Folic acid

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/choline-research/17490963.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "28d18f06c2deb6f384ef2b5e84238b05deb076778619c21ee9682d49e34ae824", "start_char": 0, "end_char": 1758, "text_sha256": "28d18f06c2deb6f384ef2b5e84238b05deb076778619c21ee9682d49e34ae824"}

experimental_model

Controlled depletion/repletion with randomized folic acid supplementation

exposure

550 mg choline/70 kg/day for 10 days, then less than 50 mg/70 kg/day up to 42 days; graded repletion

limitations

Supervised experimental depletion, not a recommended intake protocol. Liver/muscle endpoints and susceptibility differed; one cohort underlies related genetic publications.

nutrient_topic

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

organism

Human

plain_language

Folic acid did not substitute for choline in preventing these liver or muscle endpoints.

primary_references

[choline-p17490963] Sex and menopausal status influence human dietary requirements for the nutrient choline. (2007). https://pubmed.ncbi.nlm.nih.gov/17490963/ DOI: 10.1093/ajcn/85.5.1275

tissue_or_cell_type

57 adults: 26 men, 16 premenopausal and 15 postmenopausal women

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Choline: metabolism, signaling and nutrient connections (2026-09-17) · lines 1023–1034

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled depletion/repletion with randomized folic acid supplementation · source_derived_draft · unverified_draft

### choline-folate-no-organ-rescue Randomized folic acid supplementation at 400 micrograms/day did not alter the response to the choline-depletion diet. Condition category: nutrient_deficiency nutrient_topic: Choline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folic acid did not substitute for choline in preventing these liver or muscle endpoints. organism: Human tissue_or_cell_type: 57 adults: 26 men, 16 premenopausal and 15 postmenopausal women experimental_model: Controlled depletion/repletion with randomized folic acid supplementation limitations: Supervised experimental depletion, not a recommended intake protocol. Liver/muscle endpoints and susceptibility differed; one cohort underlies related genetic publications. exposure: 550 mg choline/70 kg/day for 10 days, then less than 50 mg/70 kg/day up to 42 days; graded repletion evidence_span: {"source_cache": "artifacts/choline-research/17490963.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "28d18f06c2deb6f384ef2b5e84238b05deb076778619c21ee9682d49e34ae824", "start_char": 0, "end_char": 1758, "text_sha256": "28d18f06c2deb6f384ef2b5e84238b05deb076778619c21ee9682d49e34ae824"} [choline-p17490963] Sex and menopausal status influence human dietary requirements for the nutrient choline. (2007). https://pubmed.ncbi.nlm.nih.gov/17490963/ DOI: 10.1093/ajcn/85.5.1275

evidence_span

{"source_cache": "artifacts/creatine-research/26311810.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04", "start_char": 0, "end_char": 2160, "text_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04"}

experimental_model

Twelve-week randomized placebo-controlled trial

exposure

Creatine 3 g/day, folic acid 400 micrograms/day, both, or placebo; analyzed groups 101, 153, 103 and 101 respectively

limitations

Group-average effects and exploratory within-person associations are distinct. No general claim of restored methylation or reduced disease risk.

nutrient_topic

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

organism

Bangladeshi adults

plain_language

Adding creatine did not improve the average homocysteine reduction achieved by folic acid in this trial.

primary_references

[creatine-p26311810] Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. (2015). https://pubmed.ncbi.nlm.nih.gov/26311810/ DOI: 10.3945/jn.115.216739

tissue_or_cell_type

Plasma metabolites

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 750–761

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Twelve-week randomized placebo-controlled trial · source_derived_draft · unverified_draft

### creatine-folate-creatine-hcy Homocysteine fell 23.4% with folic acid alone and 21.0% with creatine plus folic acid; the difference was not significant (P=0.41). Condition category: normal nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding creatine did not improve the average homocysteine reduction achieved by folic acid in this trial. organism: Bangladeshi adults tissue_or_cell_type: Plasma metabolites experimental_model: Twelve-week randomized placebo-controlled trial limitations: Group-average effects and exploratory within-person associations are distinct. No general claim of restored methylation or reduced disease risk. exposure: Creatine 3 g/day, folic acid 400 micrograms/day, both, or placebo; analyzed groups 101, 153, 103 and 101 respectively evidence_span: {"source_cache": "artifacts/creatine-research/26311810.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04", "start_char": 0, "end_char": 2160, "text_sha256": "055a97365d5a6d864e78eafcfa4a73bc8c425e240487580796a443cf8ef33a04"} [creatine-p26311810] Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial. (2015). https://pubmed.ncbi.nlm.nih.gov/26311810/ DOI: 10.3945/jn.115.216739

experimental_model

Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure.

exposure

Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval.

limitations

Participants already had adenomas; not a study of ordinary food folate or primary cancer prevention in everyone.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The supplement did not prevent recurrent adenomas in this trial.

primary_references

[fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1654–1664

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. · source_derived_draft · unverified_draft

### fol-adenoma-recurrence-null At the first surveillance interval, adenoma recurrence was 44.1% with folic acid and 42.4% with placebo (RR 1.04; 95% CI 0.90–1.20). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The supplement did not prevent recurrent adenomas in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. limitations: Participants already had adenomas; not a study of ordinary food folate or primary cancer prevention in everyone. exposure: Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval. [fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351

experimental_model

Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure.

exposure

Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval.

limitations

Secondary endpoint with substantial follow-up attrition and uncertainty; cannot establish that food folate causes cancer or identify the cellular mechanism.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The later follow-up raised a possible adverse signal that must remain visible.

primary_references

[fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1666–1676

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. · source_derived_draft · unverified_draft

### fol-advanced-lesion-later-signal Among 607 participants with a second follow-up, advanced lesions occurred in 11.6% versus 6.9% (RR 1.67; 95% CI 1.00–2.80; P=0.05). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The later follow-up raised a possible adverse signal that must remain visible. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. limitations: Secondary endpoint with substantial follow-up attrition and uncertainty; cannot establish that food folate causes cancer or identify the cellular mechanism. exposure: Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval. [fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351

experimental_model

Prospective nonrandomized community intervention in northern and southern China, 1993–1995.

exposure

400 micrograms/day folic acid alone from premarital examination through first trimester; actual use and adherence recorded.

limitations

Nonrandomized adherence and use can be confounded. Regional effect sizes do not define a universal biological response.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The observed benefit appeared in regions with different starting risks.

primary_references

[fol-berry1999] Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention (1999). https://pubmed.ncbi.nlm.nih.gov/10559448/ DOI: 10.1056/nejm199911113412001

tissue_or_cell_type

Community pregnancy outcomes

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1384–1394

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective nonrandomized community intervention in northern and southern China, 1993–1995. · source_derived_draft · unverified_draft

### fol-china-periconception-ntd Among women registered before the last menstrual period, NTD rates with periconceptional folic acid use versus no use were 1.0 versus 4.8 per 1000 in northern China and 0.6 versus 1.0 per 1000 in southern China; denominators were pregnancies of at least 20 weeks gestation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The observed benefit appeared in regions with different starting risks. organism: Homo sapiens tissue_or_cell_type: Community pregnancy outcomes experimental_model: Prospective nonrandomized community intervention in northern and southern China, 1993–1995. limitations: Nonrandomized adherence and use can be confounded. Regional effect sizes do not define a universal biological response. exposure: 400 micrograms/day folic acid alone from premarital examination through first trimester; actual use and adherence recorded. [fol-berry1999] Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention (1999). https://pubmed.ncbi.nlm.nih.gov/10559448/ DOI: 10.1056/nejm199911113412001

experimental_model

Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype.

exposure

Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years.

limitations

Not a trial in all populations or secondary prevention; no proof of a single homocysteine-mediated mechanism.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Adding folic acid improved the first-stroke endpoint in this particular hypertensive population.

primary_references

[fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1593–1603

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. · source_derived_draft · unverified_draft

### fol-csppt-first-stroke First stroke occurred in 2.7% with enalapril–folic acid versus 3.4% with enalapril alone (HR 0.79; 95% CI 0.68–0.93). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding folic acid improved the first-stroke endpoint in this particular hypertensive population. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. limitations: Not a trial in all populations or secondary prevention; no proof of a single homocysteine-mediated mechanism. exposure: Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years. [fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274

experimental_model

Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype.

exposure

Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years.

limitations

Secondary endpoints, event frequency and confidence intervals matter; null results do not prove identical risks.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The benefit was endpoint-specific, rather than a uniform reduction in every vascular event.

primary_references

[fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1605–1615

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. · source_derived_draft · unverified_draft

### fol-csppt-ischemic-stroke First ischemic stroke was lower with combined treatment (HR 0.76; 95% CI 0.64–0.91); hemorrhagic stroke, MI and all-cause death did not differ significantly. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The benefit was endpoint-specific, rather than a uniform reduction in every vascular event. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. limitations: Secondary endpoints, event frequency and confidence intervals matter; null results do not prove identical risks. exposure: Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years. [fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274

cross_nutrient

Directly records the combined B6/B12/folic-acid exposure.

experimental_model

Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.

exposure

Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.

limitations

Folate, B6 and B12 were administered together; their individual contributions cannot be separated.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The biochemical target changed in the trial.

primary_references

[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1617–1628

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft

### fol-hope2-homocysteine Mean homocysteine fell 2.4 micromol/L with the combined B vitamins and rose 0.8 micromol/L with placebo. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biochemical target changed in the trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Folate, B6 and B12 were administered together; their individual contributions cannot be separated. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. cross_nutrient: Directly records the combined B6/B12/folic-acid exposure. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

experimental_model

Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.

exposure

Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.

limitations

Distinct population, regimen and endpoint from CSPPT; this is an outcome boundary, not a contradiction to a biochemical reaction.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Improving homocysteine did not establish benefit for the primary clinical endpoint.

primary_references

[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1630–1640

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft

### fol-hope2-primary-outcome-null The primary cardiovascular death/MI/stroke composite occurred in 18.8% versus 19.8% (RR 0.95; 95% CI 0.84–1.07), without a significant treatment effect. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Improving homocysteine did not establish benefit for the primary clinical endpoint. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Distinct population, regimen and endpoint from CSPPT; this is an outcome boundary, not a contradiction to a biochemical reaction. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

experimental_model

Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.

exposure

Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.

limitations

Interpret secondary/component findings alongside the trial hierarchy and the reported increase in unstable-angina hospitalizations; not a general cardiovascular protection claim.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

One clinical component improved while the combined primary outcome did not.

primary_references

[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

tissue_or_cell_type

Human blood or whole-person clinical endpoints

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1642–1652

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft

### fol-hope2-stroke-secondary The stroke endpoint was lower with combined vitamins (RR 0.75; 95% CI 0.59–0.97), despite the null primary composite. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: One clinical component improved while the combined primary outcome did not. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Interpret secondary/component findings alongside the trial hierarchy and the reported increase in unstable-angina hospitalizations; not a general cardiovascular protection claim. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately.

exposure

Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei.

limitations

Micronuclei in circulating erythrocytes are strongly affected by splenic clearance; do not apply this assay relation unchanged to everyone.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

A separate marker of chromosome damage also improved.

primary_references

[fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290

tissue_or_cell_type

Human erythrocytes and reticulocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1493–1503

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. · source_derived_draft · unverified_draft

### fol-micronuclei-repletion-response Elevated micronucleus frequencies associated with low folate were reduced following supplementation. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separate marker of chromosome damage also improved. organism: Homo sapiens tissue_or_cell_type: Human erythrocytes and reticulocytes experimental_model: Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. limitations: Micronuclei in circulating erythrocytes are strongly affected by splenic clearance; do not apply this assay relation unchanged to everyone. exposure: Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei. [fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290

cross_nutrient

Cointervention with multiple vitamins and minerals is retained explicitly.

experimental_model

Randomized Hungarian first-occurrence prevention trial; known outcomes in 2104 multivitamin and 2052 trace-element recipients.

exposure

Multivitamin including 0.8 mg folic acid versus trace elements with low vitamin C; at least one month before conception through second missed period or later.

limitations

The randomized comparison cannot assign its entire effect to folic acid alone or demonstrate equivalence of other folate formulations.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The supplement containing folic acid reduced first occurrences, but it also contained other vitamins and minerals.

primary_references

[fol-czeizel1992] Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation (1992). https://pubmed.ncbi.nlm.nih.gov/1307234/ DOI: 10.1056/nejm199212243272602

tissue_or_cell_type

Pregnancy and fetal developmental outcomes

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1371–1382

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized Hungarian first-occurrence prevention trial; known outcomes in 2104 multivitamin and 2052 trace-element recipients. · source_derived_draft · unverified_draft

### fol-ntd-first-occurrence-multivitamin The Hungarian trial observed zero NTDs among 2104 known-outcome multivitamin pregnancies and six among 2052 trace-element pregnancies (P=0.029). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The supplement containing folic acid reduced first occurrences, but it also contained other vitamins and minerals. organism: Homo sapiens tissue_or_cell_type: Pregnancy and fetal developmental outcomes experimental_model: Randomized Hungarian first-occurrence prevention trial; known outcomes in 2104 multivitamin and 2052 trace-element recipients. limitations: The randomized comparison cannot assign its entire effect to folic acid alone or demonstrate equivalence of other folate formulations. exposure: Multivitamin including 0.8 mg folic acid versus trace elements with low vitamin C; at least one month before conception through second missed period or later. cross_nutrient: Cointervention with multiple vitamins and minerals is retained explicitly. [fol-czeizel1992] Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation (1992). https://pubmed.ncbi.nlm.nih.gov/1307234/ DOI: 10.1056/nejm199212243272602

experimental_model

Randomized double-blind factorial trial at 33 centers in seven countries; 1817 women with a previous NTD-affected pregnancy, 1195 informative pregnancies.

exposure

Folic acid 4 mg/day, seven other vitamins, both or neither from randomization to 12 weeks of pregnancy. Historical trial exposure.

limitations

Not every NTD was prevented. Early stopping can inflate an effect estimate; the report also supplied an adjusted estimate. The trial did not isolate a cellular mechanism.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Adding folic acid before and early in pregnancy prevented many recurrences in this high-risk trial.

primary_references

[fol-mrc1991] Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group (1991). https://pubmed.ncbi.nlm.nih.gov/1677062/ DOI: 10.1016/0140-6736(91)90133-A

tissue_or_cell_type

Pregnancy and fetal developmental outcomes

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1359–1369

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind factorial trial at 33 centers in seven countries; 1817 women with a previous NTD-affected pregnancy, 1195 informative pregnancies. · source_derived_draft · unverified_draft

### fol-ntd-recurrence-randomized The MRC trial recorded 6 NTD-affected pregnancies in folic-acid groups and 21 in groups without folic acid: relative risk 0.28 (95% CI 0.12–0.71). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding folic acid before and early in pregnancy prevented many recurrences in this high-risk trial. organism: Homo sapiens tissue_or_cell_type: Pregnancy and fetal developmental outcomes experimental_model: Randomized double-blind factorial trial at 33 centers in seven countries; 1817 women with a previous NTD-affected pregnancy, 1195 informative pregnancies. limitations: Not every NTD was prevented. Early stopping can inflate an effect estimate; the report also supplied an adjusted estimate. The trial did not isolate a cellular mechanism. exposure: Folic acid 4 mg/day, seven other vitamins, both or neither from randomization to 12 weeks of pregnancy. Historical trial exposure. [fol-mrc1991] Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group (1991). https://pubmed.ncbi.nlm.nih.gov/1677062/ DOI: 10.1016/0140-6736(91)90133-A

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.

exposure

Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.

limitations

Historical experimental intakes in eight participants do not establish a universal requirement or treatment regimen.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Different folate-related measurements did not recover identically.

primary_references

[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1433–1443

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft

### fol-repletion-endpoint-difference During repletion, elevated homocysteine decreased with total folate intake 516 but not 286 micrograms/day, while the DNA methylation readout improved across 286–516 micrograms/day. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different folate-related measurements did not recover identically. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: Historical experimental intakes in eight participants do not establish a universal requirement or treatment regimen. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately.

exposure

Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei.

limitations

Before/after study with small subgroups and attrition; not a randomized cancer outcome trial.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Restoring folate was followed by improvement in the DNA-base readout.

primary_references

[fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290

tissue_or_cell_type

Human blood-cell DNA

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1481–1491

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. · source_derived_draft · unverified_draft

### fol-uracil-repletion-response Blood DNA uracil declined after folic-acid supplementation in study completers, including the initially low-folate subgroup. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring folate was followed by improvement in the DNA-base readout. organism: Homo sapiens tissue_or_cell_type: Human blood-cell DNA experimental_model: Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. limitations: Before/after study with small subgroups and attrition; not a randomized cancer outcome trial. exposure: Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei. [fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290

experimental_model

Acute fortified-food/supplement exposure in volunteers

exposure

Acute fortified-food dosing schedules

limitations

Study-specific detectability; not a universal threshold or evidence of toxicity.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Some ingested folic acid circulated unchanged.

primary_references

[kelly1997] Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements (1997). https://pubmed.ncbi.nlm.nih.gov/9174474/ DOI: 10.1093/ajcn/65.6.1790

tissue_or_cell_type

Serum in young and older volunteers

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 411–421

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute fortified-food/supplement exposure in volunteers · source_derived_draft · unverified_draft

### folate-kelly-postprandial-umfa During the tested five-day fortified cereal/bread regimen, unchanged folic acid appeared in serum at 266 micrograms per meal. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some ingested folic acid circulated unchanged. organism: Homo sapiens tissue_or_cell_type: Serum in young and older volunteers experimental_model: Acute fortified-food/supplement exposure in volunteers limitations: Study-specific detectability; not a universal threshold or evidence of toxicity. exposure: Acute fortified-food dosing schedules [kelly1997] Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements (1997). https://pubmed.ncbi.nlm.nih.gov/9174474/ DOI: 10.1093/ajcn/65.6.1790

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Folate repletion modifies choline status.

experimental_model

Metabolic-unit depletion/repletion: 11 men, 10 women.

exposure

2-6 weeks folic-acid repletion

limitations

Not evidence folate replaces dietary choline.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Restoring folate improved the choline markers.

primary_references

[jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712

tissue_or_cell_type

Plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 718–729

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-unit depletion/repletion: 11 men, 10 women. · source_derived_draft · unverified_draft

### folate-methyl-folate-choline-repletion Folate repletion returned depressed plasma choline-status measures to baseline or above in the low-choline feeding studies. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring folate improved the choline markers. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Metabolic-unit depletion/repletion: 11 men, 10 women. limitations: Not evidence folate replaces dietary choline. exposure: 2-6 weeks folic-acid repletion cross_nutrient: Folate repletion modifies choline status. [jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Folate/betaine compensation has limits.

experimental_model

Bhmt-null and wild-type mice; four-week folate feeding.

exposure

0, 2 or 20 mg folate/kg diet

limitations

Mouse four-week experiment, not a human treatment rule.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Mus musculus

plain_language

Extra folate did not restore this missing route.

primary_references

[teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

tissue_or_cell_type

Plasma

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 668–679

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null and wild-type mice; four-week folate feeding. · source_derived_draft · unverified_draft

### folate-methyl-folate-no-hcy-rescue-bhmt Feeding 20 mg folate/kg diet did not ameliorate elevated plasma homocysteine in Bhmt-null mice. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra folate did not restore this missing route. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Bhmt-null and wild-type mice; four-week folate feeding. limitations: Mouse four-week experiment, not a human treatment rule. exposure: 0, 2 or 20 mg folate/kg diet cross_nutrient: Folate/betaine compensation has limits. [teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Bhmt-null and wild-type mice; four-week folate feeding.

exposure

Four-week feeding

limitations

No proof of restored DNA methylation.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Mus musculus

plain_language

SAM improved despite persistent high homocysteine.

primary_references

[teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

tissue_or_cell_type

Liver

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 681–691

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null and wild-type mice; four-week folate feeding. · source_derived_draft · unverified_draft

### folate-methyl-folate-sam-bhmt The 20 mg folate/kg diet increased hepatic SAM in Bhmt-null mice versus 0 and 2 mg/kg diets. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM improved despite persistent high homocysteine. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Bhmt-null and wild-type mice; four-week folate feeding. limitations: No proof of restored DNA methylation. exposure: Four-week feeding [teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Cross-sectional NHANES 2007-2008 serum vitamer measurements

exposure

Cross-sectional fortified-population sampling

limitations

Detection depends on assay sensitivity and sampling; no adverse outcome tested.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

A detectable blood marker is not by itself a harm threshold.

primary_references

[pfeiffer2015] Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults (2015). https://pubmed.ncbi.nlm.nih.gov/25733468/ DOI: 10.3945/jn.114.201210

tissue_or_cell_type

Serum; NHANES 2007-2008

trigger_kind

biomarker_context Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 423–433

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional NHANES 2007-2008 serum vitamer measurements · source_derived_draft · unverified_draft

### folate-nhanes-umfa-detection UMFA above the 0.3 nmol/L detection limit occurred in over 95% of NHANES supplement users and nonusers; fasting status influenced concentrations. Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A detectable blood marker is not by itself a harm threshold. organism: Homo sapiens tissue_or_cell_type: Serum; NHANES 2007-2008 experimental_model: Cross-sectional NHANES 2007-2008 serum vitamer measurements limitations: Detection depends on assay sensitivity and sampling; no adverse outcome tested. exposure: Cross-sectional fortified-population sampling [pfeiffer2015] Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults (2015). https://pubmed.ncbi.nlm.nih.gov/25733468/ DOI: 10.3945/jn.114.201210

experimental_model

Portal/peripheral isotope crossover in six TIPSS patients

exposure

500 nmol oral isotope-labeled folic acid, about 220 micrograms

limitations

The sixth subject had no detectable labeled portal folate at 15 minutes; small liver-disease cohort and shunt-altered peripheral kinetics.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Much folic acid reached the liver unchanged.

primary_references

[patanwala2014] Folic acid handling by the human gut: implications for food fortification and supplementation (2014). https://pubmed.ncbi.nlm.nih.gov/24944062/ DOI: 10.3945/ajcn.113.080507

tissue_or_cell_type

Hepatic portal blood

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 387–397

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Portal/peripheral isotope crossover in six TIPSS patients · source_derived_draft · unverified_draft

### folate-portal-folic-acid-unmodified Fifteen minutes after oral labeled folic acid, 80 ± 12% of portal dose-derived folate remained unchanged in five evaluable TIPSS subjects among six dosed. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Much folic acid reached the liver unchanged. organism: Homo sapiens tissue_or_cell_type: Hepatic portal blood experimental_model: Portal/peripheral isotope crossover in six TIPSS patients limitations: The sixth subject had no detectable labeled portal folate at 15 minutes; small liver-disease cohort and shunt-altered peripheral kinetics. exposure: 500 nmol oral isotope-labeled folic acid, about 220 micrograms [patanwala2014] Folic acid handling by the human gut: implications for food fortification and supplementation (2014). https://pubmed.ncbi.nlm.nih.gov/24944062/ DOI: 10.3945/ajcn.113.080507

experimental_model

Fresh human liver extracts from six donors and rat comparison

exposure

Folic acid substrate with NADPH

limitations

Reaction identity; liver rates cannot define a universal intake ceiling.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Folic acid needs a reduction step before it becomes usable folate.

primary_references

[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

tissue_or_cell_type

Liver enzyme preparations

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 351–361

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft

### folate-dhfr-folic-acid-first-reduction DHFR reduces folic acid to dihydrofolate before further reduction to tetrahydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folic acid needs a reduction step before it becomes usable folate. organism: Homo sapiens tissue_or_cell_type: Liver enzyme preparations experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Reaction identity; liver rates cannot define a universal intake ceiling. exposure: Folic acid substrate with NADPH [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

experimental_model

Fresh human liver extracts from six donors and rat comparison

exposure

Matched ex-vivo activity assay

limitations

Small tissue series; neither whole-body clearance nor harm was measured.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens and Rattus norvegicus comparison

plain_language

Human liver processing was slow and varied between samples.

primary_references

[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

tissue_or_cell_type

Fresh liver extracts

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 375–385

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft

### folate-human-liver-folic-acid-slow-processing Folic-acid reduction per gram of six human livers averaged less than 2% of rat liver activity at physiological pH, with nearly fivefold human variation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human liver processing was slow and varied between samples. organism: Homo sapiens and Rattus norvegicus comparison tissue_or_cell_type: Fresh liver extracts experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Small tissue series; neither whole-body clearance nor harm was measured. exposure: Matched ex-vivo activity assay [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106

cross_nutrient

Folic acid was given to both arms; no biochemical B6–folate synergy established.

experimental_model

Single-blind randomized cointervention in 35 RA patients: 15 control and 20 B6.

exposure

Both groups folic acid 5 mg/day; B6 group also 100 mg/day for 12 weeks. Reported cytokine result is within-group change.

limitations

The accessed abstract reports within-group significance, not a demonstrated between-group change contrast. Plasma concentration differs from cytokine production; no automatic contradiction with 2005.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

A different trial found a cytokine signal under a different exposure and measurement design.

primary_references

[b6-huang2010] Vitamin B(6) supplementation improves pro-inflammatory responses in patients with rheumatoid arthritis (2010). https://pubmed.ncbi.nlm.nih.gov/20571496/ DOI: 10.1038/ejcn.2010.107

tissue_or_cell_type

Human blood and whole-body measurements

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1510–1521

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-blind randomized cointervention in 35 RA patients: 15 control and 20 B6. · source_derived_draft · unverified_draft

### b6-ra-cointervention-cytokine-signal In the 2010 cointervention trial, plasma IL-6 and TNF declined within the B6-plus-folic-acid group over 12 weeks. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A different trial found a cytokine signal under a different exposure and measurement design. organism: Homo sapiens tissue_or_cell_type: Human blood and whole-body measurements experimental_model: Single-blind randomized cointervention in 35 RA patients: 15 control and 20 B6. limitations: The accessed abstract reports within-group significance, not a demonstrated between-group change contrast. Plasma concentration differs from cytokine production; no automatic contradiction with 2005. exposure: Both groups folic acid 5 mg/day; B6 group also 100 mg/day for 12 weeks. Reported cytokine result is within-group change. cross_nutrient: Folic acid was given to both arms; no biochemical B6–folate synergy established. [b6-huang2010] Vitamin B(6) supplementation improves pro-inflammatory responses in patients with rheumatoid arthritis (2010). https://pubmed.ncbi.nlm.nih.gov/20571496/ DOI: 10.1038/ejcn.2010.107

cross_nutrient

SLC19-family relatedness does not establish folate-thiamine competition at SLC19A3.

evidence-scope

HeLa cells

evidence_locator

Abstract

evidence_spans

[{"source_document": "artifacts/thiamine_transport_sources/rajgopal-2001-slc19a3-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1133}]

experimental_model

Transient human SLC19A3 transfection in HeLa cells.

limitations

Tested folic acid; does not exclude every folate species.

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

Related vitamin transporters need not carry the same nutrient.

primary_references

[rajgopal-2001-slc19a3] SLC19A3 encodes a second thiamine transporter ThTr2 (2001). https://pubmed.ncbi.nlm.nih.gov/11731220/ DOI: 10.1016/S0925-4439(01)00073-4

tissue_or_cell_type

HeLa cells

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 178–191

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transient human SLC19A3 transfection in HeLa cells. · source_derived_draft · unverified_draft

### b1-slc19a3-folate-specificity SLC19A3 expression did not enhance folic-acid uptake in the assay that detected increased thiamine uptake. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Related vitamin transporters need not carry the same nutrient. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Transient human SLC19A3 transfection in HeLa cells. limitations: Tested folic acid; does not exclude every folate species. cross_nutrient: SLC19-family relatedness does not establish folate-thiamine competition at SLC19A3. evidence_spans: [{"source_document": "artifacts/thiamine_transport_sources/rajgopal-2001-slc19a3-source-record.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1133}] evidence_locator: Abstract evidence-scope: HeLa cells [rajgopal-2001-slc19a3] SLC19A3 encodes a second thiamine transporter ThTr2 (2001). https://pubmed.ncbi.nlm.nih.gov/11731220/ DOI: 10.1016/S0925-4439(01)00073-4

cross_nutrient

Direct clinical comparison involving B2, vitamin A, iron and folic acid.

experimental_model

366 anemic pregnant women in rural China randomized among four groups for two months; all received iron and folic acid.

exposure

All arms: 60 mg/day iron plus 400 micrograms/day folic acid; added retinol 2000 micrograms/day, riboflavin 1 mg/day, both, or neither. Trial exposures, not recommendations.

limitations

Combination effect cannot be assigned solely to B2 or assumed to be biochemical synergy; anemic pregnant population, multiple co-deficiencies, two-month endpoint.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Homo sapiens

plain_language

Several nutrients were limiting in this population; the combination helped more than iron and folic acid alone.

primary_references

[b2-ma2008] Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking iron and folic Acid supplements (2008). https://pubmed.ncbi.nlm.nih.gov/18806105/ DOI: 10.1093/jn/138.10.1946

tissue_or_cell_type

Human clinical setting

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1604–1615

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 366 anemic pregnant women in rural China randomized among four groups for two months; all received iron and folic acid. · source_derived_draft · unverified_draft

### b2-pregnancy-multiple-nutrients Adding retinol and/or riboflavin to iron-folic-acid treatment reduced anemia prevalence more than iron-folic-acid alone; the combined retinol-riboflavin arm gained 5.4±1.1 g/L more hemoglobin than the reference arm. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several nutrients were limiting in this population; the combination helped more than iron and folic acid alone. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: 366 anemic pregnant women in rural China randomized among four groups for two months; all received iron and folic acid. limitations: Combination effect cannot be assigned solely to B2 or assumed to be biochemical synergy; anemic pregnant population, multiple co-deficiencies, two-month endpoint. exposure: All arms: 60 mg/day iron plus 400 micrograms/day folic acid; added retinol 2000 micrograms/day, riboflavin 1 mg/day, both, or neither. Trial exposures, not recommendations. cross_nutrient: Direct clinical comparison involving B2, vitamin A, iron and folic acid. [b2-ma2008] Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking iron and folic Acid supplements (2008). https://pubmed.ncbi.nlm.nih.gov/18806105/ DOI: 10.1093/jn/138.10.1946

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Separates primary flavin import from secondary folate-pool changes.

evidence_location

Abstract and folate-uptake experiments

experimental_model

Folate uptake in genetically altered isolated mitochondria

exposure

Labeled folic acid or 5-formyltetrahydrofolate in mitochondrial uptake assays.

limitations

Preserved uptake in this model does not fully resolve older human-cDNA complementation results.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Mus musculus

plain_language

The mouse experiments attributed the primary import defect to FAD, with folate uptake preserved.

primary_references

[transport-slc25a32-2022] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC11072207/ DOI: 10.1007/s00018-022-04404-0

tissue_or_cell_type

Muscle and embryonic mitochondria

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 516–528

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Folate uptake in genetically altered isolated mitochondria · source_derived_draft · unverified_draft

### transport-slc25a32-folate-uptake-preserved Slc25a32 mutant and knockout mitochondrial preparations retained folate-substrate uptake in the 2022 mouse study. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The mouse experiments attributed the primary import defect to FAD, with folate uptake preserved. organism: Mus musculus tissue_or_cell_type: Muscle and embryonic mitochondria experimental_model: Folate uptake in genetically altered isolated mitochondria limitations: Preserved uptake in this model does not fully resolve older human-cDNA complementation results. exposure: Labeled folic acid or 5-formyltetrahydrofolate in mitochondrial uptake assays. cross_nutrient: Separates primary flavin import from secondary folate-pool changes. evidence_location: Abstract and folate-uptake experiments [transport-slc25a32-2022] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC11072207/ DOI: 10.1007/s00018-022-04404-0

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency.

exposure

Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks.

limitations

Several tested domains and a short trial; the memory comparison does not prove generalized neurotoxicity.

nutrient_topic

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

organism

Homo sapiens

plain_language

Correcting the biochemical shortage was not a general cognitive enhancer in this trial.

primary_references

[b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1549–1559

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. · source_derived_draft · unverified_draft

### b12-eussen-cognition-boundary No cognitive benefit accompanied B12 alone or B12 plus folic acid over 24 weeks; memory improvement was greater with placebo than B12 alone (P=0.0036). Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Correcting the biochemical shortage was not a general cognitive enhancer in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. limitations: Several tested domains and a short trial; the memory comparison does not prove generalized neurotoxicity. exposure: Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks. [b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Direct combined B12/folic-acid exposure.

experimental_model

Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency.

exposure

Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks.

limitations

The combined group cannot isolate the contribution of folic acid versus B12.

nutrient_topic

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

organism

Homo sapiens

plain_language

The two connected vitamins changed the shared marker.

primary_references

[b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1536–1547

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. · source_derived_draft · unverified_draft

### b12-eussen-folate-homocysteine B12 plus folic acid increased red-cell folate and decreased total homocysteine by 36%; B12 treatment corrected mild biochemical deficiency. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two connected vitamins changed the shared marker. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. limitations: The combined group cannot isolate the contribution of folic acid versus B12. exposure: Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks. cross_nutrient: Direct combined B12/folic-acid exposure. [b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361

evidence_span

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experimental_model

Prospective randomized open-label pregnancy trial

exposure

Myo-inositol plus folic acid versus folic acid alone

limitations

Open-label design and selected risk group; this is neither an inositol-versus-folate comparison nor proof of a nutrient interaction.

nutrient_topic

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

organism

Homo sapiens

plain_language

An early trial suggested benefit in one risk group, with folic acid present in both groups.

primary_references

[ino-p23340885] myo-Inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study. (2013). https://pubmed.ncbi.nlm.nih.gov/23340885/ DOI: 10.2337/dc12-1371

tissue_or_cell_type

Pregnant women with a family history of type 2 diabetes

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1328–1339

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective randomized open-label pregnancy trial · source_derived_draft · unverified_draft

### ino-gdm-2013 The 2013 trial reported gestational diabetes in 6% of the myo-inositol-plus-folic-acid group versus 15.3% with folic acid alone. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: An early trial suggested benefit in one risk group, with folic acid present in both groups. organism: Homo sapiens tissue_or_cell_type: Pregnant women with a family history of type 2 diabetes experimental_model: Prospective randomized open-label pregnancy trial limitations: Open-label design and selected risk group; this is neither an inositol-versus-folate comparison nor proof of a nutrient interaction. exposure: Myo-inositol plus folic acid versus folic acid alone evidence_span: {"source_cache": "artifacts/inositol-research/23340885.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "384eb5d40ed312af297e2ecdd98b1c3f804fda5555db8984de47dc08c3cdf336", "start_char": 0, "end_char": 1685, "text_sha256": "384eb5d40ed312af297e2ecdd98b1c3f804fda5555db8984de47dc08c3cdf336"} [ino-p23340885] myo-Inositol supplementation and onset of gestational diabetes mellitus in pregnant women with a family history of type 2 diabetes: a prospective, randomized, placebo-controlled study. (2013). https://pubmed.ncbi.nlm.nih.gov/23340885/ DOI: 10.2337/dc12-1371

evidence_span

{"source_cache": "artifacts/inositol-research/40920401.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f72221b219fbb1cae0af2c44b123ab1e95c74e0ba9c10f75ed601720b96248a0", "start_char": 0, "end_char": 1949, "text_sha256": "f72221b219fbb1cae0af2c44b123ab1e95c74e0ba9c10f75ed601720b96248a0"}

experimental_model

MYPP double-blind multicenter randomized trial

exposure

Myo-inositol 2 g plus folic acid 0.2 mg twice daily versus matching folic acid control until delivery

limitations

A larger null result for a prespecified composite in PCOS pregnancy; not the same population or endpoint as the 2013 trial. Confidence limits permit benefit or harm of varying sizes.

nutrient_topic

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

organism

Homo sapiens

plain_language

The larger blinded PCOS-pregnancy trial did not demonstrate a reduction in its main complication outcome.

primary_references

[ino-p40920401] Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial. (2025). https://pubmed.ncbi.nlm.nih.gov/40920401/ DOI: 10.1001/jama.2025.13668

tissue_or_cell_type

464 pregnant individuals with PCOS at 13 Dutch hospitals

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1341–1352

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · MYPP double-blind multicenter randomized trial · source_derived_draft · unverified_draft

### ino-gdm-2025 In MYPP, the gestational-diabetes/preeclampsia/preterm-birth composite occurred in 25.0% versus 26.8% (RR 0.93, 95% CI 0.68–1.28; P=0.67). Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The larger blinded PCOS-pregnancy trial did not demonstrate a reduction in its main complication outcome. organism: Homo sapiens tissue_or_cell_type: 464 pregnant individuals with PCOS at 13 Dutch hospitals experimental_model: MYPP double-blind multicenter randomized trial limitations: A larger null result for a prespecified composite in PCOS pregnancy; not the same population or endpoint as the 2013 trial. Confidence limits permit benefit or harm of varying sizes. exposure: Myo-inositol 2 g plus folic acid 0.2 mg twice daily versus matching folic acid control until delivery evidence_span: {"source_cache": "artifacts/inositol-research/40920401.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f72221b219fbb1cae0af2c44b123ab1e95c74e0ba9c10f75ed601720b96248a0", "start_char": 0, "end_char": 1949, "text_sha256": "f72221b219fbb1cae0af2c44b123ab1e95c74e0ba9c10f75ed601720b96248a0"} [ino-p40920401] Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial. (2025). https://pubmed.ncbi.nlm.nih.gov/40920401/ DOI: 10.1001/jama.2025.13668

evidence_span

{"source_cache": "artifacts/inositol-research/26847388.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7617d160ca71553f41ce2a7346478950ed9580a4bc9cca9688d3b710ec0cf82", "start_char": 0, "end_char": 1680, "text_sha256": "a7617d160ca71553f41ce2a7346478950ed9580a4bc9cca9688d3b710ec0cf82"}

experimental_model

PONTI double-blind randomized pilot with separately described nonrandomized pregnancies

exposure

Periconceptional inositol plus folic acid versus folic acid plus placebo

limitations

47 women randomized; only 33 randomized pregnancies. The pilot was not powered to establish prevention. Corrigendum PMID 26917444 corrects the separate nonrandomized pregnancy count from 22 to 24; randomized counts used here are unchanged. Nonrandomized outcomes must not be pooled as randomized evidence.

nutrient_topic

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

organism

Homo sapiens

plain_language

The pilot supported further study but was far too small to establish efficacy or replace folic acid.

primary_references

[ino-p26847388] Inositol for the prevention of neural tube defects: a pilot randomised controlled trial. (2016). https://pubmed.ncbi.nlm.nih.gov/26847388/ DOI: 10.1017/s0007114515005322

tissue_or_cell_type

Women with a prior neural-tube-defect pregnancy

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1406–1417

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · PONTI double-blind randomized pilot with separately described nonrandomized pregnancies · source_derived_draft · unverified_draft

### ino-ponti Among randomized PONTI pregnancies, NTD recurrence occurred in 0/14 with inositol plus folic acid versus 1/19 with placebo plus folic acid. Condition category: normal nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The pilot supported further study but was far too small to establish efficacy or replace folic acid. organism: Homo sapiens tissue_or_cell_type: Women with a prior neural-tube-defect pregnancy experimental_model: PONTI double-blind randomized pilot with separately described nonrandomized pregnancies limitations: 47 women randomized; only 33 randomized pregnancies. The pilot was not powered to establish prevention. Corrigendum PMID 26917444 corrects the separate nonrandomized pregnancy count from 22 to 24; randomized counts used here are unchanged. Nonrandomized outcomes must not be pooled as randomized evidence. exposure: Periconceptional inositol plus folic acid versus folic acid plus placebo evidence_span: {"source_cache": "artifacts/inositol-research/26847388.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a7617d160ca71553f41ce2a7346478950ed9580a4bc9cca9688d3b710ec0cf82", "start_char": 0, "end_char": 1680, "text_sha256": "a7617d160ca71553f41ce2a7346478950ed9580a4bc9cca9688d3b710ec0cf82"} [ino-p26847388] Inositol for the prevention of neural tube defects: a pilot randomised controlled trial. (2016). https://pubmed.ncbi.nlm.nih.gov/26847388/ DOI: 10.1017/s0007114515005322

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Children with FOLR1 variants and patient fibroblasts

exposure

Retroviral wild-type FOLR1 expression; 5 nM radioligand

limitations

Receptor binding assay, not transcytosis.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Replacing the missing receptor restored cellular binding.

primary_references

[steinfeld2009] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19732866/ DOI: 10.1016/j.ajhg.2009.08.005

tissue_or_cell_type

Patient fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 243–253

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Children with FOLR1 variants and patient fibroblasts · source_derived_draft · unverified_draft

### folate-folr1-fibroblast-binding-rescue Introducing wild-type human FOLR1 restored specific surface folate binding in fibroblasts from the nonsense-variant patient. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Replacing the missing receptor restored cellular binding. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: Children with FOLR1 variants and patient fibroblasts limitations: Receptor binding assay, not transcytosis. exposure: Retroviral wild-type FOLR1 expression; 5 nM radioligand [steinfeld2009] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19732866/ DOI: 10.1016/j.ajhg.2009.08.005

experimental_model

Human transporter expression, electrophysiology and affected family

exposure

Folate substrates across pH conditions

limitations

Expression-system kinetics are not whole-intestine absorption fractions.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Human transporter in cellular/oocyte expression systems

plain_language

PCFT uses acidic conditions to help folate enter cells.

primary_references

[qiu2006] Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption (2006). https://pubmed.ncbi.nlm.nih.gov/17129779/ DOI: 10.1016/j.cell.2006.09.041

tissue_or_cell_type

Membrane transport models

transport_effect

raises Recorded as high-affinity proton-coupled folate uptake.

transport_pool

the expressing cell Recorded as high-affinity proton-coupled folate uptake.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 131–141

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human transporter expression, electrophysiology and affected family · source_derived_draft · unverified_draft

### folate-pcft-proton-coupled-entry Expression of human PCFT produced high-affinity, proton-coupled folate uptake with enhanced activity at acidic pH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: PCFT uses acidic conditions to help folate enter cells. organism: Human transporter in cellular/oocyte expression systems tissue_or_cell_type: Membrane transport models experimental_model: Human transporter expression, electrophysiology and affected family limitations: Expression-system kinetics are not whole-intestine absorption fractions. exposure: Folate substrates across pH conditions [qiu2006] Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption (2006). https://pubmed.ncbi.nlm.nih.gov/17129779/ DOI: 10.1016/j.cell.2006.09.041