L-Ascorbate

evidence_access

Primary abstract

experimental_model

Cell-free concentration-response experiments.

limitations

Not an established supplement dose-response in humans.

nutrient_topic

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

plain_language

The direction of an antioxidant’s effect can depend on concentration.

primary_references

Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 134–140

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free concentration-response experiments. · source_derived_draft · unverified_draft

## vanadium-ascorbate-concentration The direction of an antioxidant’s effect can depend on concentration. Ascorbate initiated NADH oxidation at lower concentrations but inhibited it at higher concentrations in the same chemical system. Model: Cell-free concentration-response experiments. Limitations: Not an established supplement dose-response in humans. Evidence access: Primary abstract Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

evidence_access

Primary abstract

experimental_model

ESR and spin-trapping chemistry; cell-free solutions.

limitations

Buffer-dependent chemistry does not establish a human depletion rate or clinical interaction.

nutrient_topic

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

plain_language

Vitamin C and phosphate together changed vanadium’s oxidation state in this assay.

primary_references

One-electron reduction of vanadate by ascorbate and related free radical generation at physiological pH. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8051539/ · DOI 10.1016/0162-0134(94)85032-1

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 94–100

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · ESR and spin-trapping chemistry; cell-free solutions. · source_derived_draft · unverified_draft

## vanadium-ascorbate-reduction Vitamin C and phosphate together changed vanadium’s oxidation state in this assay. Ascorbate generated V(IV) from vanadate in phosphate buffer at pH 7.4, but not comparably in water or the tested cacodylate buffer. Model: ESR and spin-trapping chemistry; cell-free solutions. Limitations: Buffer-dependent chemistry does not establish a human depletion rate or clinical interaction. Evidence access: Primary abstract One-electron reduction of vanadate by ascorbate and related free radical generation at physiological pH. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8051539/ · DOI 10.1016/0162-0134(94)85032-1

evidence_span

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experimental_model

High-resolution crystallography and reactivation kinetics

exposure

Ascorbate with substrate analogues and a trapped glycosyl-enzyme intermediate

limitations

Plant enzyme chemistry; does not show that vitamin C pills increase systemic sulforaphane in people.

nutrient_topic

Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. · Sulforaphane / SFN, stereochemistry specified per study

organism

Mustard plant myrosinase

plain_language

Vitamin C can help the plant enzyme carry out its reaction.

primary_references

[sulforaphane-p10978344] High resolution X-ray crystallography shows that ascorbate is a cofactor for myrosinase and substitutes for the function of the catalytic base. (2000). https://pubmed.ncbi.nlm.nih.gov/10978344/ DOI: 10.1074/jbc.m006796200

tissue_or_cell_type

Enzyme active site

Sulforaphane: formation, electrophile sensing and nutrient connections (2026-09-17) · lines 190–201

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High-resolution crystallography and reactivation kinetics · source_derived_draft · unverified_draft

### sulforaphane-ascorbate-myrosinase Ascorbate accelerated hydrolysis of the glycosyl-enzyme intermediate and occupied a position supporting its role as the catalytic base. Condition category: normal nutrient_topic: Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C can help the plant enzyme carry out its reaction. organism: Mustard plant myrosinase tissue_or_cell_type: Enzyme active site experimental_model: High-resolution crystallography and reactivation kinetics limitations: Plant enzyme chemistry; does not show that vitamin C pills increase systemic sulforaphane in people. exposure: Ascorbate with substrate analogues and a trapped glycosyl-enzyme intermediate evidence_span: {"source_cache": "artifacts/sulforaphane-research/10978344.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ed373ac9a91fa7b03d25c21c32adaf57dd2f0f9b65e1f99e9da49aab4c22b0aa", "start_char": 0, "end_char": 1511, "text_sha256": "ed373ac9a91fa7b03d25c21c32adaf57dd2f0f9b65e1f99e9da49aab4c22b0aa"} [sulforaphane-p10978344] High resolution X-ray crystallography shows that ascorbate is a cofactor for myrosinase and substitutes for the function of the catalytic base. (2000). https://pubmed.ncbi.nlm.nih.gov/10978344/ DOI: 10.1074/jbc.m006796200

evidence_span

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experimental_model

Cells with defined intracellular ascorbate concentrations against several hydroxylase inhibitors

exposure

Intracellular ascorbate loading with CoCl2, NiCl2, desferrioxamine, dimethyloxalylglycine or hypoxia

limitations

Establishes an effect of intracellular ascorbate on the HIF response. The iron-competing inhibitors are the conditions where ascorbate mattered most.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Human cells

plain_language

Vitamin C’s job here is to keep the enzyme’s iron in the right state.

primary_references

[hbot-p24495550] Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. (2014). https://pubmed.ncbi.nlm.nih.gov/24495550/ DOI: 10.1016/j.freeradbiomed.2014.01.033

tissue_or_cell_type

Cytosol and nucleus

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 998–1009

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cells with defined intracellular ascorbate concentrations against several hydroxylase inhibitors · source_derived_draft · unverified_draft

### hbot-ascorbate-iron-site The findings suggest that ascorbate acts primarily to stabilise and reduce the iron atom in the hydroxylase active site, and that the asparagine hydroxylase controlling HIF-1 transcriptional activity is particularly susceptible to fluctuations in intracellular ascorbate. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C’s job here is to keep the enzyme’s iron in the right state. organism: Human cells tissue_or_cell_type: Cytosol and nucleus experimental_model: Cells with defined intracellular ascorbate concentrations against several hydroxylase inhibitors limitations: Establishes an effect of intracellular ascorbate on the HIF response. The iron-competing inhibitors are the conditions where ascorbate mattered most. exposure: Intracellular ascorbate loading with CoCl2, NiCl2, desferrioxamine, dimethyloxalylglycine or hypoxia evidence_span: {"source_cache": "artifacts/hbot-research/24495550.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "444b204ff84635f64eebf59c2db6afa112641b24f7b309fb2bcd6da04d4d0d0a", "start_char": 0, "end_char": 1497, "text_sha256": "444b204ff84635f64eebf59c2db6afa112641b24f7b309fb2bcd6da04d4d0d0a"} [hbot-p24495550] Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. (2014). https://pubmed.ncbi.nlm.nih.gov/24495550/ DOI: 10.1016/j.freeradbiomed.2014.01.033

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

Ascorbate-deficient guinea pigs, fasting controls, and cells cultured in scorbutic serum

exposure

Vitamin C deficiency, with fasting plus ascorbate supplementation as a comparison

limitations

The study separates a direct hydroxylation defect from a growth-factor-mediated one, so it argues against reading scurvy as pure under-hydroxylation.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Guinea pig and cultured cells

plain_language

Without vitamin C the collagen cannot be stiffened properly and does not leave the cell.

primary_references

[hbot-p1720597] Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy. (1991). https://pubmed.ncbi.nlm.nih.gov/1720597/ DOI: 10.1093/ajcn/54.6.1135s

tissue_or_cell_type

Connective tissue

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 907–918

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ascorbate-deficient guinea pigs, fasting controls, and cells cultured in scorbutic serum · source_derived_draft · unverified_draft

### hbot-ascorbate-procollagen Ascorbate is required for hydroxylation of proline residues in procollagen, hydroxyproline stabilises the collagen triple-helical structure, and consequently ascorbate stimulates procollagen secretion. Condition category: nutrient_deficiency nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Without vitamin C the collagen cannot be stiffened properly and does not leave the cell. organism: Guinea pig and cultured cells tissue_or_cell_type: Connective tissue experimental_model: Ascorbate-deficient guinea pigs, fasting controls, and cells cultured in scorbutic serum limitations: The study separates a direct hydroxylation defect from a growth-factor-mediated one, so it argues against reading scurvy as pure under-hydroxylation. exposure: Vitamin C deficiency, with fasting plus ascorbate supplementation as a comparison evidence_span: {"source_cache": "artifacts/hbot-research/1720597.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b769da8d030351b117b7a349262e9b52d54aab00ca3a2679900cb1372006bc31", "start_char": 0, "end_char": 1015, "text_sha256": "b769da8d030351b117b7a349262e9b52d54aab00ca3a2679900cb1372006bc31"} [hbot-p1720597] Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy. (1991). https://pubmed.ncbi.nlm.nih.gov/1720597/ DOI: 10.1093/ajcn/54.6.1135s

evidence_span

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experimental_model

Enzyme assays of PHD2 and FIH with ascorbate, ascorbate analogues and alternative reducing agents

exposure

Prolyl and asparaginyl hydroxylation with and without ascorbate, glutathione or dithiothreitol

limitations

Purified-enzyme kinetics. It identifies which part of the ascorbate molecule matters, and shows other reductants substitute only partially.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Human enzymes

plain_language

Vitamin C makes the enzyme that destroys the low-oxygen signal work faster.

primary_references

[hbot-p20055761] 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

Purified enzyme with HIF-1alpha peptides

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 959–970

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme assays of PHD2 and FIH with ascorbate, ascorbate analogues and alternative reducing agents · source_derived_draft · unverified_draft

### hbot-ascorbate-stimulates-phd The initial rate and extent of PHD2-catalysed hydroxylation of two prolyl sites in human HIF-1alpha, and of FIH-catalysed asparaginyl hydroxylation, were increased in the presence of ascorbate; these are Fe(II) and 2-oxoglutarate-dependent oxygenases. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C makes the enzyme that destroys the low-oxygen signal work faster. organism: Human enzymes tissue_or_cell_type: Purified enzyme with HIF-1alpha peptides experimental_model: Enzyme assays of PHD2 and FIH with ascorbate, ascorbate analogues and alternative reducing agents limitations: Purified-enzyme kinetics. It identifies which part of the ascorbate molecule matters, and shows other reductants substitute only partially. exposure: Prolyl and asparaginyl hydroxylation with and without ascorbate, glutathione or dithiothreitol evidence_span: {"source_cache": "artifacts/hbot-research/20055761.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3b9ac610e9510ed4f2fd2ed696009ab95dadac196fff3a7fe1644f03ed29d1dd", "start_char": 0, "end_char": 1322, "text_sha256": "3b9ac610e9510ed4f2fd2ed696009ab95dadac196fff3a7fe1644f03ed29d1dd"} [hbot-p20055761] 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

evidence_span

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experimental_model

Cells with defined intracellular ascorbate concentrations against several hydroxylase inhibitors

exposure

Intracellular ascorbate loading with CoCl2, NiCl2, desferrioxamine, dimethyloxalylglycine or hypoxia

limitations

Establishes an effect of intracellular ascorbate on the HIF response. The iron-competing inhibitors are the conditions where ascorbate mattered most.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Human cells

plain_language

Vitamin C shuts down the low-oxygen gene programme even when the protein itself survives.

primary_references

[hbot-p24495550] Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. (2014). https://pubmed.ncbi.nlm.nih.gov/24495550/ DOI: 10.1016/j.freeradbiomed.2014.01.033

tissue_or_cell_type

Cytosol and nucleus

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 985–996

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cells with defined intracellular ascorbate concentrations against several hydroxylase inhibitors · source_derived_draft · unverified_draft

### hbot-ascorbate-suppresses-hif Ascorbate inhibited HIF-1 activity most dramatically under all mechanisms of iron competition, and HIF-1-dependent gene expression was prevented even under conditions that allowed HIF-1alpha protein stabilisation. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C shuts down the low-oxygen gene programme even when the protein itself survives. organism: Human cells tissue_or_cell_type: Cytosol and nucleus experimental_model: Cells with defined intracellular ascorbate concentrations against several hydroxylase inhibitors limitations: Establishes an effect of intracellular ascorbate on the HIF response. The iron-competing inhibitors are the conditions where ascorbate mattered most. exposure: Intracellular ascorbate loading with CoCl2, NiCl2, desferrioxamine, dimethyloxalylglycine or hypoxia evidence_span: {"source_cache": "artifacts/hbot-research/24495550.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "444b204ff84635f64eebf59c2db6afa112641b24f7b309fb2bcd6da04d4d0d0a", "start_char": 0, "end_char": 1497, "text_sha256": "444b204ff84635f64eebf59c2db6afa112641b24f7b309fb2bcd6da04d4d0d0a"} [hbot-p24495550] Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. (2014). https://pubmed.ncbi.nlm.nih.gov/24495550/ DOI: 10.1016/j.freeradbiomed.2014.01.033

evidence_span

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experimental_model

Review of prolyl 4-hydroxylase enzymology and subunit structure

exposure

Hydroxylation of proline in X-Pro-Gly sequences

limitations

An authoritative enzymology review rather than a single experiment. It is the source for the cosubstrate list, which is the point at which oxygen, iron and vitamin C meet in collagen synthesis.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Mammalian enzyme

plain_language

Vitamin C is not used up every turn; it is the reserve that resets the enzyme when a cycle misfires.

primary_references

[hbot-p2537773] Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. (1989). https://pubmed.ncbi.nlm.nih.gov/2537773/ DOI: 10.1096/fasebj.3.5.2537773

tissue_or_cell_type

Endoplasmic reticulum

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 868–879

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of prolyl 4-hydroxylase enzymology and subunit structure · source_derived_draft · unverified_draft

### hbot-ascorbate-uncoupled-cycles Ascorbate is not consumed during most catalytic cycles, but the enzyme also decarboxylates 2-oxoglutarate without subsequent hydroxylation, and ascorbate is required as a specific alternative oxygen acceptor in those uncoupled cycles. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C is not used up every turn; it is the reserve that resets the enzyme when a cycle misfires. organism: Mammalian enzyme tissue_or_cell_type: Endoplasmic reticulum experimental_model: Review of prolyl 4-hydroxylase enzymology and subunit structure limitations: An authoritative enzymology review rather than a single experiment. It is the source for the cosubstrate list, which is the point at which oxygen, iron and vitamin C meet in collagen synthesis. exposure: Hydroxylation of proline in X-Pro-Gly sequences evidence_span: {"source_cache": "artifacts/hbot-research/2537773.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe", "start_char": 0, "end_char": 2024, "text_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe"} [hbot-p2537773] Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. (1989). https://pubmed.ncbi.nlm.nih.gov/2537773/ DOI: 10.1096/fasebj.3.5.2537773

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

Ascorbate restoration and ATM perturbation in human lung-cell cultures

exposure

Chromate exposure in standard ascorbate-poor versus ascorbate-restored cells; ATM inhibition/silencing

limitations

Cr(VI) toxicology, not an experiment with dietary Cr(III). Loss of ATM activation does not mean loss of all genotoxicity or that vitamin C universally detoxifies chromium.

nutrient_topic

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

organism

Human H460 cells and normal lung fibroblasts

plain_language

Vitamin C availability changed which damage-response pathway the toxic exposure activated.

primary_references

[chromium-p25977998] Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics. (2016). https://pubmed.ncbi.nlm.nih.gov/25977998/ DOI: 10.1289/ehp.1409434

tissue_or_cell_type

DNA-damage signaling

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Chromium: transport, insulin signaling, nutrient interactions and essentiality debate (2026-09-17) · lines 1121–1132

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ascorbate restoration and ATM perturbation in human lung-cell cultures · source_derived_draft · unverified_draft

### chromium-ascorbate-atm-context Ascorbate restoration prevented Cr(VI)-induced ATM activation observed in standard ascorbate-poor human lung-cell cultures. Condition category: nutrient_deficiency nutrient_topic: Chromium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C availability changed which damage-response pathway the toxic exposure activated. organism: Human H460 cells and normal lung fibroblasts tissue_or_cell_type: DNA-damage signaling experimental_model: Ascorbate restoration and ATM perturbation in human lung-cell cultures limitations: Cr(VI) toxicology, not an experiment with dietary Cr(III). Loss of ATM activation does not mean loss of all genotoxicity or that vitamin C universally detoxifies chromium. exposure: Chromate exposure in standard ascorbate-poor versus ascorbate-restored cells; ATM inhibition/silencing evidence_span: {"source_cache": "artifacts/chromium-research/25977998.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3", "start_char": 0, "end_char": 2163, "text_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3"} [chromium-p25977998] Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics. (2016). https://pubmed.ncbi.nlm.nih.gov/25977998/ DOI: 10.1289/ehp.1409434

evidence_access

Primary abstract

experimental_model

Cell-free reaction; reported rate constant 6.3 x 10^8 M^-1 s^-1.

limitations

Chemical kinetics do not establish tissue flux or a required supplement combination.

nutrient_topic

Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine

plain_language

Vitamin C can repair an oxidized ergothioneine intermediate.

primary_references

One-electron oxidation of ergothioneine and analogues investigated by pulse radiolysis: redox reaction involving ergothioneine and vitamin C. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8615839/ · DOI 10.1042/bj3150625

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 112–118

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free reaction; reported rate constant 6.3 x 10^8 M^-1 s^-1. · source_derived_draft · unverified_draft

## ergothioneine-ascorbate-repair Vitamin C can repair an oxidized ergothioneine intermediate. In pulse-radiolysis assays, ascorbate rapidly reduced the one-electron-oxidized ergothioneine transient back toward ergothioneine, forming ascorbyl radicals. Model: Cell-free reaction; reported rate constant 6.3 x 10^8 M^-1 s^-1. Limitations: Chemical kinetics do not establish tissue flux or a required supplement combination. Evidence access: Primary abstract One-electron oxidation of ergothioneine and analogues investigated by pulse radiolysis: redox reaction involving ergothioneine and vitamin C. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8615839/ · DOI 10.1042/bj3150625

evidence_access

Primary abstract

experimental_model

Mouse embryonic stem-cell model; reversible phenotype and histone-mark measurements.

limitations

The result does not establish a supplement ratio, a clinical methylation imbalance, or vitamin C depletion by ordinary proline intake.

nutrient_topic

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

plain_language

Vitamin C and proline intersect in this experimental epigenetic response.

primary_references

L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24319666/ · DOI 10.1016/j.stemcr.2013.09.001

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 398–404

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse embryonic stem-cell model; reversible phenotype and histone-mark measurements. · source_derived_draft · unverified_draft

## l-proline-stem-cell-vitamin-c Vitamin C and proline intersect in this experimental epigenetic response. Ascorbic-acid addition or proline withdrawal reversed the reported proline-induced stem-cell state and reduced the associated H3K9/H3K36 methylation pattern. Model: Mouse embryonic stem-cell model; reversible phenotype and histone-mark measurements. Limitations: The result does not establish a supplement ratio, a clinical methylation imbalance, or vitamin C depletion by ordinary proline intake. Evidence access: Primary abstract L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24319666/ · DOI 10.1016/j.stemcr.2013.09.001

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

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

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

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

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

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

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

evidence_span

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experimental_model

Cell exposure and recombinant-enzyme assays

exposure

Ascorbate loading; BH4 or sepiapterin comparisons

limitations

Preclinical experiments; not proof that vitamin C is needed as a co-supplement with citrulline.

nutrient_topic

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

organism

Porcine aortic endothelial cells and bovine eNOS

plain_language

Vitamin C can affect cofactor availability in this cell model.

primary_references

[citrulline-p10749876] Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. (2000). https://pubmed.ncbi.nlm.nih.gov/10749876/ DOI: 10.1074/jbc.m002248200

tissue_or_cell_type

BH4 availability and NO bioactivity

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 697–708

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell exposure and recombinant-enzyme assays · source_derived_draft · unverified_draft

### citrulline-vitaminc-bh4 Ascorbate increased intracellular BH4 in porcine aortic endothelial cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C can affect cofactor availability in this cell model. organism: Porcine aortic endothelial cells and bovine eNOS tissue_or_cell_type: BH4 availability and NO bioactivity experimental_model: Cell exposure and recombinant-enzyme assays limitations: Preclinical experiments; not proof that vitamin C is needed as a co-supplement with citrulline. exposure: Ascorbate loading; BH4 or sepiapterin comparisons evidence_span: {"source_cache": "artifacts/citrulline-research/10749876.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed", "start_char": 0, "end_char": 1519, "text_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed"} [citrulline-p10749876] Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. (2000). https://pubmed.ncbi.nlm.nih.gov/10749876/ DOI: 10.1074/jbc.m002248200

evidence_span

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experimental_model

Cell exposure and recombinant-enzyme assays

exposure

Ascorbate loading; BH4 or sepiapterin comparisons

limitations

Preclinical experiments; not proof that vitamin C is needed as a co-supplement with citrulline.

nutrient_topic

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

organism

Porcine aortic endothelial cells and bovine eNOS

plain_language

Protecting the machinery can matter as well as supplying arginine.

primary_references

[citrulline-p10749876] Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. (2000). https://pubmed.ncbi.nlm.nih.gov/10749876/ DOI: 10.1074/jbc.m002248200

tissue_or_cell_type

BH4 availability and NO bioactivity

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 710–721

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell exposure and recombinant-enzyme assays · source_derived_draft · unverified_draft

### citrulline-vitaminc-no Ascorbate increased arginine-to-citrulline conversion and NO-related output in porcine endothelial cells. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protecting the machinery can matter as well as supplying arginine. organism: Porcine aortic endothelial cells and bovine eNOS tissue_or_cell_type: BH4 availability and NO bioactivity experimental_model: Cell exposure and recombinant-enzyme assays limitations: Preclinical experiments; not proof that vitamin C is needed as a co-supplement with citrulline. exposure: Ascorbate loading; BH4 or sepiapterin comparisons evidence_span: {"source_cache": "artifacts/citrulline-research/10749876.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed", "start_char": 0, "end_char": 1519, "text_sha256": "10605941fa542bd62ed4ee0fb042ea7569f3ab619f1cb893b54d7e62386712ed"} [citrulline-p10749876] Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. (2000). https://pubmed.ncbi.nlm.nih.gov/10749876/ DOI: 10.1074/jbc.m002248200

evidence_span

{"source_cache": "artifacts/cold-research/3676254.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a", "start_char": 0, "end_char": 1648, "text_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a"}

experimental_model

Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants

exposure

Ascorbate, ferrocyanide or dopamine itself as the reducing agent, with deuterium isotope effects

limitations

A kinetic comparison identifying ascorbate as the presumed physiological reductant and locating a separate binding site for it. Truncated abstract; the reductant site is inferred from kinetics and modelling.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine enzyme

plain_language

Vitamin C is what hands the enzyme back its electrons, and without it the reaction crawls.

primary_references

[cold-p3676254] Characterization of alternate reductant binding and electron transfer in the dopamine beta-monooxygenase reaction. (1987). https://pubmed.ncbi.nlm.nih.gov/3676254/ DOI: 10.1021/bi00391a013

tissue_or_cell_type

Purified enzyme

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 585–596

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants · source_derived_draft · unverified_draft

### cold-ascorbate-reductant Ascorbate is the presumed in vivo reductant of dopamine beta-monooxygenase; the one-electron reductant ferrocyanide was nearly as kinetically competent, while dopamine as sole reductant reduced enzymic copper in a rate-limiting step 40-fold slower than with ascorbate, and the reductant binds at a site physically distinct from the substrate site. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Vitamin C is what hands the enzyme back its electrons, and without it the reaction crawls. organism: Bovine enzyme tissue_or_cell_type: Purified enzyme experimental_model: Steady-state kinetics of dopamine beta-monooxygenase with structurally distinct reductants limitations: A kinetic comparison identifying ascorbate as the presumed physiological reductant and locating a separate binding site for it. Truncated abstract; the reductant site is inferred from kinetics and modelling. exposure: Ascorbate, ferrocyanide or dopamine itself as the reducing agent, with deuterium isotope effects evidence_span: {"source_cache": "artifacts/cold-research/3676254.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a", "start_char": 0, "end_char": 1648, "text_sha256": "e929132eed0f1c94ab0bdbef6e31bca7ecbed222cf9b585e17a1cfae7e93c82a"} [cold-p3676254] Characterization of alternate reductant binding and electron transfer in the dopamine beta-monooxygenase reaction. (1987). https://pubmed.ncbi.nlm.nih.gov/3676254/ DOI: 10.1021/bi00391a013

experimental_model

Purified chick-embryo enzyme kinetics.

limitations

Family-level enzyme preparation, not a human PLOD isoform comparison or lysine-supplement trial.

organism

Chicken

plain_language

Vitamin C supports the reaction, but is not consumed in every coupled turnover.

primary_references

[plod-cofactor-1980] Studies on the lysyl hydroxylase reaction. I. Initial velocity kinetics and related aspects. (1980). https://pubmed.ncbi.nlm.nih.gov/6766066/ DOI: 10.1016/0005-2744(80)90040-6

tissue_or_cell_type

Not specified as a whole tissue; see experimental model.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 427–435

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified chick-embryo enzyme kinetics. · source_derived_draft · unverified_draft

### ascorbate-lysyl-hydroxylase Ascorbate supports sustained lysyl-hydroxylase activity; the enzyme can initially turn over without ascorbate. Plain language: Vitamin C supports the reaction, but is not consumed in every coupled turnover. Condition category: normal organism: Chicken tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Purified chick-embryo enzyme kinetics. limitations: Family-level enzyme preparation, not a human PLOD isoform comparison or lysine-supplement trial. [plod-cofactor-1980] Studies on the lysyl hydroxylase reaction. I. Initial velocity kinetics and related aspects. (1980). https://pubmed.ncbi.nlm.nih.gov/6766066/ DOI: 10.1016/0005-2744(80)90040-6

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

evidence_span

{"source_cache": "artifacts/zeaxanthin-research/35740030.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c66a3183f1b2cc985ad22d5350f53aaeaf65b2519e89ddc13e0460a035903e8", "start_char": 0, "end_char": 1784, "text_sha256": "6c66a3183f1b2cc985ad22d5350f53aaeaf65b2519e89ddc13e0460a035903e8"}

experimental_model

Retinaldehyde-liposome photosensitization with cells

exposure

4 micromolar zeaxanthin, 80 micromolar alpha-tocopherol; 0.5–2 mM ascorbate

limitations

Bath concentrations and irradiation are not oral doses or established human safety limits. Combination conditions and localization matter.

nutrient_topic

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

organism

Human ARPE-19 cells and unsaturated liposomes

plain_language

A higher concentration changed the interaction.

primary_references

[zeaxanthin-p35740030] Is There an Optimal Combination of AREDS2 Antioxidants Zeaxanthin, Vitamin E and Vitamin C on Light-Induced Toxicity of Vitamin A Aldehyde to the Retina? (2022). https://pubmed.ncbi.nlm.nih.gov/35740030/ DOI: 10.3390/antiox11061132

tissue_or_cell_type

RPE injury model

Zeaxanthin: metabolism, signaling and nutrient connections (2026-09-17) · lines 951–962

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retinaldehyde-liposome photosensitization with cells · source_derived_draft · unverified_draft

### zeaxanthin-ascorbate-high At 2 mM, ascorbate exacerbated phototoxicity; zeaxanthin or alpha-tocopherol partly ameliorated it. Condition category: normal nutrient_topic: Zeaxanthin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A higher concentration changed the interaction. organism: Human ARPE-19 cells and unsaturated liposomes tissue_or_cell_type: RPE injury model experimental_model: Retinaldehyde-liposome photosensitization with cells limitations: Bath concentrations and irradiation are not oral doses or established human safety limits. Combination conditions and localization matter. exposure: 4 micromolar zeaxanthin, 80 micromolar alpha-tocopherol; 0.5–2 mM ascorbate evidence_span: {"source_cache": "artifacts/zeaxanthin-research/35740030.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c66a3183f1b2cc985ad22d5350f53aaeaf65b2519e89ddc13e0460a035903e8", "start_char": 0, "end_char": 1784, "text_sha256": "6c66a3183f1b2cc985ad22d5350f53aaeaf65b2519e89ddc13e0460a035903e8"} [zeaxanthin-p35740030] Is There an Optimal Combination of AREDS2 Antioxidants Zeaxanthin, Vitamin E and Vitamin C on Light-Induced Toxicity of Vitamin A Aldehyde to the Retina? (2022). https://pubmed.ncbi.nlm.nih.gov/35740030/ DOI: 10.3390/antiox11061132

evidence_span

{"source_cache": "artifacts/glutathione-research/6424115.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8c45563e89388d200eb64ae63d12b388ef5cca91369a585157ef27b39f525b08", "start_char": 0, "end_char": 1307, "text_sha256": "8c45563e89388d200eb64ae63d12b388ef5cca91369a585157ef27b39f525b08"}

experimental_model

Enzyme oxidation and radiolabeled binding assays

exposure

NAPQI or acetaminophen with reductants

limitations

Cell-free/microsomal finding; vitamin C is not established here as a clinical antidote.

nutrient_topic

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

organism

Mouse microsomes and cell-free cytochrome-P450 system

plain_language

Different reductants changed the same reactive intermediate by different chemistry.

primary_references

[glutathione-p6424115] N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. (1984). https://pubmed.ncbi.nlm.nih.gov/6424115/ DOI: 10.1073/pnas.81.5.1327

tissue_or_cell_type

Acetaminophen reactive-metabolite handling

Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 1061–1072

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme oxidation and radiolabeled binding assays · source_derived_draft · unverified_draft

### glutathione-napqi-ascorbate Ascorbic acid decreased binding through reduction of NAPQI to acetaminophen in the comparison. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different reductants changed the same reactive intermediate by different chemistry. organism: Mouse microsomes and cell-free cytochrome-P450 system tissue_or_cell_type: Acetaminophen reactive-metabolite handling experimental_model: Enzyme oxidation and radiolabeled binding assays limitations: Cell-free/microsomal finding; vitamin C is not established here as a clinical antidote. exposure: NAPQI or acetaminophen with reductants evidence_span: {"source_cache": "artifacts/glutathione-research/6424115.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8c45563e89388d200eb64ae63d12b388ef5cca91369a585157ef27b39f525b08", "start_char": 0, "end_char": 1307, "text_sha256": "8c45563e89388d200eb64ae63d12b388ef5cca91369a585157ef27b39f525b08"} [glutathione-p6424115] N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. (1984). https://pubmed.ncbi.nlm.nih.gov/6424115/ DOI: 10.1073/pnas.81.5.1327

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

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

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

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

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

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

evidence_access

Primary full text, recombinant methods and enzyme kinetics

experimental_model

Human PHD2 residues 181–402; NMR and enzymatic assays.

limitations

Millimolar assay exposure is relevant to local gut questions, not evidence of inhibition throughout the body at normal blood levels.

nutrient_topic

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

plain_language

It also directly affected an enzyme that normally marks HIF for degradation.

primary_references

Microbiota-derived butyrate is an endogenous HIF prolyl hydroxylase inhibitor. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34190032/ · DOI 10.1080/19490976.2021.1938380

Butyrate: microbial production, fuel use, signaling and nutrient interactions (2026-09-19) · lines 246–252

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human PHD2 residues 181–402; NMR and enzymatic assays. · source_derived_draft · unverified_draft

## butyrate-phd2-inhibition It also directly affected an enzyme that normally marks HIF for degradation. Butyrate bound and inhibited a recombinant human PHD2 catalytic fragment; kinetic analysis gave a noncompetitive Ki of 5.3 ± 0.5 mM relative to 2-oxoglutarate. Model: Human PHD2 residues 181–402; NMR and enzymatic assays. Limitations: Millimolar assay exposure is relevant to local gut questions, not evidence of inhibition throughout the body at normal blood levels. Evidence access: Primary full text, recombinant methods and enzyme kinetics Microbiota-derived butyrate is an endogenous HIF prolyl hydroxylase inhibitor. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34190032/ · DOI 10.1080/19490976.2021.1938380

evidence_access

Primary abstract

experimental_model

Cell-free model-hydroperoxide assay.

limitations

Cumene hydroperoxide is a model reagent, not direct measurement of membrane injury in humans.

nutrient_topic

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

plain_language

The same redox system can also react with a model lipid peroxide.

primary_references

One-electron reduction of vanadate by ascorbate and related free radical generation at physiological pH. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8051539/ · DOI 10.1016/0162-0134(94)85032-1

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 110–116

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free model-hydroperoxide assay. · source_derived_draft · unverified_draft

## vanadium-lipid-peroxide-radicals The same redox system can also react with a model lipid peroxide. V(IV) generated by ascorbate/vanadate chemistry produced hydroperoxide-derived radicals from cumene hydroperoxide. Model: Cell-free model-hydroperoxide assay. Limitations: Cumene hydroperoxide is a model reagent, not direct measurement of membrane injury in humans. Evidence access: Primary abstract One-electron reduction of vanadate by ascorbate and related free radical generation at physiological pH. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8051539/ · DOI 10.1016/0162-0134(94)85032-1

evidence_access

Primary abstract

experimental_model

Cell-free NADH/NADPH oxidation experiments.

limitations

Not evidence of a measured whole-body NAD shortage.

nutrient_topic

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

plain_language

Reducing equivalents can be consumed by a metal-dependent reaction.

primary_references

Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 118–124

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free NADH/NADPH oxidation experiments. · source_derived_draft · unverified_draft

## vanadium-nadh-oxidation Reducing equivalents can be consumed by a metal-dependent reaction. A vanadate/ascorbate/phosphate system oxidized NADH, with similar results for NADPH, through a proposed superoxide-initiated chain reaction. Model: Cell-free NADH/NADPH oxidation experiments. Limitations: Not evidence of a measured whole-body NAD shortage. Evidence access: Primary abstract Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

evidence_access

Primary abstract

experimental_model

Cell-free ESR spin trapping.

limitations

Chemical mechanism under specified reagents; not proof that vitamin C supplementation causes this injury in people.

nutrient_topic

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

plain_language

A reductant can enable pro-oxidant chemistry when peroxide is also present.

primary_references

One-electron reduction of vanadate by ascorbate and related free radical generation at physiological pH. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8051539/ · DOI 10.1016/0162-0134(94)85032-1

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 102–108

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free ESR spin trapping. · source_derived_draft · unverified_draft

## vanadium-peroxide-radicals A reductant can enable pro-oxidant chemistry when peroxide is also present. In phosphate/ascorbate mixtures with peroxide, reduced vanadium supported hydroxyl-radical generation; omitting phosphate sharply reduced the yield. Model: Cell-free ESR spin trapping. Limitations: Chemical mechanism under specified reagents; not proof that vitamin C supplementation causes this injury in people. Evidence access: Primary abstract One-electron reduction of vanadate by ascorbate and related free radical generation at physiological pH. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8051539/ · DOI 10.1016/0162-0134(94)85032-1

evidence_access

Primary abstract

experimental_model

Cell-free scavenger comparison.

limitations

Does not imply catalase is irrelevant to all vanadium toxicity.

nutrient_topic

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

plain_language

The scavenger comparison points to a superoxide-dependent step in this particular reaction.

primary_references

Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

Vanadium: speciation, phosphate-sensitive enzymes and cross-nutrient mechanisms (2026-09-19) · lines 126–132

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free scavenger comparison. · source_derived_draft · unverified_draft

## vanadium-sod-redox-rescue The scavenger comparison points to a superoxide-dependent step in this particular reaction. Superoxide dismutase inhibited NADH oxidation in the vanadate/ascorbate/phosphate system, whereas catalase and ethanol did not. Model: Cell-free scavenger comparison. Limitations: Does not imply catalase is irrelevant to all vanadium toxicity. Evidence access: Primary abstract Vanadate-mediated oxidation of NADH: description of an in vitro system requiring ascorbate and phosphate. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2735768/ · DOI 10.1016/0003-9861(89)90196-3

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human osteoblast-like cell inhibitor study.

limitations

Does not prove direct silicon binding or silicon as an obligatory enzyme cofactor.

nutrient_topic

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

plain_language

Intact collagen-processing machinery was needed for the response.

primary_references

Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12633784/ · DOI 10.1016/s8756-3282(02)00950-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 136–142

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

## silica-hydroxylase-block Intact collagen-processing machinery was needed for the response. Prolyl hydroxylase inhibitors abolished the orthosilicic-acid-associated collagen increase. Model: Human osteoblast-like cell inhibitor study. Limitations: Does not prove direct silicon binding or silicon as an obligatory enzyme cofactor. Evidence access: Primary abstract Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12633784/ · DOI 10.1016/s8756-3282(02)00950-x

evidence_access

Primary abstract

experimental_model

Human endothelial cells; released silicon in the ppm range.

limitations

Accessed abstract does not establish direct inhibitor binding; HIF PHD2 differs from collagen prolyl hydroxylase.

nutrient_topic

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

plain_language

A biomaterial study implicated oxygen-sensing machinery.

primary_references

Promoting angiogenesis with mesoporous microcarriers through a synergistic action of delivered silicon ion and VEGF. · 2017 · https://pubmed.ncbi.nlm.nih.gov/27918936/ · DOI 10.1016/j.biomaterials.2016.11.053

Silica: soluble silicon, cellular transport and particle-specific mechanisms (2026-09-19) · lines 272–278

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human endothelial cells; released silicon in the ppm range. · source_derived_draft · unverified_draft

## silica-microcarrier-hif A biomaterial study implicated oxygen-sensing machinery. Silicon-releasing microcarriers increased HIF1A expression and stabilization, attributed to reduced PHD2 activity in HUVECs. Model: Human endothelial cells; released silicon in the ppm range. Limitations: Accessed abstract does not establish direct inhibitor binding; HIF PHD2 differs from collagen prolyl hydroxylase. Evidence access: Primary abstract Promoting angiogenesis with mesoporous microcarriers through a synergistic action of delivered silicon ion and VEGF. · 2017 · https://pubmed.ncbi.nlm.nih.gov/27918936/ · DOI 10.1016/j.biomaterials.2016.11.053

evidence_span

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experimental_model

Randomized double-blind crossover single-dose study

exposure

Broccoli seed glucoraphanin with versus without mustard myrosinase; both arms contained ascorbic acid

limitations

Both arms included ascorbic acid, so its independent benefit cannot be inferred; conversion biomarker is not clinical efficacy.

nutrient_topic

Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. · Sulforaphane / SFN, stereochemistry specified per study

organism

Human, 16 adults, nine women and seven men

plain_language

A recent controlled product comparison confirms the importance of enzyme activity.

primary_references

[sulforaphane-p41692762] Exogenous myrosinase from mustard seed increases bioavailability of sulforaphane from a glucoraphanin-rich broccoli seed extract in a randomized clinical study. (2026). https://pubmed.ncbi.nlm.nih.gov/41692762/ DOI: 10.1038/s41598-026-39389-4

tissue_or_cell_type

Urinary metabolites and fecal microbial genes

Sulforaphane: formation, electrophile sensing and nutrient connections (2026-09-17) · lines 996–1007

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind crossover single-dose study · source_derived_draft · unverified_draft

### sulforaphane-mustard-seed-trial Myrosinase increased mean urinary-metabolite-based recovery from 18.6% to 39.8%, and early conversion during the first eight hours from 8.0% to 25.4%. Condition category: normal nutrient_topic: Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. plain_language: A recent controlled product comparison confirms the importance of enzyme activity. organism: Human, 16 adults, nine women and seven men tissue_or_cell_type: Urinary metabolites and fecal microbial genes experimental_model: Randomized double-blind crossover single-dose study limitations: Both arms included ascorbic acid, so its independent benefit cannot be inferred; conversion biomarker is not clinical efficacy. exposure: Broccoli seed glucoraphanin with versus without mustard myrosinase; both arms contained ascorbic acid evidence_span: {"source_cache": "artifacts/sulforaphane-research/41692762.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "67e337141c8012ea573d9720d5e4774bfdd1ae098c056b68991752169fbdb32a", "start_char": 0, "end_char": 1248, "text_sha256": "67e337141c8012ea573d9720d5e4774bfdd1ae098c056b68991752169fbdb32a"} [sulforaphane-p41692762] Exogenous myrosinase from mustard seed increases bioavailability of sulforaphane from a glucoraphanin-rich broccoli seed extract in a randomized clinical study. (2026). https://pubmed.ncbi.nlm.nih.gov/41692762/ DOI: 10.1038/s41598-026-39389-4

evidence_span

{"source_cache": "artifacts/mangiferin-research/15878708.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e29d024822df85f1aa0b737bb4123c869646d737c15bf05f1dc72b047a45eef3", "start_char": 0, "end_char": 1966, "text_sha256": "e29d024822df85f1aa0b737bb4123c869646d737c15bf05f1dc72b047a45eef3"}

experimental_model

Isolated mitochondrial and iron-redox assays

exposure

10 micromolar mangiferin and 50 micromolar ferrous citrate in one protection experiment

limitations

In vitro iron complexing is not evidence that oral mangiferin depletes body iron or treats iron overload.

nutrient_topic

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

organism

Rattus norvegicus and cell-free chemistry

plain_language

Iron binding changed a reaction involving vitamin C.

primary_references

[mangiferin-p15878708] Iron complexing activity of mangiferin, a naturally occurring glucosylxanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate. (2005). https://pubmed.ncbi.nlm.nih.gov/15878708/ DOI: 10.1016/j.ejphar.2005.03.007

tissue_or_cell_type

Liver mitochondria

Mangiferin: metabolism, signaling and nutrient connections (2026-09-17) · lines 692–703

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated mitochondrial and iron-redox assays · source_derived_draft · unverified_draft

### mangiferin-iron-vitamin-c Mangiferin prevented ascorbate-driven ferric iron reduction in vitro. Condition category: normal nutrient_topic: Mangiferin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron binding changed a reaction involving vitamin C. organism: Rattus norvegicus and cell-free chemistry tissue_or_cell_type: Liver mitochondria experimental_model: Isolated mitochondrial and iron-redox assays limitations: In vitro iron complexing is not evidence that oral mangiferin depletes body iron or treats iron overload. exposure: 10 micromolar mangiferin and 50 micromolar ferrous citrate in one protection experiment evidence_span: {"source_cache": "artifacts/mangiferin-research/15878708.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e29d024822df85f1aa0b737bb4123c869646d737c15bf05f1dc72b047a45eef3", "start_char": 0, "end_char": 1966, "text_sha256": "e29d024822df85f1aa0b737bb4123c869646d737c15bf05f1dc72b047a45eef3"} [mangiferin-p15878708] Iron complexing activity of mangiferin, a naturally occurring glucosylxanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate. (2005). https://pubmed.ncbi.nlm.nih.gov/15878708/ DOI: 10.1016/j.ejphar.2005.03.007

evidence_span

{"source_cache": "artifacts/hbot-research/2537773.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe", "start_char": 0, "end_char": 2024, "text_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe"}

experimental_model

Review of prolyl 4-hydroxylase enzymology and subunit structure

exposure

Hydroxylation of proline in X-Pro-Gly sequences

limitations

An authoritative enzymology review rather than a single experiment. It is the source for the cosubstrate list, which is the point at which oxygen, iron and vitamin C meet in collagen synthesis.

nutrient_topic

Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Hyperbaric oxygen therapy

organism

Mammalian enzyme

plain_language

Making collagen needs oxygen, iron, vitamin C and a Krebs-cycle acid, all four at once.

primary_references

[hbot-p2537773] Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. (1989). https://pubmed.ncbi.nlm.nih.gov/2537773/ DOI: 10.1096/fasebj.3.5.2537773

tissue_or_cell_type

Endoplasmic reticulum

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 855–866

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of prolyl 4-hydroxylase enzymology and subunit structure · source_derived_draft · unverified_draft

### hbot-p4h-cosubstrates Prolyl 4-hydroxylase catalyses formation of 4-hydroxyproline in collagens by hydroxylating proline residues in X-Pro-Gly sequences, and the reaction requires Fe2+, 2-oxoglutarate, O2 and ascorbate, involving oxidative decarboxylation of 2-oxoglutarate. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Making collagen needs oxygen, iron, vitamin C and a Krebs-cycle acid, all four at once. organism: Mammalian enzyme tissue_or_cell_type: Endoplasmic reticulum experimental_model: Review of prolyl 4-hydroxylase enzymology and subunit structure limitations: An authoritative enzymology review rather than a single experiment. It is the source for the cosubstrate list, which is the point at which oxygen, iron and vitamin C meet in collagen synthesis. exposure: Hydroxylation of proline in X-Pro-Gly sequences evidence_span: {"source_cache": "artifacts/hbot-research/2537773.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe", "start_char": 0, "end_char": 2024, "text_sha256": "3fdda2e4cf4392ec7a88b137274cee8f321255473992a2d8df781df12cad6cfe"} [hbot-p2537773] Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. (1989). https://pubmed.ncbi.nlm.nih.gov/2537773/ DOI: 10.1096/fasebj.3.5.2537773

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/chromium-research/25977998.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3", "start_char": 0, "end_char": 2163, "text_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3"}

experimental_model

Ascorbate restoration and ATM perturbation in human lung-cell cultures

exposure

Chromate exposure in standard ascorbate-poor versus ascorbate-restored cells; ATM inhibition/silencing

limitations

Cr(VI) toxicology, not an experiment with dietary Cr(III). Loss of ATM activation does not mean loss of all genotoxicity or that vitamin C universally detoxifies chromium.

nutrient_topic

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

organism

Human H460 cells and normal lung fibroblasts

plain_language

This downstream damage-response protein changed in the low-ascorbate culture condition.

primary_references

[chromium-p25977998] Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics. (2016). https://pubmed.ncbi.nlm.nih.gov/25977998/ DOI: 10.1289/ehp.1409434

tissue_or_cell_type

DNA-damage signaling

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Chromium: transport, insulin signaling, nutrient interactions and essentiality debate (2026-09-17) · lines 1134–1145

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ascorbate restoration and ATM perturbation in human lung-cell cultures · source_derived_draft · unverified_draft

### chromium-chromate-chk2 Chromate exposure induced CHK2 phosphorylation as part of the ATM response in standard ascorbate-poor human cell cultures. Condition category: nutrient_deficiency nutrient_topic: Chromium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This downstream damage-response protein changed in the low-ascorbate culture condition. organism: Human H460 cells and normal lung fibroblasts tissue_or_cell_type: DNA-damage signaling experimental_model: Ascorbate restoration and ATM perturbation in human lung-cell cultures limitations: Cr(VI) toxicology, not an experiment with dietary Cr(III). Loss of ATM activation does not mean loss of all genotoxicity or that vitamin C universally detoxifies chromium. exposure: Chromate exposure in standard ascorbate-poor versus ascorbate-restored cells; ATM inhibition/silencing evidence_span: {"source_cache": "artifacts/chromium-research/25977998.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3", "start_char": 0, "end_char": 2163, "text_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3"} [chromium-p25977998] Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics. (2016). https://pubmed.ncbi.nlm.nih.gov/25977998/ DOI: 10.1289/ehp.1409434

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/chromium-research/25977998.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3", "start_char": 0, "end_char": 2163, "text_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3"}

experimental_model

Ascorbate restoration and ATM perturbation in human lung-cell cultures

exposure

Chromate exposure in standard ascorbate-poor versus ascorbate-restored cells; ATM inhibition/silencing

limitations

Cr(VI) toxicology, not an experiment with dietary Cr(III). Loss of ATM activation does not mean loss of all genotoxicity or that vitamin C universally detoxifies chromium.

nutrient_topic

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

organism

Human H460 cells and normal lung fibroblasts

plain_language

This downstream damage-response protein changed in the low-ascorbate culture condition.

primary_references

[chromium-p25977998] Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics. (2016). https://pubmed.ncbi.nlm.nih.gov/25977998/ DOI: 10.1289/ehp.1409434

tissue_or_cell_type

DNA-damage signaling

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Chromium: transport, insulin signaling, nutrient interactions and essentiality debate (2026-09-17) · lines 1147–1158

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ascorbate restoration and ATM perturbation in human lung-cell cultures · source_derived_draft · unverified_draft

### chromium-chromate-kap1 Chromate exposure induced KAP1 phosphorylation as part of the ATM response in standard ascorbate-poor human cell cultures. Condition category: nutrient_deficiency nutrient_topic: Chromium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This downstream damage-response protein changed in the low-ascorbate culture condition. organism: Human H460 cells and normal lung fibroblasts tissue_or_cell_type: DNA-damage signaling experimental_model: Ascorbate restoration and ATM perturbation in human lung-cell cultures limitations: Cr(VI) toxicology, not an experiment with dietary Cr(III). Loss of ATM activation does not mean loss of all genotoxicity or that vitamin C universally detoxifies chromium. exposure: Chromate exposure in standard ascorbate-poor versus ascorbate-restored cells; ATM inhibition/silencing evidence_span: {"source_cache": "artifacts/chromium-research/25977998.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3", "start_char": 0, "end_char": 2163, "text_sha256": "26c325e343b04aa77acf3164d848e8127c2d6a329ff0d9968426a12bde81d0b3"} [chromium-p25977998] Different ATM Signaling in Response to Chromium(VI) Metabolism via Ascorbate and Nonascorbate Reduction: Implications for in Vitro Models and Toxicogenomics. (2016). https://pubmed.ncbi.nlm.nih.gov/25977998/ DOI: 10.1289/ehp.1409434

evidence_span

{"source_cache": "artifacts/chromium-research/36662348.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "500f334d72ca34561016a11f0c3bf866998ee364085855e54a2f29025bc916a8", "start_char": 0, "end_char": 1155, "text_sha256": "500f334d72ca34561016a11f0c3bf866998ee364085855e54a2f29025bc916a8"}

experimental_model

Characterization of pre-reacted chromium-ligand preparations and DNA-binding assays

exposure

Pre-reacted chromium cysteinate, chromium glutathione and chromium ascorbate preparations

limitations

These preparation-specific results challenge earlier assignments but do not show that Cr(VI) is harmless or directly reproduce every reductive chromate-DNA reaction.

nutrient_topic

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

organism

Cell-free chemistry

plain_language

Pre-forming a metal complex can give a different result from reducing chromate in the presence of DNA; the claimed lesion identity needs checking.

primary_references

[chromium-p36662348] Examining the Potential Formation of Ternary DNA Complexes with Chromium‑Cysteine, Chromium-Ascorbate, and Chromium-Glutathione and Implications for Their Carcinogenicity. (2023). https://pubmed.ncbi.nlm.nih.gov/36662348/ DOI: 10.1007/s12011-023-03573-8

tissue_or_cell_type

Defined chromium complexes and DNA

Chromium: transport, insulin signaling, nutrient interactions and essentiality debate (2026-09-17) · lines 1186–1197

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Characterization of pre-reacted chromium-ligand preparations and DNA-binding assays · source_derived_draft · unverified_draft

### chromium-prereacted-dna-binding-null The characterized pre-reacted Cr(III)-cysteine, -glutathione and -ascorbate preparations did not measurably bind DNA or form the proposed ternary adducts under the tested conditions. Condition category: normal nutrient_topic: Chromium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Pre-forming a metal complex can give a different result from reducing chromate in the presence of DNA; the claimed lesion identity needs checking. organism: Cell-free chemistry tissue_or_cell_type: Defined chromium complexes and DNA experimental_model: Characterization of pre-reacted chromium-ligand preparations and DNA-binding assays limitations: These preparation-specific results challenge earlier assignments but do not show that Cr(VI) is harmless or directly reproduce every reductive chromate-DNA reaction. exposure: Pre-reacted chromium cysteinate, chromium glutathione and chromium ascorbate preparations evidence_span: {"source_cache": "artifacts/chromium-research/36662348.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "500f334d72ca34561016a11f0c3bf866998ee364085855e54a2f29025bc916a8", "start_char": 0, "end_char": 1155, "text_sha256": "500f334d72ca34561016a11f0c3bf866998ee364085855e54a2f29025bc916a8"} [chromium-p36662348] Examining the Potential Formation of Ternary DNA Complexes with Chromium‑Cysteine, Chromium-Ascorbate, and Chromium-Glutathione and Implications for Their Carcinogenicity. (2023). https://pubmed.ncbi.nlm.nih.gov/36662348/ DOI: 10.1007/s12011-023-03573-8

evidence_access

Primary abstract

experimental_model

Cell-free DNA-bound copper system.

limitations

Authors inferred physiological relevance; this experiment does not establish systemic safety or clinical synergy.

nutrient_topic

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

plain_language

Vitamin C changes the relevant chemical context.

primary_references

Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11032413/ · DOI 10.1006/abbi.2000.1973

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 374–380

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free DNA-bound copper system. · source_derived_draft · unverified_draft

## resveratrol-ascorbate-context Vitamin C changes the relevant chemical context. With ascorbate present, resveratrol protected DNA in copper-based chemical experiments without lowering hydroxyl-radical formation rate, consistent with radical scavenging. Model: Cell-free DNA-bound copper system. Limitations: Authors inferred physiological relevance; this experiment does not establish systemic safety or clinical synergy. Evidence access: Primary abstract Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11032413/ · DOI 10.1006/abbi.2000.1973

evidence_access

Primary abstract

experimental_model

Cell-free copper/ascorbate and copper/peroxide systems.

limitations

Exposure and free-metal speciation limit extrapolation.

nutrient_topic

Ergothioneine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Ergothioneine

plain_language

Binding the catalyst can protect several targets.

primary_references

Ergothioneine prevents copper-induced oxidative damage to DNA and protein by forming a redox-inactive ergothioneine-copper complex. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21047085/ · DOI 10.1021/tx100214t

Ergothioneine: transport, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 128–134

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free copper/ascorbate and copper/peroxide systems. · source_derived_draft · unverified_draft

## ergothioneine-copper-oxidation Binding the catalyst can protect several targets. Ergothioneine at 0.1-1 mM protected DNA and albumin against 0.1 mM copper with ascorbate or peroxide. Model: Cell-free copper/ascorbate and copper/peroxide systems. Limitations: Exposure and free-metal speciation limit extrapolation. Evidence access: Primary abstract Ergothioneine prevents copper-induced oxidative damage to DNA and protein by forming a redox-inactive ergothioneine-copper complex. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21047085/ · DOI 10.1021/tx100214t

evidence_span

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experimental_model

Cancer-cell combinations and human-tumor xenograft experiments

exposure

Millimolar cell exposures; injected ALA/ascorbate combinations in mice

limitations

Pharmacological ascorbate and animal injection exposures are not dietary vitamin C; no clinical combination trial.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human cancer cells and mice

plain_language

The combination’s tolerability also needed measurement.

primary_references

[ala-p39493360] Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models. (2024). https://pubmed.ncbi.nlm.nih.gov/39493360/ DOI: 10.1177/11795549241283421

tissue_or_cell_type

Six cell lines; MDA-MB-231 xenografts

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 1105–1116

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer-cell combinations and human-tumor xenograft experiments · source_derived_draft · unverified_draft

### ala-ascorbate-ala-toxicity The study reported toxicity with prolonged lipoic-acid exposure and increased toxicity with tested ascorbate combinations in mice. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The combination’s tolerability also needed measurement. organism: Human cancer cells and mice tissue_or_cell_type: Six cell lines; MDA-MB-231 xenografts experimental_model: Cancer-cell combinations and human-tumor xenograft experiments limitations: Pharmacological ascorbate and animal injection exposures are not dietary vitamin C; no clinical combination trial. exposure: Millimolar cell exposures; injected ALA/ascorbate combinations in mice evidence_span: {"source_cache": "artifacts/ala-research/39493360.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266", "start_char": 0, "end_char": 1935, "text_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266"} [ala-p39493360] Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models. (2024). https://pubmed.ncbi.nlm.nih.gov/39493360/ DOI: 10.1177/11795549241283421

evidence_span

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experimental_model

Cancer-cell combinations and human-tumor xenograft experiments

exposure

Millimolar cell exposures; injected ALA/ascorbate combinations in mice

limitations

Pharmacological ascorbate and animal injection exposures are not dietary vitamin C; no clinical combination trial.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human cancer cells and mice

plain_language

Reducing an oxidant can oppose a treatment that relies on that oxidant.

primary_references

[ala-p39493360] Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models. (2024). https://pubmed.ncbi.nlm.nih.gov/39493360/ DOI: 10.1177/11795549241283421

tissue_or_cell_type

Six cell lines; MDA-MB-231 xenografts

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 1079–1090

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer-cell combinations and human-tumor xenograft experiments · source_derived_draft · unverified_draft

### ala-ascorbate-peroxide-antagonism Lipoic acid reduced pharmacological ascorbate-generated hydrogen peroxide in the tested cell experiments. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing an oxidant can oppose a treatment that relies on that oxidant. organism: Human cancer cells and mice tissue_or_cell_type: Six cell lines; MDA-MB-231 xenografts experimental_model: Cancer-cell combinations and human-tumor xenograft experiments limitations: Pharmacological ascorbate and animal injection exposures are not dietary vitamin C; no clinical combination trial. exposure: Millimolar cell exposures; injected ALA/ascorbate combinations in mice evidence_span: {"source_cache": "artifacts/ala-research/39493360.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266", "start_char": 0, "end_char": 1935, "text_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266"} [ala-p39493360] Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models. (2024). https://pubmed.ncbi.nlm.nih.gov/39493360/ DOI: 10.1177/11795549241283421

evidence_span

{"source_cache": "artifacts/ala-research/39493360.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266", "start_char": 0, "end_char": 1935, "text_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266"}

experimental_model

Cancer-cell combinations and human-tumor xenograft experiments

exposure

Millimolar cell exposures; injected ALA/ascorbate combinations in mice

limitations

Pharmacological ascorbate and animal injection exposures are not dietary vitamin C; no clinical combination trial.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human cancer cells and mice

plain_language

The combination did not provide a universal antioxidant synergy.

primary_references

[ala-p39493360] Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models. (2024). https://pubmed.ncbi.nlm.nih.gov/39493360/ DOI: 10.1177/11795549241283421

tissue_or_cell_type

Six cell lines; MDA-MB-231 xenografts

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 1092–1103

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cancer-cell combinations and human-tumor xenograft experiments · source_derived_draft · unverified_draft

### ala-ascorbate-tumor-response Lower tested lipoic-acid doses attenuated tumor-growth inhibition from high-dose ascorbate in the mouse model; the highest dose did not enhance it. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The combination did not provide a universal antioxidant synergy. organism: Human cancer cells and mice tissue_or_cell_type: Six cell lines; MDA-MB-231 xenografts experimental_model: Cancer-cell combinations and human-tumor xenograft experiments limitations: Pharmacological ascorbate and animal injection exposures are not dietary vitamin C; no clinical combination trial. exposure: Millimolar cell exposures; injected ALA/ascorbate combinations in mice evidence_span: {"source_cache": "artifacts/ala-research/39493360.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266", "start_char": 0, "end_char": 1935, "text_sha256": "9bd9ced1ace4214d80aad8e15ca5d61f8e4063f4e5838054b93e8c07a9550266"} [ala-p39493360] Combination of High-Dose Parenteral Ascorbate (Vitamin C) and Alpha-Lipoic Acid Failed to Enhance Tumor-Inhibitory Effect But Increased Toxicity in Preclinical Cancer Models. (2024). https://pubmed.ncbi.nlm.nih.gov/39493360/ DOI: 10.1177/11795549241283421

evidence_span

{"source_cache": "artifacts/ala-research/18026819.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a", "start_char": 0, "end_char": 1329, "text_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a"}

experimental_model

Human endothelial-cell and extracellular LDL oxidation experiments

exposure

40–80 micromolar lipoic acid; menadione or copper/LDL challenge

limitations

Compartment and oxidant matter; intracellular vitamin C and LDL vitamin E are distinct readouts.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human cell line and human LDL

plain_language

Protection of LDL did not guarantee protection of intracellular vitamin C.

primary_references

[ala-p18026819] alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells. (2008). https://pubmed.ncbi.nlm.nih.gov/18026819/ DOI: 10.1007/s11010-007-9650-z

tissue_or_cell_type

EA.hy926 endothelial cells; extracellular LDL

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 1027–1038

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human endothelial-cell and extracellular LDL oxidation experiments · source_derived_draft · unverified_draft

### ala-copper-challenge-ascorbate-null Lipoic acid did not prevent intracellular ascorbate loss caused by the extracellular copper/LDL challenge in the same study. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protection of LDL did not guarantee protection of intracellular vitamin C. organism: Human cell line and human LDL tissue_or_cell_type: EA.hy926 endothelial cells; extracellular LDL experimental_model: Human endothelial-cell and extracellular LDL oxidation experiments limitations: Compartment and oxidant matter; intracellular vitamin C and LDL vitamin E are distinct readouts. exposure: 40–80 micromolar lipoic acid; menadione or copper/LDL challenge evidence_span: {"source_cache": "artifacts/ala-research/18026819.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a", "start_char": 0, "end_char": 1329, "text_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a"} [ala-p18026819] alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells. (2008). https://pubmed.ncbi.nlm.nih.gov/18026819/ DOI: 10.1007/s11010-007-9650-z

evidence_span

{"source_cache": "artifacts/ala-research/18026819.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a", "start_char": 0, "end_char": 1329, "text_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a"}

experimental_model

Human endothelial-cell and extracellular LDL oxidation experiments

exposure

40–80 micromolar lipoic acid; menadione or copper/LDL challenge

limitations

Compartment and oxidant matter; intracellular vitamin C and LDL vitamin E are distinct readouts.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human cell line and human LDL

plain_language

Vitamin C was preserved under some cellular conditions.

primary_references

[ala-p18026819] alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells. (2008). https://pubmed.ncbi.nlm.nih.gov/18026819/ DOI: 10.1007/s11010-007-9650-z

tissue_or_cell_type

EA.hy926 endothelial cells; extracellular LDL

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 1001–1012

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human endothelial-cell and extracellular LDL oxidation experiments · source_derived_draft · unverified_draft

### ala-endothelial-ascorbate-sparing Lipoic acid spared intracellular ascorbate under basal and menadione-challenged conditions in endothelial cells. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C was preserved under some cellular conditions. organism: Human cell line and human LDL tissue_or_cell_type: EA.hy926 endothelial cells; extracellular LDL experimental_model: Human endothelial-cell and extracellular LDL oxidation experiments limitations: Compartment and oxidant matter; intracellular vitamin C and LDL vitamin E are distinct readouts. exposure: 40–80 micromolar lipoic acid; menadione or copper/LDL challenge evidence_span: {"source_cache": "artifacts/ala-research/18026819.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a", "start_char": 0, "end_char": 1329, "text_sha256": "a4dff4887489013858d07ce07ba538c62702962afa1588ae7cc83e308648e53a"} [ala-p18026819] alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells. (2008). https://pubmed.ncbi.nlm.nih.gov/18026819/ DOI: 10.1007/s11010-007-9650-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Two human families; genetic analysis with supporting Cyb561 knockout mouse results.

limitations

The human defect and mouse corroboration are distinct evidence; ordinary dietary vitamin C deficiency was not the intervention.

nutrient_topic

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

plain_language

A normal blood enzyme test can miss a cofactor problem inside a vesicle.

primary_references

Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29343526/ · DOI 10.1161/CIRCRESAHA.117.311949

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Tyrosine: catecholamines, thyroid chemistry, pigment, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 52–58

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two human families; genetic analysis with supporting Cyb561 knockout mouse results. · source_derived_draft · unverified_draft

## l-tyrosine-cyb-vesicle A normal blood enzyme test can miss a cofactor problem inside a vesicle. Pathogenic CYB561 variants in four patients accompanied very low norepinephrine and epinephrine despite normal plasma DBH activity; impaired intravesicular ascorbate support was the proposed functional block. Model: Two human families; genetic analysis with supporting Cyb561 knockout mouse results. Limitations: The human defect and mouse corroboration are distinct evidence; ordinary dietary vitamin C deficiency was not the intervention. Evidence access: Primary abstract Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29343526/ · DOI 10.1161/CIRCRESAHA.117.311949

cross_nutrient

Zinc(II) ion (absorbed_nutrient_ion); Iron (coadministered_nutrient); L-Ascorbate (coadministered_ligand)

evidence_location

Indexed primary abstract.

evidence_span

{"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044}

experimental_model

Human 65Zn tracer study with whole-body counting after two weeks

exposure

Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons.

limitations

Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows.

nutrient_topic

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

organism

Homo sapiens

plain_language

The high iron-to-zinc ratio reduced zinc uptake in the fasting solution.

primary_references

[zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

tissue_or_cell_type

Intestinal absorption

Zinc: transport, enzyme loading, deficiency and nutrient interactions (2026-09-17) · lines 1226–1239

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human 65Zn tracer study with whole-body counting after two weeks · source_derived_draft · unverified_draft

### zn-clin-iron-fasting Fasting-water zinc absorption was 59%, 58% and 34% at ferrous Fe:Zn molar ratios of 1:1, 2.5:1 and 25:1 respectively; inhibition was significant at the highest ratio. Condition category: normal nutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect. plain_language: The high iron-to-zinc ratio reduced zinc uptake in the fasting solution. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Human 65Zn tracer study with whole-body counting after two weeks limitations: Meal matrix, iron ratio and ligand differed. Absolute administered amounts and sample sizes were not verified in the indexed abstract; no universal spacing rule follows. exposure: Ferrous iron with ascorbic acid; Fe:Zn molar ratios 1:1, 2.5:1 and 25:1, in fasting water or a meal; histidine and iron-preloading comparisons. cross_nutrient: Zinc(II) ion (absorbed_nutrient_ion); Iron (coadministered_nutrient); L-Ascorbate (coadministered_ligand) evidence_location: Indexed primary abstract. evidence_span: {"source_cache": "artifacts/zinc-clinical-sources/sandstrom1985.abstract.txt", "locator": "Primary indexed abstract; complete local file", "file_sha256": "aa462f6a961ec4190690f8def1be1f5e54491574698b131992161a989103ca76", "utf8_bytes": 1044} [zn-clin-sandstrom1985] Oral iron, dietary ligands and zinc absorption. (1985). https://pubmed.ncbi.nlm.nih.gov/3973750/ DOI: 10.1093/jn/115.3.411

evidence_span

{"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"}

experimental_model

Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation

exposure

Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin

limitations

Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic.

nutrient_topic

Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol

organism

Sheep

plain_language

The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite.

primary_references

[apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

tissue_or_cell_type

Seminal vesicle microsomes

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 129–140

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation · source_derived_draft · unverified_draft

### apap-the-enzyme-makes-napqi Using acetaminophen as a probe, at low concentrations it is converted in a cooxidation reaction with arachidonic acid to the dimer 4,4-dihydroxy-3,3-biacetanilide and other polymeric products, and the electrophilic metabolite N-acetyl-p-benzoquinone imine was detected directly and indirectly by its reaction with glutathione to form 3-S-glutathionylacetaminophen; the same products were formed by the synthase with hydrogen peroxide in reactions not inhibited by indomethacin, and formation of all products was inhibited by ascorbic acid and butylated hydroxyanisole. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The prostaglandin enzyme can itself turn the drug into the liver-damaging metabolite. organism: Sheep tissue_or_cell_type: Seminal vesicle microsomes experimental_model: Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation limitations: Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic. exposure: Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin evidence_span: {"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"} [apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

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

evidence_access

Primary abstract

experimental_model

Cell-free iron-loaded liposomes.

limitations

Ascorbate participated in the oxidation-initiating system; this is not evidence that vitamin C regenerates astaxanthin or that astaxanthin removes body iron.

nutrient_topic

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

plain_language

Its effect depended on the surrounding iron and oxidant chemistry.

primary_references

Astaxanthin and peridinin inhibit oxidative damage in Fe(2+)-loaded liposomes: scavenging oxyradicals or changing membrane permeability? · 2001 · https://pubmed.ncbi.nlm.nih.gov/11594777/ · DOI 10.1006/bbrc.2001.5765

Astaxanthin: transport, membrane chemistry, signaling and nutrient interactions (2026-09-19) · lines 174–180

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cell-free iron-loaded liposomes. · source_derived_draft · unverified_draft

## astaxanthin-iron-ascorbate Its effect depended on the surrounding iron and oxidant chemistry. Astaxanthin reduced lipid damage in iron-loaded liposomes challenged using peroxide or ascorbate-dependent initiating systems. Model: Cell-free iron-loaded liposomes. Limitations: Ascorbate participated in the oxidation-initiating system; this is not evidence that vitamin C regenerates astaxanthin or that astaxanthin removes body iron. Evidence access: Primary abstract Astaxanthin and peridinin inhibit oxidative damage in Fe(2+)-loaded liposomes: scavenging oxyradicals or changing membrane permeability? · 2001 · https://pubmed.ncbi.nlm.nih.gov/11594777/ · DOI 10.1006/bbrc.2001.5765

evidence_access

Primary abstract

experimental_model

Cell-free 10 mM amino-acid comparison.

limitations

Not evidence that dietary histidine damages human DNA.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

The breakdown product did not behave like the intact peptide.

primary_references

Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15853927/ · DOI 10.1111/j.1742-7843.2005.pto_03.x

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 316–322

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cell-free 10 mM amino-acid comparison. · source_derived_draft · unverified_draft

## carnosine-histidine-metal The breakdown product did not behave like the intact peptide. Histidine increased DNA damage in the tested iron/peroxide/ascorbate system and weakened carnosine protection when combined with it. Model: Cell-free 10 mM amino-acid comparison. Limitations: Not evidence that dietary histidine damages human DNA. Evidence access: Primary abstract Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15853927/ · DOI 10.1111/j.1742-7843.2005.pto_03.x

evidence_access

Primary abstract

experimental_model

Cell-free metal-catalyzed oxidation.

limitations

Millimolar assay; does not show safe systemic metal chelation.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

Its chemical protection depended on the oxidation system.

primary_references

Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15853927/ · DOI 10.1111/j.1742-7843.2005.pto_03.x

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 308–314

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cell-free metal-catalyzed oxidation. · source_derived_draft · unverified_draft

## carnosine-metal-dna Its chemical protection depended on the oxidation system. At 10 mM, carnosine reduced DNA damage caused by copper- or iron/peroxide/ascorbate systems. Model: Cell-free metal-catalyzed oxidation. Limitations: Millimolar assay; does not show safe systemic metal chelation. Evidence access: Primary abstract Antioxidant properties of carnosine re-evaluated with oxidizing systems involving iron and copper ions. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15853927/ · DOI 10.1111/j.1742-7843.2005.pto_03.x

evidence_access

Primary abstract

experimental_model

Chemical analysis, mouse tissues and human neuroblastoma cells.

limitations

Product formation is distinct from simple removal of oxidants.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

An oxidation product can retain biological activity.

primary_references

2-Oxo-histidine-containing dipeptides are functional oxidation products. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30504220/ · DOI 10.1074/jbc.RA118.006111

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 340–346

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Chemical analysis, mouse tissues and human neuroblastoma cells. · source_derived_draft · unverified_draft

## carnosine-oxo-product An oxidation product can retain biological activity. Oxidation of carnosine produced 2-oxo-carnosine; mechanistic analysis supported imidazole-radical formation followed by oxygen addition. Model: Chemical analysis, mouse tissues and human neuroblastoma cells. Limitations: Product formation is distinct from simple removal of oxidants. Evidence access: Primary abstract 2-Oxo-histidine-containing dipeptides are functional oxidation products. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30504220/ · DOI 10.1074/jbc.RA118.006111

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/cold-research/3949732.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1", "start_char": 0, "end_char": 2000, "text_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1"}

experimental_model

Intact bovine chromaffin granules undergoing dopamine beta-hydroxylase turnover with labelled ascorbate

exposure

Tyramine- or dopamine-stimulated turnover with extragranular ascorbate

limitations

An in vitro demonstration in intact granules. Ascorbate itself does not cross the membrane, which is precisely why a shuttle is required.

nutrient_topic

Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. · Cold water immersion

organism

Bovine

plain_language

Every molecule of noradrenaline made costs the vesicle a molecule of vitamin C.

primary_references

[cold-p3949732] Evidence for an ascorbate shuttle for the transfer of reducing equivalents across chromaffin granule membranes. (1986). https://pubmed.ncbi.nlm.nih.gov/3949732/ DOI: 10.1016/s0021-9258(17)35819-2

tissue_or_cell_type

Adrenal chromaffin granules

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 611–622

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact bovine chromaffin granules undergoing dopamine beta-hydroxylase turnover with labelled ascorbate · source_derived_draft · unverified_draft

### cold-ascorbate-depletion-in-granule Incubation with tyramine produced a time-dependent decrease in reduced intragranular ascorbate proportional to extragranular tyramine concentration over 50 microM to 2 mM. Condition category: nutrient_deficiency nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Every molecule of noradrenaline made costs the vesicle a molecule of vitamin C. organism: Bovine tissue_or_cell_type: Adrenal chromaffin granules experimental_model: Intact bovine chromaffin granules undergoing dopamine beta-hydroxylase turnover with labelled ascorbate limitations: An in vitro demonstration in intact granules. Ascorbate itself does not cross the membrane, which is precisely why a shuttle is required. exposure: Tyramine- or dopamine-stimulated turnover with extragranular ascorbate evidence_span: {"source_cache": "artifacts/cold-research/3949732.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1", "start_char": 0, "end_char": 2000, "text_sha256": "9db1233389aeb375adfd655ea04f39ccb05e22773f367aaa1292bb21698242e1"} [cold-p3949732] Evidence for an ascorbate shuttle for the transfer of reducing equivalents across chromaffin granule membranes. (1986). https://pubmed.ncbi.nlm.nih.gov/3949732/ DOI: 10.1016/s0021-9258(17)35819-2

cross_nutrient

Inorganic phosphate (Pi; protonation depends on pH) (tested_addition); L-Ascorbate (tested_addition); Manganese (measured_nutrient)

evidence_span

{"source_cache": "artifacts/manganese-clinical-sources/davidsson1991.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "7570e2285532eac2292b252a3813f1be97b46d68529a4d4150a88b4f9038676a", "start_char": 0, "end_char": 912, "text_sha256": "7570e2285532eac2292b252a3813f1be97b46d68529a4d4150a88b4f9038676a", "text_characters": 912}

experimental_model

Paired radiotracer test-meal study in adults

exposure

Human milk, infant formula and wheat bread used as adult test meals; individual mineral and dietary-component additions.

limitations

These were adult experiments even when milk or infant formula was the matrix. Added amounts were not independently verified from the indexed abstract; no universal interaction or spacing rule follows.

nutrient_topic

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

organism

Homo sapiens

plain_language

The tested additions had no detectable effect in this formula matrix.

primary_references

[mn-clin-davidsson1991] The effect of individual dietary components on manganese absorption in humans. (1991). https://pubmed.ncbi.nlm.nih.gov/1957822/ DOI: 10.1093/ajcn/54.6.1065

tissue_or_cell_type

Intestinal absorption

Manganese: enzyme cofactors, glycosylation, transport and nutrient interactions (2026-09-17) · lines 1062–1074

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Paired radiotracer test-meal study in adults · source_derived_draft · unverified_draft

### mn-clin-meal-formula-additions Adding phytate, phosphate or ascorbic acid to the formula test meals did not significantly alter manganese absorption in adults. Condition category: normal nutrient_topic: Manganese research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tested additions had no detectable effect in this formula matrix. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Paired radiotracer test-meal study in adults limitations: These were adult experiments even when milk or infant formula was the matrix. Added amounts were not independently verified from the indexed abstract; no universal interaction or spacing rule follows. exposure: Human milk, infant formula and wheat bread used as adult test meals; individual mineral and dietary-component additions. cross_nutrient: Inorganic phosphate (Pi; protonation depends on pH) (tested_addition); L-Ascorbate (tested_addition); Manganese (measured_nutrient) evidence_span: {"source_cache": "artifacts/manganese-clinical-sources/davidsson1991.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "7570e2285532eac2292b252a3813f1be97b46d68529a4d4150a88b4f9038676a", "start_char": 0, "end_char": 912, "text_sha256": "7570e2285532eac2292b252a3813f1be97b46d68529a4d4150a88b4f9038676a", "text_characters": 912} [mn-clin-davidsson1991] The effect of individual dietary components on manganese absorption in humans. (1991). https://pubmed.ncbi.nlm.nih.gov/1957822/ DOI: 10.1093/ajcn/54.6.1065

experimental_model

Recombinant human PLOD3 structural and biochemical assays.

limitations

This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.

organism

Human

plain_language

The collagen enzyme needs an iron-containing catalytic site and reaction partners.

primary_references

[plod3-2018] Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3 (2018). https://www.nature.com/articles/s41467-018-05631-5 DOI: 10.1038/s41467-018-05631-5

tissue_or_cell_type

Not specified as a whole tissue; see experimental model.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 417–425

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human PLOD3 structural and biochemical assays. · source_derived_draft · unverified_draft

### plod3-collagen-hydroxylation PLOD3 hydroxylates peptidyl lysine using Fe(II), 2-oxoglutarate and oxygen. Plain language: The collagen enzyme needs an iron-containing catalytic site and reaction partners. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Recombinant human PLOD3 structural and biochemical assays. limitations: This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [plod3-2018] Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3 (2018). https://www.nature.com/articles/s41467-018-05631-5 DOI: 10.1038/s41467-018-05631-5

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

evidence_span

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experimental_model

Retinaldehyde-liposome photosensitization with cells

exposure

4 micromolar zeaxanthin, 80 micromolar alpha-tocopherol; 0.5–2 mM ascorbate

limitations

Bath concentrations and irradiation are not oral doses or established human safety limits. Combination conditions and localization matter.

nutrient_topic

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

organism

Human ARPE-19 cells and unsaturated liposomes

plain_language

Vitamin C added protection under this condition.

primary_references

[zeaxanthin-p35740030] Is There an Optimal Combination of AREDS2 Antioxidants Zeaxanthin, Vitamin E and Vitamin C on Light-Induced Toxicity of Vitamin A Aldehyde to the Retina? (2022). https://pubmed.ncbi.nlm.nih.gov/35740030/ DOI: 10.3390/antiox11061132

tissue_or_cell_type

RPE injury model

Zeaxanthin: metabolism, signaling and nutrient connections (2026-09-17) · lines 938–949

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retinaldehyde-liposome photosensitization with cells · source_derived_draft · unverified_draft

### zeaxanthin-ascorbate-low Adding 0.5 mM ascorbate to the combination raised viability to approximately 69%. Condition category: normal nutrient_topic: Zeaxanthin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C added protection under this condition. organism: Human ARPE-19 cells and unsaturated liposomes tissue_or_cell_type: RPE injury model experimental_model: Retinaldehyde-liposome photosensitization with cells limitations: Bath concentrations and irradiation are not oral doses or established human safety limits. Combination conditions and localization matter. exposure: 4 micromolar zeaxanthin, 80 micromolar alpha-tocopherol; 0.5–2 mM ascorbate evidence_span: {"source_cache": "artifacts/zeaxanthin-research/35740030.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c66a3183f1b2cc985ad22d5350f53aaeaf65b2519e89ddc13e0460a035903e8", "start_char": 0, "end_char": 1784, "text_sha256": "6c66a3183f1b2cc985ad22d5350f53aaeaf65b2519e89ddc13e0460a035903e8"} [zeaxanthin-p35740030] Is There an Optimal Combination of AREDS2 Antioxidants Zeaxanthin, Vitamin E and Vitamin C on Light-Induced Toxicity of Vitamin A Aldehyde to the Retina? (2022). https://pubmed.ncbi.nlm.nih.gov/35740030/ DOI: 10.3390/antiox11061132

evidence_span

{"source_cache": "artifacts/zeaxanthin-research/22924673.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0acdf0e77d224421d61b41baeefd396ff54e53488a85dee22bfb04b0f827c177", "start_char": 0, "end_char": 1415, "text_sha256": "0acdf0e77d224421d61b41baeefd396ff54e53488a85dee22bfb04b0f827c177"}

experimental_model

Rose-bengal photosensitization with antioxidant combinations

exposure

Visible-light exposures; ascorbate 0.35–1.4 mM with lipophilic antioxidants

limitations

Different photosensitizer and exposure duration from the retinaldehyde study; do not treat this as a universal contradiction or dietary safety threshold.

nutrient_topic

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

organism

Human ARPE-19 cells

plain_language

Protection had limits under a different light challenge.

primary_references

[zeaxanthin-p22924673] Concentration dependence of vitamin C in combinations with vitamin E and zeaxanthin on light-induced toxicity to retinal pigment epithelial cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22924673/ DOI: 10.1111/j.1751-1097.2012.01228.x

tissue_or_cell_type

Cultured RPE model

Zeaxanthin: metabolism, signaling and nutrient connections (2026-09-17) · lines 964–975

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rose-bengal photosensitization with antioxidant combinations · source_derived_draft · unverified_draft

### zeaxanthin-ascorbate-rescue-limit The vitamin E–zeaxanthin combination did not prevent the deleterious high-ascorbate effect in the rose-bengal model. Condition category: normal nutrient_topic: Zeaxanthin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protection had limits under a different light challenge. organism: Human ARPE-19 cells tissue_or_cell_type: Cultured RPE model experimental_model: Rose-bengal photosensitization with antioxidant combinations limitations: Different photosensitizer and exposure duration from the retinaldehyde study; do not treat this as a universal contradiction or dietary safety threshold. exposure: Visible-light exposures; ascorbate 0.35–1.4 mM with lipophilic antioxidants evidence_span: {"source_cache": "artifacts/zeaxanthin-research/22924673.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0acdf0e77d224421d61b41baeefd396ff54e53488a85dee22bfb04b0f827c177", "start_char": 0, "end_char": 1415, "text_sha256": "0acdf0e77d224421d61b41baeefd396ff54e53488a85dee22bfb04b0f827c177"} [zeaxanthin-p22924673] Concentration dependence of vitamin C in combinations with vitamin E and zeaxanthin on light-induced toxicity to retinal pigment epithelial cells. (2012). https://pubmed.ncbi.nlm.nih.gov/22924673/ DOI: 10.1111/j.1751-1097.2012.01228.x

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Sequential peroxide reduction and iron challenge

exposure

Photoperoxidation → GSH/PHGPX → iron-dependent challenge.

limitations

Ascorbate participates in this deliberately pro-oxidizing assay; this is not evidence that normal vitamin C intake damages membranes.

nutrient_topic

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

organism

Human-derived cell-free membranes

plain_language

Removing membrane hydroperoxides prevented an iron-driven burst of further oxidation.

primary_references

[ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

tissue_or_cell_type

Erythrocyte ghosts

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 578–590

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Sequential peroxide reduction and iron challenge · source_derived_draft · unverified_draft

### ver-peroxide-removal-iron-burst GSH/PHGPX pretreatment completely suppressed the subsequent radical-peroxidation burst when photooxidized erythrocyte ghosts were challenged with ascorbate/iron or xanthine/xanthine-oxidase/iron. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing membrane hydroperoxides prevented an iron-driven burst of further oxidation. organism: Human-derived cell-free membranes tissue_or_cell_type: Erythrocyte ghosts experimental_model: Sequential peroxide reduction and iron challenge limitations: Ascorbate participates in this deliberately pro-oxidizing assay; this is not evidence that normal vitamin C intake damages membranes. exposure: Photoperoxidation → GSH/PHGPX → iron-dependent challenge. cross_nutrient: true evidence_location: Primary abstract [ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

evidence_span

{"source_cache": "artifacts/nasunin-research/extract2016.publisher-abstract.txt", "locator": "Primary publisher abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "59f579b08c2eb270f935d58dfb0a751867b624b099b5eea3674abc1bb8ec0115", "start_char": 0, "end_char": 1165, "text_sha256": "59f579b08c2eb270f935d58dfb0a751867b624b099b5eea3674abc1bb8ec0115"}

experimental_model

Purified crystals versus semi-purified extracts in EPR and neutrophil assays

exposure

Chlorogenic-acid-depleted extracts; purified NAS and D3R comparisons

limitations

Mixture composition does not demonstrate pharmacological synergy. Human cells outside the body are not a clinical trial; assays differ from colon-cell ROS experiments.

nutrient_topic

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

organism

Cell-free assays and isolated human neutrophils

plain_language

The extract result cannot be assigned entirely to nasunin.

primary_references

[nasunin-pextract2016] Characterization and antioxidant activity of semi-purified extracts and pure delphinidin-glycosides from eggplant peel ( Solanum melongena L.) (2016). https://www.sciencedirect.com/science/article/abs/pii/S1756464615005368 DOI: 10.1016/j.jff.2015.10.032

tissue_or_cell_type

Radical and luminol-amplified chemiluminescence readouts

Nasunin: identity, redox chemistry and nutrient connections (2026-09-17) · lines 640–651

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified crystals versus semi-purified extracts in EPR and neutrophil assays · source_derived_draft · unverified_draft

### nasunin-mixture-components The authors attributed additional extract activity to constituents including ascorbate and glutathione. Condition category: normal nutrient_topic: Nasunin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The extract result cannot be assigned entirely to nasunin. organism: Cell-free assays and isolated human neutrophils tissue_or_cell_type: Radical and luminol-amplified chemiluminescence readouts experimental_model: Purified crystals versus semi-purified extracts in EPR and neutrophil assays limitations: Mixture composition does not demonstrate pharmacological synergy. Human cells outside the body are not a clinical trial; assays differ from colon-cell ROS experiments. exposure: Chlorogenic-acid-depleted extracts; purified NAS and D3R comparisons evidence_span: {"source_cache": "artifacts/nasunin-research/extract2016.publisher-abstract.txt", "locator": "Primary publisher abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "59f579b08c2eb270f935d58dfb0a751867b624b099b5eea3674abc1bb8ec0115", "start_char": 0, "end_char": 1165, "text_sha256": "59f579b08c2eb270f935d58dfb0a751867b624b099b5eea3674abc1bb8ec0115"} [nasunin-pextract2016] Characterization and antioxidant activity of semi-purified extracts and pure delphinidin-glycosides from eggplant peel ( Solanum melongena L.) (2016). https://www.sciencedirect.com/science/article/abs/pii/S1756464615005368 DOI: 10.1016/j.jff.2015.10.032