primary_references
[pitkanen-2023] Vitamin C boosts DNA demethylation in TET2 germline mutation carriers (2023). https://pubmed.ncbi.nlm.nih.gov/36639817/ DOI: 10.1186/s13148-022-01404-6
tissue
Blood cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 193–201
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Clinical trial of one year in a single lymphoma-predisposition family; genome-wide methylation and expression · source_derived_draft · unverified_draft
## vitamin-c-reduces-hypermethylation-in-tet2-carriers One year of oral vitamin C at 1 g/day in members of a family carrying a heterozygous truncating germline TET2 mutation reduced the proportion of hypermethylated loci and diminished gene-expression differences between carriers and non-carrier relatives. Model/species: Clinical trial of one year in a single lymphoma-predisposition family; genome-wide methylation and expression Organism: Homo sapiens Tissue/system: Blood cells Exposure: Oral vitamin C 1 g/day Duration: One year Limits: One family, no disease endpoint measured. A methylation change is a biomarker, not a demonstration that lymphoma risk fell. Registered as EudraCT 2018-000155-41. Primary reference: [pitkanen-2023] Vitamin C boosts DNA demethylation in TET2 germline mutation carriers (2023). https://pubmed.ncbi.nlm.nih.gov/36639817/ DOI: 10.1186/s13148-022-01404-6
Complete structured claim and evidence
In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.
L-Ascorbate → Haematologic response in TET2-mutant clonal cytopenia of undetermined significance source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Response assessed at week 20
experimental_model
Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038
exposure
High-dose intravenous ascorbic acid
limitations
Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed.
organism
Homo sapiens
plain_language
In the one published trial of this idea in patients, nobody responded.
primary_references
[guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962
tissue
Blood and bone marrow
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 203–211
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038 · source_derived_draft · unverified_draft
## ascorbate-no-response-in-ccus-trial In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20. Model/species: Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038 Organism: Homo sapiens Tissue/system: Blood and bone marrow Exposure: High-dose intravenous ascorbic acid Duration: Response assessed at week 20 Limits: Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed. Primary reference: [guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Removing SVCT1 made mice lose more filtered vitamin C in urine.

Condition: machinery_impairment · Slc23a1 knockout versus wild type

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Slc23a1 deletion raised renal ascorbate fractional excretion about 16–18-fold in female mice and 6–7-fold in males; female reabsorption was essentially abolished.

Scope: Slc23a1 knockout mice and wild-type controls

Ascorbate depletion accelerates leukaemogenesis alongside a driver mutation

Condition: nutrient_deficiency · Systemic dietary ascorbate depletion in mice unable to synthesise ascorbate.

Normal role: Haematopoietic stem cells hold unusually high ascorbate, which falls with differentiation, and ascorbate supports Tet2 dioxygenase function.

Recorded consequence: Haematopoietic stem cell frequency and function rose, partly through reduced Tet2 function, and depletion cooperated with Flt3 internal tandem duplication to accelerate leukaemogenesis. Restoring dietary ascorbate reversed the acceleration.

Scope: Ascorbate-synthesis-deficient mice, with and without a Flt3 internal tandem duplication.

Renal vitamin C wasting lowered circulating vitamin C in these mice.

Condition: machinery_impairment · Slc23a1 knockout versus wild type

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Plasma ascorbate was approximately 50–70% lower in Slc23a1-null mice than wild-type mice.

Scope: Slc23a1 knockout mice and wild-type controls

The dioxygenase ascorbate acts through is lost

Condition: machinery_impairment · Somatic mutation, conditional deletion, inactivation or short-hairpin knockdown of TET2.

Normal role: TET2 is an Fe(II)- and 2-oxoglutarate-dependent dioxygenase that ascorbate supports. In haematopoiesis it maintains 5-hydroxymethylcytosine, restrains stem-cell self-renewal and restrains monocyte/macrophage skewing.

Recorded consequence: Marrow 5-hydroxymethylcytosine falls, precursors skew toward monocyte and macrophage lineages, stem-cell self-renewal rises, and mice progress to myeloproliferation and haematological malignancy. Restoring Tet2 expression reverses the aberrant self-renewal, which is what identifies the enzyme rather than a correlate as the responsible component.

Scope: Patient bone marrow, conditional and inactivated mouse models, and a reversible RNAi mouse.

Maternal loss of the renal vitamin C transporter threatened newborn survival.

Condition: machinery_impairment · Breeding Slc23a1-null dams

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Pups born to Slc23a1-null dams had approximately 45% perinatal mortality, including heterozygous and homozygous-null pups.

Scope: Slc23a1 knockout mice and wild-type controls

What ascorbate can and cannot do once TET2 is damaged

Condition: machinery_impairment · TET2 mutation, germline truncation or knockout, with ascorbate then supplied.

Normal role: Ascorbate supports TET-family dioxygenase activity and DNA demethylation.

Recorded consequence: Ascorbate raises 5-hydroxymethylcytosine in Tet2-deficient cells and lowers hypermethylation in germline carriers, but it does not restore oxidation products to wild-type levels when TET2 is absent, its effect depends on the particular mutation and on lysine acetylation, and in the one published phase 2 trial no patient met response criteria.

Scope: Mouse haematopoietic cells, human HAP1 and myeloid neoplasia cell systems, one family trial and one phase 2 trial.

Additional vitamin C rescued survival in this maternal transporter-loss model.

Condition: machinery_impairment · Slc23a1-null dams; 330 mg/L drinking-water ascorbate during pregnancy

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Providing Slc23a1-null pregnant mice 330 mg/L ascorbate in drinking water from mating to delivery prevented the excess perinatal mortality of their null offspring.

Scope: Slc23a1 knockout mice and wild-type controls

These mice could partly compensate for urinary loss by making more vitamin C.

Condition: machinery_impairment · Slc23a1 knockout

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Slc23a1-null mice increased endogenous ascorbate synthesis despite losing as much as 70% of their body ascorbate stores in urine daily.

Scope: Slc23a1 knockout mice and wild-type controls

Without SVCT2, these embryonic cells took up very little reduced vitamin C.

Condition: machinery_impairment · Homozygous SVCT2 gene deletion

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Embryonic fibroblasts from SVCT2-null mice retained less than 5% of normal ascorbic-acid uptake.

Scope: SVCT2-null mouse embryos, newborns and embryonic fibroblasts

Severe loss of cellular vitamin C transport was lethal around birth in mice.

Condition: machinery_impairment · Homozygous SVCT2 gene deletion

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: SVCT2-null mice died within minutes of birth with respiratory failure and intraparenchymal brain hemorrhage.

Scope: SVCT2-null mouse embryos, newborns and embryonic fibroblasts

Low cellular ascorbate changes the response to toxic chromate

Condition: nutrient_deficiency · Standard cultured cells contain very low ascorbate compared with restored cultures.

Normal role: Ascorbate alters intracellular chromium reduction chemistry and damage-response signaling.

Recorded consequence: Chromate activated ATM strongly in the ascorbate-poor cultures; this response was absent after ascorbate restoration.

Scope: Human cell cultures exposed to Cr(VI), not a dietary chromium deficiency.

Increasing maternal supply did not overcome the fetus’s missing SVCT2 machinery.

Condition: machinery_impairment · Prenatal maternal supplementation with SVCT2-null fetuses

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Maternal prenatal ascorbic-acid supplementation did not raise fetal blood ascorbate in SVCT2-null mouse fetuses.

Scope: SVCT2-null mouse embryos, newborns and embryonic fibroblasts

Depleting glutathione impaired the red cells’ vitamin C recycling capacity.

Condition: machinery_impairment · Up to 1 mM diethyl maleate ex vivo

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Diethyl maleate depletion of erythrocyte GSH by 75–90% reduced the combined uptake and conversion of DHA to ascorbate in human cells.

Scope: Human volunteer erythrocytes ex vivo

Vitamin C shortage altered an epigenetic step in germ-cell development.

Condition: nutrient_deficiency · Maternal vitamin C withdrawal in a diet-dependent Gulo-null model.

Normal role: Maternal vitamin C supports germline demethylation during this developmental window.

Recorded consequence: Maternal vitamin C withdrawal increased Dazl-promoter methylation in female fetal germ cells, with reduced Dazl expression.

Scope: Same-genotype nutritional comparison and bisulfite sequencing; Mus musculus

When noradrenaline synthesis draws on the vitamin C pool

Condition: nutrient_deficiency · Sustained catecholamine synthesis, as driven experimentally by tyramine or dopamine.

Normal role: Ascorbate inside the chromaffin granule donates electrons to dopamine beta-hydroxylase and is re-reduced from the cytosolic pool by a transmembrane shuttle.

Recorded consequence: Intragranular reduced ascorbate falls roughly one for one with product formed, and is restored by extragranular ascorbate.

Scope: Intact bovine chromaffin granules

A second nutrient shortage affected the germ-cell program also studied in vitamin A biology.

Condition: nutrient_deficiency · Maternal vitamin C withdrawal during early gestation.

Normal role: Adequate vitamin C supports the timing of female germ-cell differentiation.

Recorded consequence: Maternal vitamin C deficiency delayed female fetal meiotic progression, with reduced STRA8 expression.

Scope: Nutrient withdrawal with histology and meiotic staging; Mus musculus

When ascorbate runs out in connective tissue

Condition: nutrient_deficiency · Dietary vitamin C deficiency.

Normal role: Ascorbate keeps the iron in prolyl 4-hydroxylase reduced so proline residues in procollagen can be hydroxylated, and hydroxyproline stabilises the collagen triple helix.

Recorded consequence: Procollagen secretion falls, and collagen synthesis falls further than proline under-hydroxylation alone explains, alongside induced IGF-binding proteins.

Scope: Guinea pig scurvy and cultured cells

Long-term low intake reduced the brain vitamin C pool.

Condition: nutrient_deficiency · Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Chronic prenatal and postnatal vitamin C restriction lowered brain total vitamin C in day-70 female guinea pigs.

Scope: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

A larger fraction of the smaller brain vitamin C pool was oxidized.

Condition: nutrient_deficiency · Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Chronically vitamin-C-restricted guinea pigs had a higher brain DHA percentage despite lower total brain vitamin C.

Scope: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

The measured brain regions did not compensate by detectably increasing SVCT2 abundance.

Condition: nutrient_deficiency · Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Dietary vitamin C restriction did not significantly alter SVCT2 mRNA or protein in guinea pig hippocampus, cerebellum or frontal cortex at day 70.

Scope: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

Low vitamin C increased a marker of brain lipid oxidation.

Condition: nutrient_deficiency · Prenatal/postnatal 100/100 mg vitamin C/kg diet versus 900/750 mg/kg controls; female offspring at day 70

Normal role: Transport and recycling maintain available reduced vitamin C.

Recorded consequence: Chronically vitamin-C-restricted guinea pigs had higher brain malondialdehyde than vitamin-C-sufficient controls at day 70.

Scope: Thirty female guinea pig offspring, control/deficient/repleted diets, postnatal day 70

Low vitamin C and muscle carnitine in guinea pigs

Condition: nutrient_deficiency · Low versus high dietary vitamin C producing 12% versus 100% tissue saturation

Normal role: Ascorbate supports carnitine-pathway hydroxylases; tissue carnitine also depends on intake, transport and excretion.

Recorded consequence: Lower muscle carnitine

Scope: Guinea-pig skeletal muscle

Vitamin C deficiency with pair-fed liver comparison

Condition: nutrient_deficiency · Vitamin C deficient diet, with control and underfed pair-fed groups

Normal role: Ascorbate supports carnitine-pathway hydroxylases; tissue carnitine also depends on intake, transport and excretion.

Recorded consequence: Lower hepatic carnitine concentration

Scope: Guinea-pig liver

Preserved carnitine precursor response during vitamin C deficiency

Condition: nutrient_deficiency · 28-day vitamin C deficient diet; precursor 0.5 mmol/kg/day on days 19–28

Normal role: Ascorbate supports carnitine-pathway hydroxylases; tissue carnitine also depends on intake, transport and excretion.

Recorded consequence: Preserved 32–40 micromol/kg/day estimated synthesis increase

Scope: Guinea-pig whole-body precursor-loading assay

Preserved carnitine precursor response during vitamin C deficiency

Condition: nutrient_deficiency · 28-day vitamin C deficient diet; precursor 0.5 mmol/kg/day on days 19–28

Normal role: Ascorbate supports carnitine-pathway hydroxylases; tissue carnitine also depends on intake, transport and excretion.

Recorded consequence: Preserved 41–50 micromol/kg/day estimated synthesis increase

Scope: Guinea-pig whole-body precursor-loading assay

Increased urinary carnitine loss in scorbutic guinea pigs

Condition: nutrient_deficiency · Vitamin C deficient diet for 28 days without precursor loading

Normal role: Ascorbate supports carnitine-pathway hydroxylases; tissue carnitine also depends on intake, transport and excretion.

Recorded consequence: Approximately threefold free and total urinary carnitine output

Scope: Guinea-pig urine, days 19–28

Tet1/Tet2 loss blocks vitamin C response

Condition: machinery_impairment · Combined Tet1 and Tet2 knockout

Normal role: Tet1/Tet2 oxidize DNA methylcytosine

Recorded consequence: Vitamin C derivative fails to induce the measured 5hmC/promoter-demethylation response

Scope: Tet1/Tet2 double-knockout ESCs versus wild type; dot blot and DIP-qPCR; Mus musculus; Embryonic stem cells

Jhdm1a/1b impairment during reprogramming

Condition: machinery_impairment · Experimental loss of Jhdm1a/1b function

Normal role: Jhdm1a/1b support vitamin C-enhanced reprogramming

Recorded consequence: Reduced vitamin C-associated reprogramming response

Scope: Mouse fibroblast reprogramming with Jhdm1a/1b gain/loss of function; Mus musculus; Embryonic fibroblasts

Ascorbate-free HeLa oxygen sensing

Condition: nutrient_deficiency · Adaptation to defined medium without serum or ascorbate

Normal role: HIF pathway responds to reduced oxygen availability

Recorded consequence: Tested hypoxic HIF stabilization and reporter response persist

Scope: HeLa adapted to serum-free Ham F-12; HIF immunoblot and luciferase reporter; Homo sapiens; Cervical carcinoma cells

Vitamin C depletion in synthesis-null mice

Condition: nutrient_deficiency · Dietary vitamin C withdrawal in Gulo-null males followed by 8% oxygen

Normal role: HIF-linked renal erythropoietin signaling responds to oxygen shortage

Recorded consequence: Strong plasma EPO induction remains despite scorbutic depletion

Scope: Dietary withdrawal in adult male Gulo-null mice with supplemented-genotype controls; Mus musculus; Plasma erythropoietin; kidney Epo mRNA supporting endpoint

SOD2 loss increases ascorbate vulnerability

Condition: machinery_impairment · SOD2 knockout in A549 cells

Normal role: SOD2 limits mitochondrial superoxide and supports iron homeostasis

Recorded consequence: Higher basal labile iron and lower clonogenic survival after ascorbate

Scope: SOD2-null versus parental A549; calcein/BIP labile-iron assay and clonogenic survival; Homo sapiens; Lung adenocarcinoma cells

Depletion produces a pattern of scurvy signs

Condition: nutrient_deficiency · Vitamin C removed from the diet in a historical metabolic experiment.

Normal role: Ascorbate supports selected enzyme and redox reactions; blood measurements and clinical outcomes do not directly quantify every tissue reaction.

Recorded consequence: Skin, gum and hemorrhagic abnormalities appeared in the four completers.

Scope: Small historical prisoner cohort.

Vascular responsiveness can change without loss of every autonomic reflex

Condition: nutrient_deficiency · Three months of vitamin C deprivation followed by repletion in five volunteers.

Normal role: Ascorbate supports selected enzyme and redox reactions; blood measurements and clinical outcomes do not directly quantify every tissue reaction.

Recorded consequence: Forearm vasoconstriction was lower during deficiency, while several resting and reflex endpoints were similar.

Scope: Small before/after clinical scurvy experiment.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23)Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · unverified_draftRead preserved source
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Does mature erythrocyte GLUT1 preferentially transport DHA through a segregated pool?The 2008 study interpreted glucose-insensitive DHA accumulation as a stomatin-regulated substrate switch. The 2014 primary kinetic study explicitly argues against that model and finds shared sugar/DHA transport and competition.Read the recorded disagreement
Historical DBH spectroscopy: does ascorbate reduction change copper ligation?The 1988 and 1989 bovine-enzyme studies agree on Cu(II)-to-Cu(I) reduction but explicitly disagree about average ligand number and sulfur/heavy-atom ligation in the reduced state. This is a published structural interpretation disagreement, not an error correction in this ledger.Read the recorded disagreement
Vitamin C suppresses leukaemia in animals and cells, but the published patient trial found no responsePreclinical work restores TET2 function with vitamin C and slows leukaemia in mice and xenografts. The one registered phase 2 trial in TET2-mutant clonal cytopenia found no haematologic responses at week 20. The studies differ in species, disease stage, endpoint and duration, so this is recorded as a difference in what was tested rather than as a refutation of the mechanism. It is kept visible because the mechanistic records alone would otherwise read as clinical support.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Does dietary vitamin A deficiency lower TET2 expression or activity in haematopoietic cells?The ledger records that retinol raises Tet2 transcription through an intron-1 retinoic acid response element in mouse embryonic stem cells, and this collection records that all-trans retinoic acid induces TET2 transcription in myeloid leukaemia cells. Neither is a depletion experiment, and no record here measures TET2 in a vitamin-A-deficient animal. The depletion direction cannot be obtained by negating the supplementation result.
Does the mouse Tet2 intron-1 retinoic acid response element operate in human haematopoietic cells?The element was mapped by a 104-base-pair deletion in mouse embryonic stem cells. The 2025 study reports receptor-alpha-mediated TET2 transcription in human myeloid leukaemia cells but does not show that the same element carries it.
Why did the preclinical ascorbate results not reproduce in the clonal cytopenia trial?Disease stage, the 20-week window, eight evaluable patients, transporter-dependent uptake and mutation-dependent restoration are all recorded here as candidate explanations, and no study recorded in this collection separates them.
Does raising TET2 activity change any cancer incidence endpoint in people?Every disease endpoint in this collection is either an animal model, a xenograft, a colony assay or a methylation biomarker. The one human trial with a clinical response endpoint was negative.
Do the retinol and ascorbate effects on stem-cell reprogramming apply to adult human tissues at nutritional exposures?The cited assays use engineered and defined stem-cell culture conditions. The recorded combination does not establish a dietary anti-aging or disease-treatment effect.
How do individual tissue pools and enzyme occupancy relate to plasma vitamin C?Plasma, leukocytes, dietary dose and kidney loss have different concentration curves; none alone determines all intracellular reactions.
Which vascular mechanisms explain the historical scurvy response pattern?Forearm responsiveness changed while resting catecholamines and selected reflexes did not; the study did not isolate a specific enzyme.
Who gains additional iron-repletion benefit from vitamin C in real diets?Cell transport, single-meal challenges, complete diets and clinical iron replacement measure different steps. The anemia trial did not specifically select severe vitamin C deficiency.
Which factors explain individual oxalate responses and actual stone incidence?Short crossover tracer data identify heterogeneous metabolic responses but do not count newly formed stones.
What mediates the unfavorable LOVIT composite outcome?The randomized clinical result does not establish a specific redox, metabolic, renal or withdrawal mechanism.
Will the small pancreatic combination-trial benefit replicate, and what mediates it?Early stopping, sample size and 90% intervals limit certainty; tumor redox measurements were unavailable. This trial cannot validate a universal anticancer claim.
How much does dietary vitamin C shortage reduce basal human carnitine synthesis, separately from renal loss and dietary intake?Guinea-pig concentrations fall, but precursor-loaded urine-based estimates show preserved synthesis; human intracellular basal flux is not established by these studies.
How frequently do coupled and uncoupled collagen-hydroxylase cycles occur in each human tissue in vivo?Purified chick assays establish different ascorbate stoichiometry, not the physiological partition between cycles.
What mechanism increases TH protein in SH-SY5Y cells and what concentrations reproduce this in normal human neurons?Pooled Results/Fig.4 and Discussion describe different exposure thresholds; promoter mechanism and in-vivo extrapolation were not demonstrated.
Does cell-free ascorbate-mediated rat PAM inactivation occur at meaningful rates in intact secretory granules?The purified oxidative-inactivation assay cannot establish physiological harm, while cofactor-dependent activity is independently supported.
How much ascorbate is needed by each TET or HIF hydroxylase in a particular intact human tissue remains unresolved by these biochemical and culture experiments.Iron redox state, other reductants, oxygen, enzyme abundance and culture adaptation alter responses.
These pharmacological culture studies do not establish clinical anticancer efficacy or predict net peroxide exposure in every tumor.Medium iron speciation, extracellular scavenging, cell density and intracellular iron handling produce context-dependent results; human trials belong to the clinical module.
Exact preparation/dose/construct details in the Wang and Flashman abstract-level extractions and exact ascorbate dose in Scarpa were not recovered.Primary abstracts support qualitative findings; quantitative protocols must not be invented.
The quantitative contribution of DHA transport versus SVCT uptake to individual human tissues in ordinary nutritional conditions remains unresolved by the included experiments.Purified transporters, oxidized-substrate challenges and knockout models do not measure all intact human tissue fluxes.
The 1997 GLUT clone donor species and some older purified-assay details were not resolved from accessible primary abstracts.Avoided guessing species-specific protein identities or unstated concentrations; family-level GLUT nodes retained with host identified.
Selenium-deficiency effects on human cellular vitamin C repletion cannot be quantified from rat liver depletion studies.Multiple selenoproteins change and rats retain vitamin C biosynthesis.
A stable brain SVCT2 abundance does not explain all brain vitamin C retention or exclude changes in transport activity.Expression, localization, activity and redox recycling are different readouts.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

Vitamin C

The mechanisms

Rat SVCT1 expressed in Xenopus oocytes mediated stereospecific, concentrative uptake of reduced L-ascorbate driven by the sodium electrochemical gradient.

Rat SVCT2 expressed in Xenopus oocytes mediated stereospecific, concentrative uptake of reduced L-ascorbate driven by the sodium electrochemical gradient.

Rat SVCT2 tissue distribution included brain and eye, whereas SVCT1 distribution favored intestinal, kidney and liver epithelia.

Slc23a1 deletion raised renal ascorbate fractional excretion about 16–18-fold in female mice and 6–7-fold in males; female reabsorption was essentially abolished.

Plasma ascorbate was approximately 50–70% lower in Slc23a1-null mice than wild-type mice.

Pups born to Slc23a1-null dams had approximately 45% perinatal mortality, including heterozygous and homozygous-null pups.

Providing Slc23a1-null pregnant mice 330 mg/L ascorbate in drinking water from mating to delivery prevented the excess perinatal mortality of their null offspring.

Slc23a1-null mice increased endogenous ascorbate synthesis despite losing as much as 70% of their body ascorbate stores in urine daily.

Embryonic fibroblasts from SVCT2-null mice retained less than 5% of normal ascorbic-acid uptake.

SVCT2-null mice died within minutes of birth with respiratory failure and intraparenchymal brain hemorrhage.

Maternal prenatal ascorbic-acid supplementation did not raise fetal blood ascorbate in SVCT2-null mouse fetuses.

Mammalian GLUT1 expressed in Xenopus oocytes transported DHA with apparent Km 1.1 ± 0.2 mM; reduced ascorbate was not transported in the screen.

Mammalian GLUT3 expressed in Xenopus oocytes transported DHA with apparent Km 1.7 ± 0.3 mM; reduced ascorbate was not transported in the screen.

D-glucose inhibited GLUT1- and GLUT3-mediated DHA uptake in the oocyte expression system.

Isolated rat adipocytes transported DHA and reduced the internalized vitamin completely to ascorbate; the study identified GLUT4-mediated DHA transport.

Preincubation of isolated rat adipocytes with 0.67 µM insulin increased DHA transport 6–8-fold; intracellular DHA reduction was complete both before and after insulin.

Human erythrocytes rapidly took up supplied DHA and accumulated ascorbate to concentrations up to 2 mM in the ex vivo assay.

During DHA reduction by human erythrocytes, 5 mM D-glucose maintained GSH and NADH concentrations whereas NADPH still declined; without glucose all three fell.

Diethyl maleate depletion of erythrocyte GSH by 75–90% reduced the combined uptake and conversion of DHA to ascorbate in human cells.

Purified human placental glutaredoxin catalyzed GSH-dependent reduction of DHA to ascorbate.

Purified bovine liver protein disulfide isomerase catalyzed DHA reduction with GSH; apparent DHA Km was 1.0 mM.

Purified rat liver thioredoxin reductase reduced DHA using NADPH, with apparent DHA Km 2.5 mM and turnover 90 min−1.

Adding 2.8 µM rat liver thioredoxin lowered apparent DHA Km of the thioredoxin-reductase system from 2.5 to 0.7 mM without materially increasing turnover.

Selenium-deficient rats had 33% less liver ascorbate together with an 88% fall in thioredoxin-reductase activity; liver GSH content was unchanged.

Purified rat liver thioredoxin reductase decreased ascorbyl radical measured by electron paramagnetic resonance while consuming NADPH; DHA controls could not explain the signal.

Dialyzed liver cytosol from selenium-deficient rats lost NADPH-dependent ascorbyl-radical reducing activity attributed to thioredoxin reductase.

Rat liver microsomes reduced ascorbyl radical using NADH, and this activity was insensitive to selenium depletion.

Chronic prenatal and postnatal vitamin C restriction lowered brain total vitamin C in day-70 female guinea pigs.

Chronically vitamin-C-restricted guinea pigs had a higher brain DHA percentage despite lower total brain vitamin C.

Dietary vitamin C restriction did not significantly alter SVCT2 mRNA or protein in guinea pig hippocampus, cerebellum or frontal cortex at day 70.

Chronically vitamin-C-restricted guinea pigs had higher brain malondialdehyde than vitamin-C-sufficient controls at day 70.

Stomatin transfection increased DHA uptake in human A431 cells while GLUT1 abundance was unchanged; GLUT1 knockdown reduced uptake.

Montel-Hagen et al. reported that 5 mM glucose did not inhibit DHA accumulation in mature human erythrocytes and interpreted this as preferential DHA transport.

Human erythrocyte and inside-out-vesicle kinetic assays showed DHA and 3-O-methylglucose competing at both membrane faces, consistent with transport through the same GLUT1 complex.

Four weeks of two SunGold kiwifruit daily increased neutrophil vitamin C content in young men initially selected for plasma vitamin C below 50 µmol/L (p=0.016).

Following the four-week kiwifruit intervention, stimulated neutrophil chemotaxis increased about 20% in paired ex vivo assays (n=12, p=0.041); unstimulated migration did not change.

Purified chick collagen prolyl hydroxylase completed approximately 15–30 rapid catalytic cycles in 5–10 seconds without added ascorbate before activity declined.

In chick collagen hydroxylase assays, complete proline hydroxylation was coupled to 2-oxoglutarate decarboxylation while ascorbate was not consumed in most catalytic cycles.

Chick collagen prolyl hydroxylase consumed ascorbate stoichiometrically during uncoupled 2-oxoglutarate decarboxylation in the absence of peptide substrate.

Chick collagen lysyl hydroxylase consumed ascorbate stoichiometrically during uncoupled 2-oxoglutarate decarboxylation in the absence of peptide substrate.

After 2-oxoglutarate-associated inactivation of chick prolyl hydroxylase, ascorbate decreased its ferric EPR signal and partly restored activity, supporting reduction of enzyme-bound Fe(III).

With 2-oxoglutarate present, added Fe(II) did not partly reactivate the inactivated chick prolyl hydroxylase as ascorbate did; reduction by Fe(II) was possible in the absence of 2-oxoglutarate.

Prolonged ascorbate exposure increased collagenous protein synthesis about eightfold in cultured human skin fibroblasts without a significant change in noncollagen protein synthesis.

Human skin fibroblast lysyl hydroxylase activity increased approximately threefold after the study ascorbate treatment.

In the same human fibroblast culture study, measured collagen prolyl hydroxylase activity decreased after ascorbate treatment even while collagen synthesis increased.

Omission controls with recombinant human MBP-TMLH-a showed that ascorbate, Fe(II) and 2-oxoglutarate were each needed for efficient conversion of free trimethyllysine to 3-hydroxytrimethyllysine.

Increasing ascorbate supplementation increased carnitine accumulation from gamma-butyrobetaine in primary guinea-pig hepatocytes after four hours.

Gamma-butyrobetaine supplementation lowered both reduced and total cellular vitamin C content during the guinea-pig hepatocyte carnitine-synthesis experiment.

Guinea pigs with tissue vitamin C around 12% saturation had significantly lower muscle carnitine than animals near 100% saturation, without the customary overt hypovitaminosis-C signs in this experiment.

Hepatic carnitine was 148 +/- 9.8 nmol/g in vitamin-C-deficient guinea pigs versus 249 +/- 16.1 in controls; pair-fed animals measured 181 +/- 14.1 nmol/g (means +/- SEM).

Oral trimethyllysine increased urine-based estimated carnitine synthesis by 32–40 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response.

Oral gamma-butyrobetaine increased urine-based estimated carnitine synthesis by 41–50 micromol/kg/day across ascorbate-replete, deficient and pair-fed guinea-pig groups; vitamin C deficiency did not abolish the precursor response.

Without carnitine-precursor supplements, vitamin-C-deficient guinea pigs excreted approximately three times as much free and total carnitine as replete animals on days 19–28; pair feeding alone did not produce that pattern.

Ascorbate reduced enzyme-bound copper in purified bovine dopamine beta-hydroxylase from Cu(II) to Cu(I), as examined by X-ray absorption spectroscopy.

Coupling bovine DBH tyramine hydroxylation to semidehydroascorbate reductase identified semidehydroascorbate as the immediate enzymic oxidation product of ascorbate.

Adding 100 micromolar ascorbate to SH-SY5Y cultures increased intracellular norepinephrine over six hours in parallel with ascorbate accumulation.

In pooled SH-SY5Y immunoblots after 24 hours, TH protein rose to a maximum around 170% of control; statistical significance in Results/Fig.4 was reached at 1000 micromolar loading ascorbate (approximately 1.6–2.5 mM intracellular).

Sepiapterin increased norepinephrine content in SH-SY5Y cultures and 50 micromolar ascorbate increased the response further after 24 hours.

Bovine intermediate-pituitary granule amidation of D-Tyr-Val-Gly responded to ascorbate, with apparent substrate Km and Vmax changing as the ascorbate concentration changed.

Pituitary peptide-amidating activity inhibited by divalent-metal chelators was restored above control by copper addition; the assayed reaction also required molecular oxygen.

Expression of the bovine PHM-only construct in HEK293 cells increased secreted PHM activity, demonstrating a functional hydroxylating domain separable from the PAL portion of PAM.

Purified bovine pituitary PAL catalyzed amidation of N-acetyl-Tyr-Val-alpha-hydroxyglycine, with reported Km 38 micromolar and turnover 220/s for this synthetic intermediate.

In time- and concentration-dependent purified-protein experiments, ascorbate inactivated the full amidation activity of recombinant rat 75-kDa PAM measured with dansyl-Tyr-Val-Gly.

Under conditions that inactivated hydroxylase-dependent rat PAM amidation, ascorbate did not impair conversion of the pre-hydroxylated dansyl-Tyr-Val-alpha-hydroxyglycine intermediate to its amide.

Scott et al. interpreted the ascorbate-reduced bovine DBH spectrum as a decrease from roughly four to two N/O ligands plus a sulfur-containing ligand at 2.30 angstrom, compared with the oxidized enzyme.

Blumberg et al. found little average coordination change after ascorbate reduction: four nitrogen ligands best fit both forms, at 1.97 angstrom oxidized and 2.05 angstrom reduced; they found no sulfur or chlorine ligation and explicitly opposed the earlier interpretation.

Vitamin C increased hydroxymethylcytosine production by recombinant human TET1 catalytic domain in the reported pH 8.0 assay containing Fe(II) and 2-oxoglutarate. This demonstrates assay enhancement, without establishing obligatory ascorbate binding.

Adding L-ascorbic acid 2-phosphate to mouse ESC medium rapidly increased global DNA 5hmC and promoter-associated 5hmC, preceding later methylcytosine loss.

After vitamin C derivative treatment, numerous mouse ESC promoters lost methylcytosine; imprinted regions and IAP retroelements were relatively resistant, so the effect was not indiscriminate erasure of genomic methylation.

Combined Tet1/Tet2 deletion in mouse ESCs abolished the vitamin-C-induced increase in 5hmC and promoter demethylation observed in wild-type cells; residual antibody signal was not interpreted as robust Tet activity.

Ascorbate restored murine TET1-CD activity with ferric iron or under pH 8.0 conditions that rapidly oxidized Fe(II); iron-redox measurements support provision of reduced iron as the rescue mechanism.

At pH 6.8 with sufficient Fe(II), murine TET1-CD remained active without ascorbate and adding ascorbate did not increase the measured activity; substrate-free preincubation also did not rapidly destroy activity.

Retinol supplementation increased Tet2 transcription in mouse naïve ESCs within 8 h and after 72 h; Tet3 also responded, whereas evidence did not support direct retinol stimulation of TET catalytic efficiency.

Deleting a 104-bp intronic segment encompassing the mouse Tet2 retinoic-acid response element prevented the normal retinol-dependent Tet2 mRNA increase, supporting a cis-regulatory requirement.

Ascorbate co-treatment increased Oct4:GFP-positive colony formation during KLF4-driven mouse EpiSC reprogramming and shifted the optimum toward lower retinol concentration; higher retinol suppressed colony formation rather than improving it indefinitely.

Vitamin C treatment reduced H3K36me2/3 in mouse embryonic fibroblasts during culture and reprogramming, linking the intervention to histone methylation changes.

Jhdm1a/1b gain- and loss-of-function experiments identified these histone demethylases as functional effectors of vitamin-C-enhanced mouse somatic-cell reprogramming. Loss-of-function reduced the response rather than being corrected by vitamin C alone.

Ascorbate increased the initial rate and extent of PHD2-catalyzed hydroxylation at both tested human HIF-1 alpha prolyl sites in purified-enzyme peptide experiments.