Nutrient chapter

Vitamin A

Vitamin A is a family of nutrient activities involved in vision, gene regulation and tissue function. Retinol, retinal isomers, retinoic acid, retinyl esters and provitamin carotenoids have separate records because they perform different roles.

197 recorded mechanisms · 46 availability situations · 4 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

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

Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid.
Cytochrome P450 26B1 / CYP26B1 → 4-Hydroxy-all-trans-retinoic acid source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays.
exposure
Substrate series with NADPH and P450 reductase.
limitations
Lower in vitro turnover than CYP26A1 does not mean lower importance in every tissue.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein in insect cells
outcome
Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid.
plain_language
A second independent P450 enzyme also removes the signaling precursor.
primary_references
[va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007
tissue_or_cell_type
Reconstituted enzyme/microsomes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 616–628
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. · source_derived_draft · unverified_draft
### va-cyp26b1-primary-hydroxylation Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second independent P450 enzyme also removes the signaling precursor. organism: Homo sapiens recombinant protein in insect cells tissue_or_cell_type: Reconstituted enzyme/microsomes experimental_model: Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. limitations: Lower in vitro turnover than CYP26A1 does not mean lower importance in every tissue. exposure: Substrate series with NADPH and P450 reductase. outcome: Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid. evidence_location: Abstract [va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007
Complete structured claim and evidence
Lrat-null mice retained only trace hepatic retinyl esters.
Lecithin:retinol acyltransferase / LRAT → Hepatic retinyl ester storage source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Abstract
experimental_model
Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet.
exposure
Lrat deletion on a retinoid-sufficient control diet.
limitations
Adipose stores were preserved or increased; deficiency is not uniform across tissues.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Lrat-null mice retained only trace hepatic retinyl esters.
plain_language
Loss of LRAT removes most liver vitamin A storage.
primary_references
[va-obyrne-2005] Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT) (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC1352312/ DOI: 10.1074/jbc.M507924200
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 332–344
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet. · source_derived_draft · unverified_draft
### va-lrat-loss-stores Lrat-null mice retained only trace hepatic retinyl esters. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of LRAT removes most liver vitamin A storage. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet. limitations: Adipose stores were preserved or increased; deficiency is not uniform across tissues. exposure: Lrat deletion on a retinoid-sufficient control diet. outcome: Lrat-null mice retained only trace hepatic retinyl esters. evidence_location: Abstract [va-obyrne-2005] Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT) (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC1352312/ DOI: 10.1074/jbc.M507924200
Complete structured claim and evidence
Recombinant RPE65 catalyzed conversion of all-trans-retinyl esters to 11-cis-retinol in visual-cycle reconstitution.
RPE65 retinoid isomerohydrolase → 11-cis-retinol source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant enzyme reconstitution
limitations
Production of the aldehyde requires a subsequent oxidation step.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
QBI-293A human cells and COS-1 monkey cells
plain_language
RPE65 converts the ester pool into the cis alcohol needed for chromophore renewal.
primary_references
[moiseyev-2005] RPE65 is the isomerohydrolase in the retinoid visual cycle (2005). https://pubmed.ncbi.nlm.nih.gov/16116091/ DOI: 10.1073/pnas.0503460102
tissue_or_cell_type
RPE visual-cycle biochemical model
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 666–675
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme reconstitution · source_derived_draft · unverified_draft
### a-vision-rpe65-isomerization Recombinant RPE65 catalyzed conversion of all-trans-retinyl esters to 11-cis-retinol in visual-cycle reconstitution. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RPE65 converts the ester pool into the cis alcohol needed for chromophore renewal. organism: QBI-293A human cells and COS-1 monkey cells tissue_or_cell_type: RPE visual-cycle biochemical model experimental_model: Recombinant enzyme reconstitution limitations: Production of the aldehyde requires a subsequent oxidation step. [moiseyev-2005] RPE65 is the isomerohydrolase in the retinoid visual cycle (2005). https://pubmed.ncbi.nlm.nih.gov/16116091/ DOI: 10.1073/pnas.0503460102
Complete structured claim and evidence
FeSO4 restored chelator-inhibited RPE65 isomerohydrolase activity in bovine microsomes and recombinant assays; ferric salts did not.
Ferrous iron → RPE65 retinoid isomerohydrolase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Iron availability at RPE65 enables formation of the cis-retinoid visual-cycle intermediate.
experimental_model
Chelation and metal rescue
limitations
This is enzyme-cofactor evidence, not a human iron-deficiency threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus; recombinant RPE65 in human 293A cells
plain_language
Ferrous iron is required for this vitamin A recycling enzyme.
primary_references
[moiseyev-2006] RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle (2006). https://pubmed.ncbi.nlm.nih.gov/16319067/ DOI: 10.1074/jbc.M508903200
tissue_or_cell_type
RPE microsomes and cultured-cell preparations
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 677–687
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chelation and metal rescue · source_derived_draft · unverified_draft
### a-vision-rpe65-iron FeSO4 restored chelator-inhibited RPE65 isomerohydrolase activity in bovine microsomes and recombinant assays; ferric salts did not. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Ferrous iron is required for this vitamin A recycling enzyme. organism: Bos taurus; recombinant RPE65 in human 293A cells tissue_or_cell_type: RPE microsomes and cultured-cell preparations experimental_model: Chelation and metal rescue limitations: This is enzyme-cofactor evidence, not a human iron-deficiency threshold. cross_nutrient: Iron availability at RPE65 enables formation of the cis-retinoid visual-cycle intermediate. [moiseyev-2006] RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle (2006). https://pubmed.ncbi.nlm.nih.gov/16319067/ DOI: 10.1074/jbc.M508903200
Complete structured claim and evidence
Bovine RDH5 expressed in COS cells oxidized 11-cis-retinol using NAD+; NADP did not support the tested activity.
11-cis-retinol dehydrogenase / RDH5 → 11-cis-retinal source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant p32/RDH5 activity assay
limitations
Cofactor specificity is biochemical; no niacin-deficiency phenotype was tested.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus protein; COS cells
plain_language
RDH5 oxidizes the cis alcohol into the visual chromophore.
primary_references
[simon-1995] The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases (1995). https://pubmed.ncbi.nlm.nih.gov/7836368/ DOI: 10.1074/jbc.270.3.1107
tissue_or_cell_type
RPE-derived enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 723–732
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant p32/RDH5 activity assay · source_derived_draft · unverified_draft
### a-vision-rdh5-oxidation Bovine RDH5 expressed in COS cells oxidized 11-cis-retinol using NAD+; NADP did not support the tested activity. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RDH5 oxidizes the cis alcohol into the visual chromophore. organism: Bos taurus protein; COS cells tissue_or_cell_type: RPE-derived enzyme experimental_model: Recombinant p32/RDH5 activity assay limitations: Cofactor specificity is biochemical; no niacin-deficiency phenotype was tested. [simon-1995] The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases (1995). https://pubmed.ncbi.nlm.nih.gov/7836368/ DOI: 10.1074/jbc.270.3.1107
Complete structured claim and evidence
Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays.
Retinol dehydrogenase 10 / RDH10 → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
NAD-dependent retinol oxidation connects vitamin A metabolism to nicotinamide redox-cofactor availability.
evidence_location
Results: cofactor preference
experimental_model
Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells.
exposure
1 micromolar retinol and 1 millimolar NAD+ versus NADP+.
limitations
Cofactor specificity does not establish an effect of dietary niacin deficiency.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens protein in Spodoptera frugiperda Sf9 cells
outcome
Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays.
plain_language
RDH10 uses the oxidized nicotinamide cofactor to make retinal.
primary_references
[va-belyaeva-2008] Kinetic Analysis of Human Enzyme RDH10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2459273/ DOI: 10.1074/jbc.M800019200
tissue_or_cell_type
Microsomes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 487–500
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells. · source_derived_draft · unverified_draft
### va-rdh10-retinol-oxidation Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RDH10 uses the oxidized nicotinamide cofactor to make retinal. organism: Homo sapiens protein in Spodoptera frugiperda Sf9 cells tissue_or_cell_type: Microsomes experimental_model: Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells. limitations: Cofactor specificity does not establish an effect of dietary niacin deficiency. exposure: 1 micromolar retinol and 1 millimolar NAD+ versus NADP+. outcome: Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays. evidence_location: Results: cofactor preference cross_nutrient: NAD-dependent retinol oxidation connects vitamin A metabolism to nicotinamide redox-cofactor availability. [va-belyaeva-2008] Kinetic Analysis of Human Enzyme RDH10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2459273/ DOI: 10.1074/jbc.M800019200
Complete structured claim and evidence
Müller-cell-directed CRALBP restoration in Rlbp1-null/Gnat1-null mice improved cone recovery in the isolated-retina paradigm.
Cellular retinaldehyde-binding protein / CRALBP → Cone dark adaptation source_derived_draftungraded
Experimental context and source evidence
experimental_model
Cell-directed AAV rescue; ex vivo cone ERG
intervention
AAV protein restoration in genetic knockout
limitations
Rescue from global deletion is not equivalent to deleting only Müller CRALBP in an intact eye.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Müller-cell CRALBP can support a retinal route for cone pigment renewal.
primary_references
[xue-2015] CRALBP supports the mammalian retinal visual cycle and cone vision (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4319437/ DOI: 10.1172/JCI79651
tissue_or_cell_type
Müller glia and cone retina
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 882–892
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-directed AAV rescue; ex vivo cone ERG · source_derived_draft · unverified_draft
### a-vision-muller-cralbp-cones Müller-cell-directed CRALBP restoration in Rlbp1-null/Gnat1-null mice improved cone recovery in the isolated-retina paradigm. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Müller-cell CRALBP can support a retinal route for cone pigment renewal. organism: Mus musculus tissue_or_cell_type: Müller glia and cone retina experimental_model: Cell-directed AAV rescue; ex vivo cone ERG limitations: Rescue from global deletion is not equivalent to deleting only Müller CRALBP in an intact eye. intervention: AAV protein restoration in genetic knockout [xue-2015] CRALBP supports the mammalian retinal visual cycle and cone vision (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4319437/ DOI: 10.1172/JCI79651
Complete structured claim and evidence
RPE-selective CRALBP deletion slowed bulk visual chromophore regeneration approximately 15-fold in mice.
RPE-selective CRALBP loss → 11-cis-retinal regeneration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Timed RPE-selective knockout; post-bleach HPLC
limitations
Bulk recovery mainly reflects rods; not a direct human effect size.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RPE CRALBP strongly supports replenishment of cis retinal.
primary_references
[bassetto-2024] Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors (2024). https://pubmed.ncbi.nlm.nih.gov/38676924/ DOI: 10.1016/j.celrep.2024.114143
tissue_or_cell_type
RPE/whole-eye retinoids
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 860–869
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Timed RPE-selective knockout; post-bleach HPLC · source_derived_draft · unverified_draft
### a-vision-rpe-cralbp-chromophore RPE-selective CRALBP deletion slowed bulk visual chromophore regeneration approximately 15-fold in mice. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RPE CRALBP strongly supports replenishment of cis retinal. organism: Mus musculus tissue_or_cell_type: RPE/whole-eye retinoids experimental_model: Timed RPE-selective knockout; post-bleach HPLC limitations: Bulk recovery mainly reflects rods; not a direct human effect size. [bassetto-2024] Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors (2024). https://pubmed.ncbi.nlm.nih.gov/38676924/ DOI: 10.1016/j.celrep.2024.114143
Complete structured claim and evidence
Retinol supplementation increased Tet2 transcription in mouse naïve ESCs within 8 h and after 72 h; Tet3 also responded, whereas evidence did not support direct retinol stimulation of TET catalytic efficiency.
All-trans-retinol → Mouse Tet2 gene source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 3A–C
experimental_model
Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification
exposure
Retinol titration 0–50 ng/mL; 8-h and 72-h transcript assays.
limitations
Retinoid signaling and response depend on culture context; no claim that vitamin A supplementation demethylates adult human tissues.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin A raised expression of DNA-modifying enzymes through a different route from vitamin C’s iron-redox effect.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Naïve embryonic stem cells
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1047–1059
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification · source_derived_draft · unverified_draft
### c-reg-retinol-tet2-expression Retinol supplementation increased Tet2 transcription in mouse naïve ESCs within 8 h and after 72 h; Tet3 also responded, whereas evidence did not support direct retinol stimulation of TET catalytic efficiency. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A raised expression of DNA-modifying enzymes through a different route from vitamin C’s iron-redox effect. organism: Mus musculus tissue_or_cell_type: Naïve embryonic stem cells experimental_model: Mouse naïve ESCs in vitamin-A-free N2B27/2i medium; transcript quantification limitations: Retinoid signaling and response depend on culture context; no claim that vitamin A supplementation demethylates adult human tissues. exposure: Retinol titration 0–50 ng/mL; 8-h and 72-h transcript assays. cross_nutrient: true evidence_location: Figure 3A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Deleting a 104-bp intronic segment encompassing the mouse Tet2 retinoic-acid response element prevented the normal retinol-dependent Tet2 mRNA increase, supporting a cis-regulatory requirement.
Mouse Tet2 gene → Mouse Tet2 gene source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Figure 3E–F
experimental_model
CRISPR Tet2 ΔRARE naïve ESCs compared with wild type
exposure
Retinol titration as in Figure 3F; 104-bp deletion NCBI37 chr3:133197151–133197253.
limitations
Deletion tests the segment rather than one isolated nucleotide; this is engineered machinery impairment, not vitamin A deficiency.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
The vitamin A response depended on a specific DNA control sequence in the Tet2 gene.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Naïve embryonic stem cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1061–1073
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CRISPR Tet2 ΔRARE naïve ESCs compared with wild type · source_derived_draft · unverified_draft
### c-reg-tet2-rare-deletion Deleting a 104-bp intronic segment encompassing the mouse Tet2 retinoic-acid response element prevented the normal retinol-dependent Tet2 mRNA increase, supporting a cis-regulatory requirement. Condition category: machinery_impairment nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: The vitamin A response depended on a specific DNA control sequence in the Tet2 gene. organism: Mus musculus tissue_or_cell_type: Naïve embryonic stem cells experimental_model: CRISPR Tet2 ΔRARE naïve ESCs compared with wild type limitations: Deletion tests the segment rather than one isolated nucleotide; this is engineered machinery impairment, not vitamin A deficiency. exposure: Retinol titration as in Figure 3F; 104-bp deletion NCBI37 chr3:133197151–133197253. cross_nutrient: true evidence_location: Figure 3E–F [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Ascorbate co-treatment increased Oct4:GFP-positive colony formation during KLF4-driven mouse EpiSC reprogramming and shifted the optimum toward lower retinol concentration; higher retinol suppressed colony formation rather than improving it indefinitely.
L-Ascorbate → Reprogramming to induced pluripotency source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Figure 4A–C
experimental_model
KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts
exposure
50 µg/mL ascorbate with 0–50 ng/mL retinol; day-6 colony endpoint; combined optimum reported near 3.13 ng/mL retinol.
limitations
Reprogramming reporter assay, not demonstrated tissue rejuvenation or therapy; relationship to DNA modification is supported by complementary experiments, not sole-cause proof.
nutrient_topic
Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C
organism
Mus musculus
plain_language
Vitamin A and C worked together in this stem-cell culture protocol, but more vitamin A was not always better.
primary_references
[c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
tissue_or_cell_type
Epiblast stem-cell culture
Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1075–1087
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts · source_derived_draft · unverified_draft
### c-reg-retinol-ascorbate-reprogramming Ascorbate co-treatment increased Oct4:GFP-positive colony formation during KLF4-driven mouse EpiSC reprogramming and shifted the optimum toward lower retinol concentration; higher retinol suppressed colony formation rather than improving it indefinitely. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A and C worked together in this stem-cell culture protocol, but more vitamin A was not always better. organism: Mus musculus tissue_or_cell_type: Epiblast stem-cell culture experimental_model: KLF4-expressing OEC-2 mouse EpiSCs switched to vitamin-A-free 2i/LIF; Oct4:GFP colony counts limitations: Reprogramming reporter assay, not demonstrated tissue rejuvenation or therapy; relationship to DNA modification is supported by complementary experiments, not sole-cause proof. exposure: 50 µg/mL ascorbate with 0–50 ng/mL retinol; day-6 colony endpoint; combined optimum reported near 3.13 ng/mL retinol. cross_nutrient: true evidence_location: Figure 4A–C [c-reg-hore] Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms. (2016). https://pubmed.ncbi.nlm.nih.gov/27729528/ DOI: 10.1073/pnas.1608679113
Complete structured claim and evidence
Sequencing the TET2 coding region in 320 patients found somatic deletions or mutations in 19% of myelodysplastic syndromes (15 of 81), 12% of myeloproliferative disorders (24 of 198), 24% of secondary acute myeloid leukaemia (5 of 21) and 22% of chronic myelomonocytic leukaemia (2 of 9).
Human TET2 → TET2 mutation frequency across human myeloid neoplasms source_derived_draftungraded
Experimental context and source evidence
duration
Cross-sectional
experimental_model
320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses
exposure
No intervention; observational sequencing of patient material
limitations
A mutation frequency is an association, not a demonstration that TET2 loss caused any of these cancers. Ascertainment was partly enriched: six patients were selected for 4q24 rearrangements and five for a JAK2 V617F-positive dominant clone.
organism
Homo sapiens
plain_language
About one in seven patients with these blood cancers carried a damaged copy of TET2.
primary_references
[delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
tissue
Haematopoietic cells and bone marrow
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 13–21
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · 320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses · source_derived_draft · unverified_draft
## tet2-mutated-across-myeloid-neoplasms Sequencing the TET2 coding region in 320 patients found somatic deletions or mutations in 19% of myelodysplastic syndromes (15 of 81), 12% of myeloproliferative disorders (24 of 198), 24% of secondary acute myeloid leukaemia (5 of 21) and 22% of chronic myelomonocytic leukaemia (2 of 9). Model/species: 320 patients with myeloid cancers; molecular, cytogenetic, comparative-genomic-hybridization and SNP analyses Organism: Homo sapiens Tissue/system: Haematopoietic cells and bone marrow Exposure: No intervention; observational sequencing of patient material Duration: Cross-sectional Limits: A mutation frequency is an association, not a demonstration that TET2 loss caused any of these cancers. Ascertainment was partly enriched: six patients were selected for 4q24 rearrangements and five for a JAK2 V617F-positive dominant clone. Primary reference: [delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
Complete structured claim and evidence
TET2 defects were present in haematopoietic stem cells and preceded the JAK2 V617F mutation in the five analysed samples from patients with myeloproliferative disorders.
Human TET2 → Order of TET2 and JAK2 V617F acquisition in human myeloproliferative clones source_derived_draftungraded
Experimental context and source evidence
duration
Cross-sectional
experimental_model
Five myeloproliferative-disorder patient samples with clonal analysis of progenitors
exposure
No intervention; clonal ordering within patient samples
limitations
Five samples. Order of acquisition in a clone does not by itself establish which lesion drives the disease.
organism
Homo sapiens
plain_language
Where both were present, the TET2 damage came first.
primary_references
[delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
tissue
Haematopoietic stem and progenitor cells
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 23–31
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Five myeloproliferative-disorder patient samples with clonal analysis of progenitors · source_derived_draft · unverified_draft
## tet2-defect-precedes-jak2-v617f TET2 defects were present in haematopoietic stem cells and preceded the JAK2 V617F mutation in the five analysed samples from patients with myeloproliferative disorders. Model/species: Five myeloproliferative-disorder patient samples with clonal analysis of progenitors Organism: Homo sapiens Tissue/system: Haematopoietic stem and progenitor cells Exposure: No intervention; clonal ordering within patient samples Duration: Cross-sectional Limits: Five samples. Order of acquisition in a clone does not by itself establish which lesion drives the disease. Primary reference: [delhommeau-2009] Mutation in TET2 in myeloid cancers (2009). https://pubmed.ncbi.nlm.nih.gov/19474426/ DOI: 10.1056/nejmoa0810069
Complete structured claim and evidence
Bone marrow from patients carrying TET2 mutations showed uniformly low 5-hydroxymethylcytosine in genomic DNA compared with bone marrow from healthy controls, and the mutations compromised catalytic activity in the same study.
Human TET2 → Bone-marrow genomic 5-hydroxymethylcytosine content source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Cross-sectional
experimental_model
Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein
exposure
No intervention; naturally occurring mutations
limitations
Samples with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites, so the downstream methylation consequence is not a simple global gain.
organism
Homo sapiens
plain_language
Patients with a damaged TET2 had less of the chemical mark the enzyme makes.
primary_references
[ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
tissue
Bone marrow genomic DNA
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 33–41
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein · source_derived_draft · unverified_draft
## tet2-mutation-lowers-marrow-5hmc Bone marrow from patients carrying TET2 mutations showed uniformly low 5-hydroxymethylcytosine in genomic DNA compared with bone marrow from healthy controls, and the mutations compromised catalytic activity in the same study. Model/species: Patient bone-marrow samples with and without TET2 mutations; catalytic assays of mutant protein Organism: Homo sapiens Tissue/system: Bone marrow genomic DNA Exposure: No intervention; naturally occurring mutations Duration: Cross-sectional Limits: Samples with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites, so the downstream methylation consequence is not a simple global gain. Primary reference: [ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
Complete structured claim and evidence
Short-hairpin-RNA depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte and macrophage lineages in culture.
Mouse Tet2 → Monocyte and macrophage lineage skewing of mouse haematopoietic precursors source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Culture experiment
experimental_model
Mouse haematopoietic precursors with shRNA knockdown, in culture
exposure
shRNA-mediated Tet2 depletion
limitations
A culture differentiation bias is not leukaemia, and knockdown is not the patient mutation.
organism
Mus musculus
plain_language
Removing Tet2 pushed young blood cells toward one lineage.
primary_references
[ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
tissue
Cultured haematopoietic precursors
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 43–51
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Mouse haematopoietic precursors with shRNA knockdown, in culture · source_derived_draft · unverified_draft
## tet2-depletion-skews-mouse-precursors Short-hairpin-RNA depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte and macrophage lineages in culture. Model/species: Mouse haematopoietic precursors with shRNA knockdown, in culture Organism: Mus musculus Tissue/system: Cultured haematopoietic precursors Exposure: shRNA-mediated Tet2 depletion Duration: Culture experiment Limits: A culture differentiation bias is not leukaemia, and knockdown is not the patient mutation. Primary reference: [ko-2010] Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 (2010). https://pubmed.ncbi.nlm.nih.gov/21057493/ DOI: 10.1038/nature09586
Complete structured claim and evidence
Conditional deletion of Tet2 in the mouse haematopoietic compartment increased stem-cell self-renewal in competitive transplant assays, and Tet2 heterozygous mice also showed increased self-renewal and extramedullary haematopoiesis.
Mouse Tet2 → Mouse haematopoietic stem and progenitor cell self-renewal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
In vivo, to the development of disease
experimental_model
Conditional Tet2-knockout mice; competitive transplantation
exposure
Conditional genetic deletion of Tet2; homozygous and heterozygous
limitations
Haploinsufficiency means one damaged copy already changes the phenotype; this is a genetic model, not a nutritional one.
organism
Mus musculus
plain_language
Losing Tet2 made blood stem cells renew themselves more than they should.
primary_references
[moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
tissue
Haematopoietic stem cell compartment
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 53–61
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Conditional Tet2-knockout mice; competitive transplantation · source_derived_draft · unverified_draft
## tet2-loss-increases-hspc-self-renewal Conditional deletion of Tet2 in the mouse haematopoietic compartment increased stem-cell self-renewal in competitive transplant assays, and Tet2 heterozygous mice also showed increased self-renewal and extramedullary haematopoiesis. Model/species: Conditional Tet2-knockout mice; competitive transplantation Organism: Mus musculus Tissue/system: Haematopoietic stem cell compartment Exposure: Conditional genetic deletion of Tet2; homozygous and heterozygous Duration: In vivo, to the development of disease Limits: Haploinsufficiency means one damaged copy already changes the phenotype; this is a genetic model, not a nutritional one. Primary reference: [moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
Complete structured claim and evidence
Conditional Tet2 loss produced progressive enlargement of the haematopoietic stem-cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis and extramedullary haematopoiesis.
Mouse Tet2 → Myeloproliferation in mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Progressive, in vivo
experimental_model
Conditional Tet2-knockout mice followed in vivo
exposure
Conditional genetic deletion of Tet2
limitations
Myeloproliferation in a conditional knockout mouse is not the same entity as a human myelodysplastic syndrome, and this model deletes the gene rather than reproducing a point mutation.
organism
Mus musculus
plain_language
Mice without Tet2 went on to develop a blood disorder of overgrowth.
primary_references
[moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
tissue
Bone marrow, spleen and peripheral blood
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 63–71
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Conditional Tet2-knockout mice followed in vivo · source_derived_draft · unverified_draft
## tet2-loss-causes-myeloproliferation Conditional Tet2 loss produced progressive enlargement of the haematopoietic stem-cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis and extramedullary haematopoiesis. Model/species: Conditional Tet2-knockout mice followed in vivo Organism: Mus musculus Tissue/system: Bone marrow, spleen and peripheral blood Exposure: Conditional genetic deletion of Tet2 Duration: Progressive, in vivo Limits: Myeloproliferation in a conditional knockout mouse is not the same entity as a human myelodysplastic syndrome, and this model deletes the gene rather than reproducing a point mutation. Primary reference: [moran-crusio-2011] Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation (2011). https://pubmed.ncbi.nlm.nih.gov/21723200/ DOI: 10.1016/j.ccr.2011.06.001
Complete structured claim and evidence
Inactivating Tet2 in mouse perturbed both early and late haematopoiesis in a cell-autonomous manner, gave the cells a competitive advantage, and eventually led to the development of haematological malignancies.
Mouse Tet2 → Haematological malignancy in mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
In vivo, to malignancy
experimental_model
Tet2-inactivated mice; competitive repopulation
exposure
Genetic inactivation of Tet2
limitations
A different group from the conditional-knockout study above, but the same group as the 2009 human mutation survey in this collection, so that survey and this mouse model are one line of evidence rather than two.
organism
Mus musculus
plain_language
A second group's mice also developed blood cancers after Tet2 was switched off.
primary_references
[quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
tissue
Myeloid and lymphoid compartments
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 73–81
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet2-inactivated mice; competitive repopulation · source_derived_draft · unverified_draft
## tet2-inactivation-causes-mouse-malignancy Inactivating Tet2 in mouse perturbed both early and late haematopoiesis in a cell-autonomous manner, gave the cells a competitive advantage, and eventually led to the development of haematological malignancies. Model/species: Tet2-inactivated mice; competitive repopulation Organism: Mus musculus Tissue/system: Myeloid and lymphoid compartments Exposure: Genetic inactivation of Tet2 Duration: In vivo, to malignancy Limits: A different group from the conditional-knockout study above, but the same group as the 2009 human mutation survey in this collection, so that survey and this mouse model are one line of evidence rather than two. Primary reference: [quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
Complete structured claim and evidence
TET2 mutations were observed in human lymphoid disorders and could be detected in immature progenitors that retained myeloid colony-forming potential.
Human TET2 → TET2 mutation in human lymphoid neoplasms source_derived_draftungraded
Experimental context and source evidence
duration
Cross-sectional
experimental_model
Human lymphoid disorder samples with progenitor colony assays
exposure
No intervention; observational sequencing
limitations
Detection in a progenitor shows where the mutation sits in the hierarchy, not that it caused the lymphoid tumour.
organism
Homo sapiens
plain_language
The same damaged gene also turns up in lymphoid cancers, not only myeloid ones.
primary_references
[quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
tissue
Lymphoid tumour cells and immature progenitors
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 83–91
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human lymphoid disorder samples with progenitor colony assays · source_derived_draft · unverified_draft
## tet2-mutation-in-lymphoid-disorders TET2 mutations were observed in human lymphoid disorders and could be detected in immature progenitors that retained myeloid colony-forming potential. Model/species: Human lymphoid disorder samples with progenitor colony assays Organism: Homo sapiens Tissue/system: Lymphoid tumour cells and immature progenitors Exposure: No intervention; observational sequencing Duration: Cross-sectional Limits: Detection in a progenitor shows where the mutation sits in the hierarchy, not that it caused the lymphoid tumour. Primary reference: [quivoron-2011] TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis (2011). https://pubmed.ncbi.nlm.nih.gov/21723201/ DOI: 10.1016/j.ccr.2011.06.003
Complete structured claim and evidence
Restoring endogenous Tet2 expression in a reversible transgenic RNAi mouse reversed aberrant haematopoietic stem and progenitor cell self-renewal both in vitro and in vivo.
Mouse Tet2 → Mouse haematopoietic stem and progenitor cell self-renewal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
In vitro and in vivo after restoration
experimental_model
Reversible transgenic RNAi mouse permitting Tet2 knockdown and restoration
exposure
Genetic restoration of endogenous Tet2 expression after knockdown
limitations
Restoring a knockdown is not the same as correcting a mutated allele in a patient, and the reversal was measured as self-renewal rather than as cure of an established leukaemia.
organism
Mus musculus
plain_language
Switching Tet2 back on undid the abnormal renewal, which is the strongest sign the enzyme itself was responsible.
primary_references
[cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
tissue
Haematopoietic stem and progenitor cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 93–101
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Reversible transgenic RNAi mouse permitting Tet2 knockdown and restoration · source_derived_draft · unverified_draft
## tet2-restoration-reverses-self-renewal Restoring endogenous Tet2 expression in a reversible transgenic RNAi mouse reversed aberrant haematopoietic stem and progenitor cell self-renewal both in vitro and in vivo. Model/species: Reversible transgenic RNAi mouse permitting Tet2 knockdown and restoration Organism: Mus musculus Tissue/system: Haematopoietic stem and progenitor cells Exposure: Genetic restoration of endogenous Tet2 expression after knockdown Duration: In vitro and in vivo after restoration Limits: Restoring a knockdown is not the same as correcting a mutated allele in a patient, and the reversal was measured as self-renewal rather than as cure of an established leukaemia. Primary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
Complete structured claim and evidence
Vitamin C treatment enhanced 5-hydroxymethylcytosine formation in Tet2-deficient mouse haematopoietic stem and progenitor cells, mimicking genetic Tet2 restoration.
L-Ascorbate → DNA 5-hydroxymethylcytosine residues source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Treatment in culture and in vivo
experimental_model
Tet2-deficient mouse haematopoietic stem and progenitor cells
exposure
Vitamin C as a cofactor of Fe(II)- and 2-oxoglutarate-dependent dioxygenases
limitations
Vitamin C is a cofactor for the whole family of Fe(II)- and 2-oxoglutarate-dependent dioxygenases, so raised 5hmC in a Tet2-deficient cell does not establish that TET2 itself was reactivated.
organism
Mus musculus
plain_language
Vitamin C raised the same chemical mark that restoring the enzyme raises.
primary_references
[cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
tissue
Haematopoietic stem and progenitor cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 103–111
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet2-deficient mouse haematopoietic stem and progenitor cells · source_derived_draft · unverified_draft
## ascorbate-raises-5hmc-in-tet2-deficient-hspc Vitamin C treatment enhanced 5-hydroxymethylcytosine formation in Tet2-deficient mouse haematopoietic stem and progenitor cells, mimicking genetic Tet2 restoration. Model/species: Tet2-deficient mouse haematopoietic stem and progenitor cells Organism: Mus musculus Tissue/system: Haematopoietic stem and progenitor cells Exposure: Vitamin C as a cofactor of Fe(II)- and 2-oxoglutarate-dependent dioxygenases Duration: Treatment in culture and in vivo Limits: Vitamin C is a cofactor for the whole family of Fe(II)- and 2-oxoglutarate-dependent dioxygenases, so raised 5hmC in a Tet2-deficient cell does not establish that TET2 itself was reactivated. Primary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
Complete structured claim and evidence
Vitamin C treatment suppressed leukaemic colony formation by human leukaemia cells and slowed leukaemia progression in primary human acute-myeloid-leukaemia patient-derived xenografts.
L-Ascorbate → Human acute myeloid leukaemia colony formation and xenograft progression source_derived_draftungraded
Experimental context and source evidence
duration
Colony assays and xenograft progression
experimental_model
Human leukaemia cell lines and primary human AML patient-derived xenografts
exposure
Pharmacological vitamin C
limitations
Pharmacological vitamin C in a xenograft is not dietary intake, and a xenograft host lacks an intact immune system.
organism
Homo sapiens cells in mouse xenograft hosts
plain_language
Vitamin C slowed human leukaemia cells in a dish and in mice carrying them.
primary_references
[cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
tissue
Leukaemic blasts
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 113–121
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human leukaemia cell lines and primary human AML patient-derived xenografts · source_derived_draft · unverified_draft
## ascorbate-suppresses-aml-colony-formation Vitamin C treatment suppressed leukaemic colony formation by human leukaemia cells and slowed leukaemia progression in primary human acute-myeloid-leukaemia patient-derived xenografts. Model/species: Human leukaemia cell lines and primary human AML patient-derived xenografts Organism: Homo sapiens cells in mouse xenograft hosts Tissue/system: Leukaemic blasts Exposure: Pharmacological vitamin C Duration: Colony assays and xenograft progression Limits: Pharmacological vitamin C in a xenograft is not dietary intake, and a xenograft host lacks an intact immune system. Primary reference: [cimmino-2017] Restoration of TET2 function blocks aberrant self-renewal and leukemia progression (2017). https://pubmed.ncbi.nlm.nih.gov/28823558/ DOI: 10.1016/j.cell.2017.07.032
Complete structured claim and evidence
Systemic ascorbate depletion in mice increased haematopoietic stem cell frequency and function, in part by reducing the function of Tet2, and haematopoietic stem cells were shown to hold unusually high ascorbate that falls with differentiation.
L-Ascorbate → Mouse haematopoietic stem cell frequency source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
duration
Systemic depletion in vivo
experimental_model
Mice under systemic ascorbate depletion; metabolomics of rare cell populations isolated directly from tissues
exposure
Systemic ascorbate depletion; the retrieved abstract does not state the strain or the depletion protocol
limitations
The retrieved abstract does not state the strain or protocol used to deplete ascorbate. Mice ordinarily synthesise their own ascorbate, so a mouse depletion model is not equivalent to human dietary deficiency, and more stem cells is not by itself a disease.
organism
Mus musculus
plain_language
Taking vitamin C away made blood stem cells multiply more, partly by slowing the enzyme.
primary_references
[agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
tissue
Haematopoietic stem cells
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 123–131
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Mice under systemic ascorbate depletion; metabolomics of rare cell populations isolated directly from tissues · source_derived_draft · unverified_draft
## ascorbate-depletion-raises-hsc-frequency Systemic ascorbate depletion in mice increased haematopoietic stem cell frequency and function, in part by reducing the function of Tet2, and haematopoietic stem cells were shown to hold unusually high ascorbate that falls with differentiation. Model/species: Mice under systemic ascorbate depletion; metabolomics of rare cell populations isolated directly from tissues Organism: Mus musculus Tissue/system: Haematopoietic stem cells Exposure: Systemic ascorbate depletion; the retrieved abstract does not state the strain or the depletion protocol Duration: Systemic depletion in vivo Limits: The retrieved abstract does not state the strain or protocol used to deplete ascorbate. Mice ordinarily synthesise their own ascorbate, so a mouse depletion model is not equivalent to human dietary deficiency, and more stem cells is not by itself a disease. Primary reference: [agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
Complete structured claim and evidence
Systemic ascorbate depletion cooperated with Flt3 internal tandem duplication to accelerate leukaemogenesis in mice, and restoring dietary ascorbate reversed that acceleration.
L-Ascorbate → Leukaemogenesis in Flt3-internal-tandem-duplication mice source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
duration
To leukaemia onset
experimental_model
Ascorbate-depleted mice carrying Flt3 internal tandem duplication
exposure
Dietary ascorbate depletion, with dietary ascorbate restoration as the reversal arm
limitations
Depletion acted together with a leukaemic driver mutation; this is not evidence that ascorbate shortage alone causes leukaemia. The authors note possible non-cell-autonomous mechanisms.
organism
Mus musculus
plain_language
In mice already carrying a leukaemia mutation, vitamin C shortage made the disease come faster, and feeding it back undid that.
primary_references
[agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
tissue
Haematopoietic system
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 133–141
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Ascorbate-depleted mice carrying Flt3 internal tandem duplication · source_derived_draft · unverified_draft
## ascorbate-depletion-accelerates-leukaemogenesis Systemic ascorbate depletion cooperated with Flt3 internal tandem duplication to accelerate leukaemogenesis in mice, and restoring dietary ascorbate reversed that acceleration. Model/species: Ascorbate-depleted mice carrying Flt3 internal tandem duplication Organism: Mus musculus Tissue/system: Haematopoietic system Exposure: Dietary ascorbate depletion, with dietary ascorbate restoration as the reversal arm Duration: To leukaemia onset Limits: Depletion acted together with a leukaemic driver mutation; this is not evidence that ascorbate shortage alone causes leukaemia. The authors note possible non-cell-autonomous mechanisms. Primary reference: [agathocleous-2017] Ascorbate regulates haematopoietic stem cell function and leukaemogenesis (2017). https://pubmed.ncbi.nlm.nih.gov/28825709/ DOI: 10.1038/nature23876
Complete structured claim and evidence
All-trans retinoic acid induced retinoic-acid-receptor-alpha-mediated TET2 transcription in myeloid leukaemia cells.
All-trans-retinoic acid → Human TET2 source_derived_draftungraded
Experimental context and source evidence
duration
Culture treatment
experimental_model
Myeloid leukaemia cell lines and primary human AML models
exposure
All-trans retinoic acid
limitations
A transcript rise is not a measured rise in enzyme activity, and pharmacological ATRA is not dietary vitamin A.
organism
Homo sapiens
plain_language
Retinoic acid made leukaemia cells produce more of the TET2 enzyme.
primary_references
[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
tissue
Myeloid leukaemia cells
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 143–151
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Myeloid leukaemia cell lines and primary human AML models · source_derived_draft · unverified_draft
## atra-induces-tet2-transcription All-trans retinoic acid induced retinoic-acid-receptor-alpha-mediated TET2 transcription in myeloid leukaemia cells. Model/species: Myeloid leukaemia cell lines and primary human AML models Organism: Homo sapiens Tissue/system: Myeloid leukaemia cells Exposure: All-trans retinoic acid Duration: Culture treatment Limits: A transcript rise is not a measured rise in enzyme activity, and pharmacological ATRA is not dietary vitamin A. Primary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
Complete structured claim and evidence
All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival.
All-trans-retinoic acid → Leukaemia stem cell self-renewal in human acute myeloid leukaemia models source_derived_draftungraded
Experimental context and source evidence
duration
In vivo to survival
experimental_condition
Untreated or single-agent primary human AML models All-trans retinoic acid administered · All-trans-retinoic acid Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_condition
Untreated or single-agent primary human AML models Ascorbate administered · L-Ascorbate Condition belongs to the full experimental contrast; do not separate a joint intervention.
experimental_contrast
{"intervention": "All-trans retinoic acid plus ascorbate", "comparator": "Untreated or single-agent primary human AML models", "endpoint": "Leukaemia stem cell self-renewal and survival", "effect_direction": "decrease", "combination": "joint", "conditions": [{"entity_slug": "all-trans-retinoic-acid", "state": "All-trans retinoic acid administered"}, {"entity_slug": "ascorbate", "state": "Ascorbate administered"}]} Explicit extracted experimental comparison; source-derived draft.
experimental_model
Tet1/2/3-deficient mice and primary human AML models
exposure
All-trans retinoic acid combined with ascorbate
limitations
A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone.
organism
Mus musculus and Homo sapiens
plain_language
Retinoic acid and vitamin C together worked better than either was expected to alone.
primary_references
[celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
tissue
Leukaemia stem cells
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 153–161
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Tet1/2/3-deficient mice and primary human AML models · source_derived_draft · unverified_draft
## atra-with-ascorbate-reduces-lsc-self-renewal All-trans retinoic acid together with ascorbate induced differentiation and inhibited leukaemia stem cell self-renewal in a TET2-dependent manner in primary human acute-myeloid-leukaemia models, sensitised the cells to targeted therapies in vivo and improved survival. Model/species: Tet1/2/3-deficient mice and primary human AML models Organism: Mus musculus and Homo sapiens Tissue/system: Leukaemia stem cells Exposure: All-trans retinoic acid combined with ascorbate Duration: In vivo to survival Limits: A joint intervention: the two agents were given together and this record cannot be read as the separate effect of either. TET2-dependence was shown with TET-deficient mice, which removes three paralogs rather than TET2 alone. Primary reference: [celrep-2025] Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation (2025). https://pubmed.ncbi.nlm.nih.gov/41037397/ DOI: 10.1016/j.celrep.2025.116379
Complete structured claim and evidence
In patient-derived primary acute-myeloid-leukaemia cells, vitamin C restored TET2 activity only when SLC2A3 was expressed, and SLC2A3 knockdown in the KG-1 cell line decreased the response to vitamin C.
Human GLUT3 / SLC2A3 → Cellular ascorbate uptake source_derived_draftungraded
Experimental context and source evidence
duration
Culture experiments
experimental_model
AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis
exposure
Vitamin C, with and without SLC2A3 knockdown
limitations
Below-median SLC2A3 expression was associated with poorer overall survival, which is an association within a database cohort and not an experimental outcome.
organism
Homo sapiens
plain_language
If the cell cannot take vitamin C in, the vitamin cannot restore the enzyme.
primary_references
[liu-2020] Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration (2020). https://pubmed.ncbi.nlm.nih.gov/32203209/ DOI: 10.1038/s41416-020-0788-8
tissue
Leukaemic blasts
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 163–171
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis · source_derived_draft · unverified_draft
## slc2a3-gates-vitamin-c-tet2-restoration In patient-derived primary acute-myeloid-leukaemia cells, vitamin C restored TET2 activity only when SLC2A3 was expressed, and SLC2A3 knockdown in the KG-1 cell line decreased the response to vitamin C. Model/species: AML cell lines, an SLC2A3-knockdown line and patient-derived primary AML cells; TCGA and TARGET expression analysis Organism: Homo sapiens Tissue/system: Leukaemic blasts Exposure: Vitamin C, with and without SLC2A3 knockdown Duration: Culture experiments Limits: Below-median SLC2A3 expression was associated with poorer overall survival, which is an association within a database cohort and not an experimental outcome. Primary reference: [liu-2020] Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration (2020). https://pubmed.ncbi.nlm.nih.gov/32203209/ DOI: 10.1038/s41416-020-0788-8
Complete structured claim and evidence
The ability of ascorbic acid to restore TET2 activity in cells depended on N-terminal and C-terminal lysine acetylation and on the nature of the TET2 mutation.
L-Ascorbate → Human TET2 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Culture experiments
experimental_model
TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation
exposure
Ascorbic acid, with pharmacological modulation of acetyltransferases and histone deacetylases
limitations
Which mutations respond is not resolved here; the study proposes combinations rather than demonstrating clinical benefit.
organism
Homo sapiens
plain_language
Whether vitamin C can revive the enzyme depends on which mutation the patient has.
primary_references
[mustafi-2020] Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia (2020). https://pubmed.ncbi.nlm.nih.gov/32895473/ DOI: 10.1038/s42003-020-01220-9
tissue
Myeloid neoplasia cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 173–181
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation · source_derived_draft · unverified_draft
## ascorbate-restoration-depends-on-mutation-and-acetylation The ability of ascorbic acid to restore TET2 activity in cells depended on N-terminal and C-terminal lysine acetylation and on the nature of the TET2 mutation. Model/species: TET2-mutant myeloid neoplasia cell systems with acetyltransferase and deacetylase modulation Organism: Homo sapiens Tissue/system: Myeloid neoplasia cells Exposure: Ascorbic acid, with pharmacological modulation of acetyltransferases and histone deacetylases Duration: Culture experiments Limits: Which mutations respond is not resolved here; the study proposes combinations rather than demonstrating clinical benefit. Primary reference: [mustafi-2020] Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia (2020). https://pubmed.ncbi.nlm.nih.gov/32895473/ DOI: 10.1038/s42003-020-01220-9
Complete structured claim and evidence
TET2 knockout in human HAP1 cells lowered 5-hydroxymethylcytosine and 5-formylcytosine measured by 2D-UPLC-MS/MS, and vitamin C treatment did not restore them to the levels seen in treated wild-type cells, so loss of one TET paralog was not compensated by the remaining ones.
Human TET2 → Cytosine oxidation products in human HAP1 TET-knockout cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Culture experiments
experimental_model
Human HAP1 cells with single and double TET knockouts
exposure
Vitamin C treatment of wild-type and TET-knockout cells
limitations
A near-haploid cell line, not a haematopoietic cell; a knockout is not a patient's point mutation.
organism
Homo sapiens
plain_language
Vitamin C cannot fully substitute for a TET2 that is missing.
primary_references
[kusmierek-2025] Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells (2025). https://pubmed.ncbi.nlm.nih.gov/41287077/ DOI: 10.1186/s13072-025-00634-1
tissue
HAP1 cell line
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 183–191
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Human HAP1 cells with single and double TET knockouts · source_derived_draft · unverified_draft
## vitamin-c-cannot-replace-lost-tet2 TET2 knockout in human HAP1 cells lowered 5-hydroxymethylcytosine and 5-formylcytosine measured by 2D-UPLC-MS/MS, and vitamin C treatment did not restore them to the levels seen in treated wild-type cells, so loss of one TET paralog was not compensated by the remaining ones. Model/species: Human HAP1 cells with single and double TET knockouts Organism: Homo sapiens Tissue/system: HAP1 cell line Exposure: Vitamin C treatment of wild-type and TET-knockout cells Duration: Culture experiments Limits: A near-haploid cell line, not a haematopoietic cell; a knockout is not a patient's point mutation. Primary reference: [kusmierek-2025] Loss of TET2 activity limits the ability of vitamin C to activate DNA demethylation in human HAP1 cells (2025). https://pubmed.ncbi.nlm.nih.gov/41287077/ DOI: 10.1186/s13072-025-00634-1
Complete structured claim and evidence
One year of oral vitamin C at 1 g/day in members of a family carrying a heterozygous truncating germline TET2 mutation reduced the proportion of hypermethylated loci and diminished gene-expression differences between carriers and non-carrier relatives.
L-Ascorbate → DNA hypermethylation in TET2 germline mutation carriers source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
One year
experimental_model
Clinical trial of one year in a single lymphoma-predisposition family; genome-wide methylation and expression
exposure
Oral vitamin C 1 g/day
limitations
One family, no disease endpoint measured. A methylation change is a biomarker, not a demonstration that lymphoma risk fell. Registered as EudraCT 2018-000155-41.
organism
Homo sapiens
plain_language
A year of vitamin C shifted the DNA marks in people born with a damaged TET2, but no cancer outcome was measured.
primary_references
[pitkanen-2023] Vitamin C boosts DNA demethylation in TET2 germline mutation carriers (2023). https://pubmed.ncbi.nlm.nih.gov/36639817/ DOI: 10.1186/s13148-022-01404-6
tissue
Blood cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 193–201
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Clinical trial of one year in a single lymphoma-predisposition family; genome-wide methylation and expression · source_derived_draft · unverified_draft
## vitamin-c-reduces-hypermethylation-in-tet2-carriers One year of oral vitamin C at 1 g/day in members of a family carrying a heterozygous truncating germline TET2 mutation reduced the proportion of hypermethylated loci and diminished gene-expression differences between carriers and non-carrier relatives. Model/species: Clinical trial of one year in a single lymphoma-predisposition family; genome-wide methylation and expression Organism: Homo sapiens Tissue/system: Blood cells Exposure: Oral vitamin C 1 g/day Duration: One year Limits: One family, no disease endpoint measured. A methylation change is a biomarker, not a demonstration that lymphoma risk fell. Registered as EudraCT 2018-000155-41. Primary reference: [pitkanen-2023] Vitamin C boosts DNA demethylation in TET2 germline mutation carriers (2023). https://pubmed.ncbi.nlm.nih.gov/36639817/ DOI: 10.1186/s13148-022-01404-6
Complete structured claim and evidence
In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20.
L-Ascorbate → Haematologic response in TET2-mutant clonal cytopenia of undetermined significance source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
duration
Response assessed at week 20
experimental_model
Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038
exposure
High-dose intravenous ascorbic acid
limitations
Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed.
organism
Homo sapiens
plain_language
In the one published trial of this idea in patients, nobody responded.
primary_references
[guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962
tissue
Blood and bone marrow
trigger_kind
machinery_impairment Imported condition classification; unverified.
TET2 loss and malignancy: the step between a nutrient-responsive enzyme and the disease (2026-09-23) · lines 203–211
Original AI-assisted curation of twelve primary studies located by Europe PMC title search, with every statement drafted from the retrieved abstract. Two pairs share a laboratory and are recorded as one line of evidence each. Genetic loss of function, pharmacological exposure and dietary depletion are kept as separate record types. Not publisher full text. · supports · Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038 · source_derived_draft · unverified_draft
## ascorbate-no-response-in-ccus-trial In a phase 2 trial of high-dose intravenous ascorbic acid in TET2-mutant clonal cytopenia of undetermined significance, none of the eight patients evaluable for response met International Working Group Myelodysplasia Syndromes/Neoplasms criteria at week 20. Model/species: Phase 2 single-arm trial, 10 enrolled and 8 evaluable; NCT03418038 Organism: Homo sapiens Tissue/system: Blood and bone marrow Exposure: High-dose intravenous ascorbic acid Duration: Response assessed at week 20 Limits: Eight evaluable patients and a 20-week assessment. A null in clonal cytopenia does not test prevention over years, nor treatment of established leukaemia, and the trial did not report whether TET2 activity or 5hmC changed. Primary reference: [guarnera-2024] High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations (2024). https://pubmed.ncbi.nlm.nih.gov/39352751/ DOI: 10.1182/blood.2024024962
Complete structured claim and evidence
SCARB1 supported intestinal beta-carotene absorption in mice on a high-fat diet.
Scavenger receptor class B type 1 / SCARB1 → Intestinal beta-carotene absorption source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Scarb1-knockout mice, intestinal brush-border vesicles and transfected COS-7 cells.
exposure
Wild-type versus Scarb1-knockout mice; high-fat feeding.
limitations
Dependence was diet/model specific; this does not establish exclusive human transport.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
SCARB1 supported intestinal beta-carotene absorption in mice on a high-fat diet.
plain_language
The intestinal receptor helps beta-carotene enter the body.
primary_references
[va-vanbennekum-2005] Class B scavenger receptor-mediated intestinal absorption of dietary beta-carotene and cholesterol (2005). https://pubmed.ncbi.nlm.nih.gov/15766282/ DOI: 10.1021/bi0484320
tissue_or_cell_type
Small-intestinal brush border
transport_direction
intestinal lumen to enterocyte
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 116–129
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Scarb1-knockout mice, intestinal brush-border vesicles and transfected COS-7 cells. · source_derived_draft · unverified_draft
### va-scarb1-beta-carotene-uptake SCARB1 supported intestinal beta-carotene absorption in mice on a high-fat diet. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The intestinal receptor helps beta-carotene enter the body. organism: Mus musculus tissue_or_cell_type: Small-intestinal brush border experimental_model: Scarb1-knockout mice, intestinal brush-border vesicles and transfected COS-7 cells. limitations: Dependence was diet/model specific; this does not establish exclusive human transport. exposure: Wild-type versus Scarb1-knockout mice; high-fat feeding. outcome: SCARB1 supported intestinal beta-carotene absorption in mice on a high-fat diet. evidence_location: Abstract transport_direction: intestinal lumen to enterocyte [va-vanbennekum-2005] Class B scavenger receptor-mediated intestinal absorption of dietary beta-carotene and cholesterol (2005). https://pubmed.ncbi.nlm.nih.gov/15766282/ DOI: 10.1021/bi0484320
Complete structured claim and evidence
Purified human BCO1 cleaved all-trans-beta-carotene centrally to all-trans-retinal.
Beta-carotene oxygenase 1 / BCO1 → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
evidence_location
Figure 3
experimental_model
Purified human BCO1 expressed in E. coli; substrate incubations and HPLC.
exposure
20 micromolar beta-carotene, 500 ng enzyme/200 microliters, 37 C, 15 minutes.
limitations
Purified-enzyme rates do not determine dietary conversion efficiency.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens protein expressed in Escherichia coli
outcome
Purified human BCO1 cleaved all-trans-beta-carotene centrally to all-trans-retinal.
plain_language
BCO1 turns a carotenoid precursor into retinal.
primary_references
[va-delasena-2013] Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1) (2013). https://pubmed.ncbi.nlm.nih.gov/24187135/ DOI: 10.1074/jbc.M113.507160
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 131–143
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human BCO1 expressed in E. coli; substrate incubations and HPLC. · source_derived_draft · unverified_draft
### va-bco1-central-cleavage Purified human BCO1 cleaved all-trans-beta-carotene centrally to all-trans-retinal. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: BCO1 turns a carotenoid precursor into retinal. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Cell-free enzyme experimental_model: Purified human BCO1 expressed in E. coli; substrate incubations and HPLC. limitations: Purified-enzyme rates do not determine dietary conversion efficiency. exposure: 20 micromolar beta-carotene, 500 ng enzyme/200 microliters, 37 C, 15 minutes. outcome: Purified human BCO1 cleaved all-trans-beta-carotene centrally to all-trans-retinal. evidence_location: Figure 3 [va-delasena-2013] Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1) (2013). https://pubmed.ncbi.nlm.nih.gov/24187135/ DOI: 10.1074/jbc.M113.507160
Complete structured claim and evidence
Human BCO1 generated retinal from alpha-carotene in substrate assays.
Beta-carotene oxygenase 1 / BCO1 → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Purified human BCO1 expressed in E. coli; substrate incubations and HPLC.
exposure
Purified BCO1 and alpha-carotene concentration series.
limitations
Lower catalytic efficiency than beta-carotene under these assay conditions.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens protein expressed in Escherichia coli
outcome
Human BCO1 generated retinal from alpha-carotene in substrate assays.
plain_language
Alpha-carotene can feed retinal production.
primary_references
[va-delasena-2013] Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1) (2013). https://pubmed.ncbi.nlm.nih.gov/24187135/ DOI: 10.1074/jbc.M113.507160
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 145–157
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human BCO1 expressed in E. coli; substrate incubations and HPLC. · source_derived_draft · unverified_draft
### va-bco1-alpha-carotene Human BCO1 generated retinal from alpha-carotene in substrate assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Alpha-carotene can feed retinal production. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Cell-free enzyme experimental_model: Purified human BCO1 expressed in E. coli; substrate incubations and HPLC. limitations: Lower catalytic efficiency than beta-carotene under these assay conditions. exposure: Purified BCO1 and alpha-carotene concentration series. outcome: Human BCO1 generated retinal from alpha-carotene in substrate assays. evidence_location: Abstract [va-delasena-2013] Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1) (2013). https://pubmed.ncbi.nlm.nih.gov/24187135/ DOI: 10.1074/jbc.M113.507160
Complete structured claim and evidence
Human BCO1 generated retinal from beta-cryptoxanthin in substrate assays.
Beta-carotene oxygenase 1 / BCO1 → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Purified human BCO1 expressed in E. coli; substrate incubations and HPLC.
exposure
Purified BCO1 and beta-cryptoxanthin concentration series.
limitations
Does not quantify competition with the BCO2 pathway in vivo.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens protein expressed in Escherichia coli
outcome
Human BCO1 generated retinal from beta-cryptoxanthin in substrate assays.
plain_language
This hydroxylated carotenoid also supplies retinal in vitro.
primary_references
[va-delasena-2013] Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1) (2013). https://pubmed.ncbi.nlm.nih.gov/24187135/ DOI: 10.1074/jbc.M113.507160
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 159–171
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human BCO1 expressed in E. coli; substrate incubations and HPLC. · source_derived_draft · unverified_draft
### va-bco1-beta-cryptoxanthin Human BCO1 generated retinal from beta-cryptoxanthin in substrate assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This hydroxylated carotenoid also supplies retinal in vitro. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Cell-free enzyme experimental_model: Purified human BCO1 expressed in E. coli; substrate incubations and HPLC. limitations: Does not quantify competition with the BCO2 pathway in vivo. exposure: Purified BCO1 and beta-cryptoxanthin concentration series. outcome: Human BCO1 generated retinal from beta-cryptoxanthin in substrate assays. evidence_location: Abstract [va-delasena-2013] Substrate specificity of purified recombinant human beta-carotene 15,15'-oxygenase (BCO1) (2013). https://pubmed.ncbi.nlm.nih.gov/24187135/ DOI: 10.1074/jbc.M113.507160
Complete structured claim and evidence
Isotope tracing showed that oxygen incorporated into both BCO1-generated retinal products originated from molecular oxygen.
Molecular oxygen → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Recombinant human BCO1 with isotopically labeled oxygen and water.
exposure
18O2 versus H2-18O incubations with beta-carotene.
limitations
Reaction chemistry; no claim about clinical hypoxia or oxygen supplementation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein
outcome
Isotope tracing showed that oxygen incorporated into both BCO1-generated retinal products originated from molecular oxygen.
plain_language
BCO1 cleavage uses oxygen gas to make the two retinal aldehydes.
primary_references
[va-delasena-2014] The human enzyme that converts dietary provitamin A carotenoids to vitamin A is a dioxygenase (2014). https://pubmed.ncbi.nlm.nih.gov/24668807/ DOI: 10.1074/jbc.M114.557710
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 173–185
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BCO1 with isotopically labeled oxygen and water. · source_derived_draft · unverified_draft
### va-bco1-dioxygen-incorporation Isotope tracing showed that oxygen incorporated into both BCO1-generated retinal products originated from molecular oxygen. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: BCO1 cleavage uses oxygen gas to make the two retinal aldehydes. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Recombinant human BCO1 with isotopically labeled oxygen and water. limitations: Reaction chemistry; no claim about clinical hypoxia or oxygen supplementation. exposure: 18O2 versus H2-18O incubations with beta-carotene. outcome: Isotope tracing showed that oxygen incorporated into both BCO1-generated retinal products originated from molecular oxygen. evidence_location: Abstract [va-delasena-2014] The human enzyme that converts dietary provitamin A carotenoids to vitamin A is a dioxygenase (2014). https://pubmed.ncbi.nlm.nih.gov/24668807/ DOI: 10.1074/jbc.M114.557710
Complete structured claim and evidence
Desferrioxamine reduced beta-carotene-cleaving activity in human intestinal mucosa and TC7 cells.
Desferrioxamine → Beta-carotene central cleavage source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Iron availability supports provitamin A cleavage in this in vitro model.
evidence_location
Abstract
experimental_model
Human small-intestinal mucosa and Caco-2 TC7 cells; desferrioxamine and iron addition.
exposure
Increasing desferrioxamine concentrations.
limitations
Drug-induced chelation; BCO1 protein abundance and human dietary deficiency were not directly established.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
outcome
Desferrioxamine reduced beta-carotene-cleaving activity in human intestinal mucosa and TC7 cells.
plain_language
Sequestering iron limited conversion of provitamin A to retinal.
primary_references
[va-during-2001] beta-Carotene 15,15'-Dioxygenase activity in human tissues and cells: evidence of an iron dependency (2001). https://pubmed.ncbi.nlm.nih.gov/12031257/ DOI: 10.1016/S0955-2863(01)00184-X
tissue_or_cell_type
Small-intestinal mucosa and Caco-2 TC7 cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 187–200
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human small-intestinal mucosa and Caco-2 TC7 cells; desferrioxamine and iron addition. · source_derived_draft · unverified_draft
### va-iron-chelation-cleavage Desferrioxamine reduced beta-carotene-cleaving activity in human intestinal mucosa and TC7 cells. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Sequestering iron limited conversion of provitamin A to retinal. organism: Homo sapiens tissue_or_cell_type: Small-intestinal mucosa and Caco-2 TC7 cells experimental_model: Human small-intestinal mucosa and Caco-2 TC7 cells; desferrioxamine and iron addition. limitations: Drug-induced chelation; BCO1 protein abundance and human dietary deficiency were not directly established. exposure: Increasing desferrioxamine concentrations. outcome: Desferrioxamine reduced beta-carotene-cleaving activity in human intestinal mucosa and TC7 cells. evidence_location: Abstract cross_nutrient: Iron availability supports provitamin A cleavage in this in vitro model. [va-during-2001] beta-Carotene 15,15'-Dioxygenase activity in human tissues and cells: evidence of an iron dependency (2001). https://pubmed.ncbi.nlm.nih.gov/12031257/ DOI: 10.1016/S0955-2863(01)00184-X
Complete structured claim and evidence
Adding iron reversed desferrioxamine inhibition of carotenoid cleavage in TC7 cells.
Iron → Beta-carotene central cleavage source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Direct cellular iron-to-vitamin-A precursor interaction.
evidence_location
Abstract
experimental_model
Human small-intestinal mucosa and Caco-2 TC7 cells; desferrioxamine and iron addition.
exposure
Iron added during the chelation experiment.
limitations
Accessible source does not resolve the added salt/speciation; not a clinical repletion result.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
outcome
Adding iron reversed desferrioxamine inhibition of carotenoid cleavage in TC7 cells.
plain_language
Iron restored the inhibited retinal-producing reaction.
primary_references
[va-during-2001] beta-Carotene 15,15'-Dioxygenase activity in human tissues and cells: evidence of an iron dependency (2001). https://pubmed.ncbi.nlm.nih.gov/12031257/ DOI: 10.1016/S0955-2863(01)00184-X
tissue_or_cell_type
Caco-2 TC7 cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 202–215
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human small-intestinal mucosa and Caco-2 TC7 cells; desferrioxamine and iron addition. · source_derived_draft · unverified_draft
### va-iron-rescue-cleavage Adding iron reversed desferrioxamine inhibition of carotenoid cleavage in TC7 cells. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron restored the inhibited retinal-producing reaction. organism: Homo sapiens tissue_or_cell_type: Caco-2 TC7 cells experimental_model: Human small-intestinal mucosa and Caco-2 TC7 cells; desferrioxamine and iron addition. limitations: Accessible source does not resolve the added salt/speciation; not a clinical repletion result. exposure: Iron added during the chelation experiment. outcome: Adding iron reversed desferrioxamine inhibition of carotenoid cleavage in TC7 cells. evidence_location: Abstract cross_nutrient: Direct cellular iron-to-vitamin-A precursor interaction. [va-during-2001] beta-Carotene 15,15'-Dioxygenase activity in human tissues and cells: evidence of an iron dependency (2001). https://pubmed.ncbi.nlm.nih.gov/12031257/ DOI: 10.1016/S0955-2863(01)00184-X
Complete structured claim and evidence
Substitution of conserved histidines or Glu405 in mouse BCO1 abolished cleavage and reduced protein-bound iron.
Beta-carotene oxygenase 1 / BCO1 → Iron source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Links enzyme-bound iron to vitamin A precursor processing.
evidence_location
Abstract
experimental_model
Site-directed mutant mouse BCO1; cleavage assays and protein-bound iron spectroscopy.
exposure
Individual alanine substitutions at conserved catalytic-site residues.
limitations
Coordination inferred from mutagenesis and iron measurements, not a dietary iron trial.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus recombinant protein
outcome
Substitution of conserved histidines or Glu405 in mouse BCO1 abolished cleavage and reduced protein-bound iron.
plain_language
An intact iron-binding environment is necessary for this enzyme to work.
primary_references
[va-poliakov-2005] Key role of conserved histidines in recombinant mouse beta-carotene 15,15'-monooxygenase-1 activity (2005). https://pubmed.ncbi.nlm.nih.gov/15951442/ DOI: 10.1074/jbc.M500409200
tissue_or_cell_type
Cell-free protein
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 217–230
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutant mouse BCO1; cleavage assays and protein-bound iron spectroscopy. · source_derived_draft · unverified_draft
### va-bco1-iron-binding-machinery Substitution of conserved histidines or Glu405 in mouse BCO1 abolished cleavage and reduced protein-bound iron. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An intact iron-binding environment is necessary for this enzyme to work. organism: Mus musculus recombinant protein tissue_or_cell_type: Cell-free protein experimental_model: Site-directed mutant mouse BCO1; cleavage assays and protein-bound iron spectroscopy. limitations: Coordination inferred from mutagenesis and iron measurements, not a dietary iron trial. exposure: Individual alanine substitutions at conserved catalytic-site residues. outcome: Substitution of conserved histidines or Glu405 in mouse BCO1 abolished cleavage and reduced protein-bound iron. evidence_location: Abstract cross_nutrient: Links enzyme-bound iron to vitamin A precursor processing. [va-poliakov-2005] Key role of conserved histidines in recombinant mouse beta-carotene 15,15'-monooxygenase-1 activity (2005). https://pubmed.ncbi.nlm.nih.gov/15951442/ DOI: 10.1074/jbc.M500409200
Complete structured claim and evidence
Recombinant murine BCO2 cleaved beta-cryptoxanthin mainly to beta-apo-10-prime-carotenal.
Beta-carotene oxygenase 2 / BCO2 → Beta-apo-10'-carotenal source_derived_draftungraded
Experimental context and source evidence
evidence_location
Figure 10A
experimental_model
Recombinant murine BCO2 and Bco1/Bco2-knockout mice given carotenoids.
exposure
BCO2 incubated with beta-cryptoxanthin.
limitations
Intermediate transport and whole-body human pathway contribution were not established.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus recombinant protein
outcome
Recombinant murine BCO2 cleaved beta-cryptoxanthin mainly to beta-apo-10-prime-carotenal.
plain_language
BCO2 makes an apocarotenoid intermediate rather than directly performing BCO1 central cleavage.
primary_references
[va-amengual-2013] Two Carotenoid Oxygenases Contribute to Mammalian Provitamin A Metabolism (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3837149/ DOI: 10.1074/jbc.M113.501049
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 232–244
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant murine BCO2 and Bco1/Bco2-knockout mice given carotenoids. · source_derived_draft · unverified_draft
### va-bco2-eccentric-cryptoxanthin Recombinant murine BCO2 cleaved beta-cryptoxanthin mainly to beta-apo-10-prime-carotenal. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: BCO2 makes an apocarotenoid intermediate rather than directly performing BCO1 central cleavage. organism: Mus musculus recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Recombinant murine BCO2 and Bco1/Bco2-knockout mice given carotenoids. limitations: Intermediate transport and whole-body human pathway contribution were not established. exposure: BCO2 incubated with beta-cryptoxanthin. outcome: Recombinant murine BCO2 cleaved beta-cryptoxanthin mainly to beta-apo-10-prime-carotenal. evidence_location: Figure 10A [va-amengual-2013] Two Carotenoid Oxygenases Contribute to Mammalian Provitamin A Metabolism (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3837149/ DOI: 10.1074/jbc.M113.501049
Complete structured claim and evidence
Bco2-null mice accumulated more hepatic beta-cryptoxanthin than wild-type and Bco1-null mice after repeated injections.
Beta-carotene oxygenase 2 / BCO2 → Beta-cryptoxanthin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Figure 10B
experimental_model
Recombinant murine BCO2 and Bco1/Bco2-knockout mice given carotenoids.
exposure
Twelve-week-old females; pharmacological beta-cryptoxanthin injections on three consecutive days; n=3/genotype.
limitations
Injection bypasses intestinal absorption; not nutritional deficiency.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Bco2-null mice accumulated more hepatic beta-cryptoxanthin than wild-type and Bco1-null mice after repeated injections.
plain_language
Removing BCO2 impaired clearance of this carotenoid.
primary_references
[va-amengual-2013] Two Carotenoid Oxygenases Contribute to Mammalian Provitamin A Metabolism (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3837149/ DOI: 10.1074/jbc.M113.501049
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 246–258
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant murine BCO2 and Bco1/Bco2-knockout mice given carotenoids. · source_derived_draft · unverified_draft
### va-bco2-loss-cryptoxanthin Bco2-null mice accumulated more hepatic beta-cryptoxanthin than wild-type and Bco1-null mice after repeated injections. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing BCO2 impaired clearance of this carotenoid. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Recombinant murine BCO2 and Bco1/Bco2-knockout mice given carotenoids. limitations: Injection bypasses intestinal absorption; not nutritional deficiency. exposure: Twelve-week-old females; pharmacological beta-cryptoxanthin injections on three consecutive days; n=3/genotype. outcome: Bco2-null mice accumulated more hepatic beta-cryptoxanthin than wild-type and Bco1-null mice after repeated injections. evidence_location: Figure 10B [va-amengual-2013] Two Carotenoid Oxygenases Contribute to Mammalian Provitamin A Metabolism (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3837149/ DOI: 10.1074/jbc.M113.501049
Complete structured claim and evidence
Retinoic-acid receptor signaling increased intestinal ISX expression.
All-trans-retinoic acid → Intestine-specific homeobox protein / ISX source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Mouse diet/retinoic-acid interventions and human cell lines.
exposure
Retinoic-acid treatment with receptor-dependent tests.
limitations
Pharmacological treatment supports feedback circuitry, not a universal dietary threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus and Homo sapiens cell lines
outcome
Retinoic-acid receptor signaling increased intestinal ISX expression.
plain_language
The active retinoid metabolite induces a brake on further precursor uptake.
primary_references
[va-lobo-2010] ISX is a retinoic acid-sensitive gatekeeper that controls intestinal beta,beta-carotene absorption and vitamin A production (2010). https://pubmed.ncbi.nlm.nih.gov/20061533/ DOI: 10.1096/fj.09-150995
tissue_or_cell_type
Intestine and cultured cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 260–272
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse diet/retinoic-acid interventions and human cell lines. · source_derived_draft · unverified_draft
### va-retinoic-acid-isx-feedback Retinoic-acid receptor signaling increased intestinal ISX expression. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The active retinoid metabolite induces a brake on further precursor uptake. organism: Mus musculus and Homo sapiens cell lines tissue_or_cell_type: Intestine and cultured cells experimental_model: Mouse diet/retinoic-acid interventions and human cell lines. limitations: Pharmacological treatment supports feedback circuitry, not a universal dietary threshold. exposure: Retinoic-acid treatment with receptor-dependent tests. outcome: Retinoic-acid receptor signaling increased intestinal ISX expression. evidence_location: Abstract [va-lobo-2010] ISX is a retinoic acid-sensitive gatekeeper that controls intestinal beta,beta-carotene absorption and vitamin A production (2010). https://pubmed.ncbi.nlm.nih.gov/20061533/ DOI: 10.1096/fj.09-150995
Complete structured claim and evidence
ISX bound upstream SCARB1 regulatory motifs and repressed intestinal SCARB1 expression.
Intestine-specific homeobox protein / ISX → Scavenger receptor class B type 1 / SCARB1 source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets.
exposure
Isx genotypes and promoter-binding experiments.
limitations
Tissue-specific regulation, not suppression in every organ.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus and promoter-binding preparations
outcome
ISX bound upstream SCARB1 regulatory motifs and repressed intestinal SCARB1 expression.
plain_language
The feedback factor lowers the uptake receptor.
primary_references
[va-widjajaadhi-2015] A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4424956/ DOI: 10.1093/hmg/ddv072
tissue_or_cell_type
Jejunum and DNA-binding assays
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 274–286
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets. · source_derived_draft · unverified_draft
### va-isx-scarb1-repression ISX bound upstream SCARB1 regulatory motifs and repressed intestinal SCARB1 expression. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The feedback factor lowers the uptake receptor. organism: Mus musculus and promoter-binding preparations tissue_or_cell_type: Jejunum and DNA-binding assays experimental_model: Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets. limitations: Tissue-specific regulation, not suppression in every organ. exposure: Isx genotypes and promoter-binding experiments. outcome: ISX bound upstream SCARB1 regulatory motifs and repressed intestinal SCARB1 expression. evidence_location: Abstract [va-widjajaadhi-2015] A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4424956/ DOI: 10.1093/hmg/ddv072
Complete structured claim and evidence
ISX recognized upstream BCO1 regulatory motifs and repressed its expression.
Intestine-specific homeobox protein / ISX → Beta-carotene oxygenase 1 / BCO1 source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets.
exposure
ISX binding and gene-expression experiments.
limitations
Does not establish a fixed carotenoid conversion ratio.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus and promoter-binding preparations
outcome
ISX recognized upstream BCO1 regulatory motifs and repressed its expression.
plain_language
The same feedback factor limits the carotenoid-cleaving enzyme.
primary_references
[va-widjajaadhi-2015] A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4424956/ DOI: 10.1093/hmg/ddv072
tissue_or_cell_type
Intestinal epithelium
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 288–300
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets. · source_derived_draft · unverified_draft
### va-isx-bco1-repression ISX recognized upstream BCO1 regulatory motifs and repressed its expression. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same feedback factor limits the carotenoid-cleaving enzyme. organism: Mus musculus and promoter-binding preparations tissue_or_cell_type: Intestinal epithelium experimental_model: Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets. limitations: Does not establish a fixed carotenoid conversion ratio. exposure: ISX binding and gene-expression experiments. outcome: ISX recognized upstream BCO1 regulatory motifs and repressed its expression. evidence_location: Abstract [va-widjajaadhi-2015] A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4424956/ DOI: 10.1093/hmg/ddv072
Complete structured claim and evidence
Isx-deficient mice had higher hepatic alpha-tocopherol; the Isx/Bco2 double mutant showed about twice wild-type levels.
Intestine-specific homeobox protein / ISX → Alpha-tocopherol source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Retinoid/ISX control of a shared intestinal transporter affects vitamin E status.
evidence_location
Figure 7
experimental_model
Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets.
exposure
Females; ten weeks of AIN93G with 75 IU vitamin E/kg, with or without 50 mg zeaxanthin/kg.
limitations
Accumulation is not a clinical benefit; compound mutants had a larger effect than Isx single mutants.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Isx-deficient mice had higher hepatic alpha-tocopherol; the Isx/Bco2 double mutant showed about twice wild-type levels.
plain_language
Disrupting vitamin A feedback also changed vitamin E accumulation.
primary_references
[va-widjajaadhi-2015] A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4424956/ DOI: 10.1093/hmg/ddv072
tissue_or_cell_type
Jejunum and liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 302–315
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets. · source_derived_draft · unverified_draft
### va-isx-loss-tocopherol Isx-deficient mice had higher hepatic alpha-tocopherol; the Isx/Bco2 double mutant showed about twice wild-type levels. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Disrupting vitamin A feedback also changed vitamin E accumulation. organism: Mus musculus tissue_or_cell_type: Jejunum and liver experimental_model: Isx, Bco1, Bco2 and Scarb1 mouse mutants; promoter binding and controlled diets. limitations: Accumulation is not a clinical benefit; compound mutants had a larger effect than Isx single mutants. exposure: Females; ten weeks of AIN93G with 75 IU vitamin E/kg, with or without 50 mg zeaxanthin/kg. outcome: Isx-deficient mice had higher hepatic alpha-tocopherol; the Isx/Bco2 double mutant showed about twice wild-type levels. evidence_location: Figure 7 cross_nutrient: Retinoid/ISX control of a shared intestinal transporter affects vitamin E status. [va-widjajaadhi-2015] A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4424956/ DOI: 10.1093/hmg/ddv072
Complete structured claim and evidence
Human and rat liver LRAT activity transferred the sn-1 acyl group of phosphatidylcholine to CRBP-bound retinol.
Phosphatidylcholine → Retinyl ester formation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Phosphatidylcholine-dependent retinol storage links retinoid metabolism to choline-containing phospholipid availability.
evidence_location
Abstract
experimental_model
Human and rat liver microsomes supplied phosphatidylcholine and CRBP-bound retinol.
exposure
Exogenous phosphatidylcholine plus CRBP-bound retinol.
limitations
Biochemical donor requirement; dietary choline deficiency was not tested.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens and Rattus norvegicus
outcome
Human and rat liver LRAT activity transferred the sn-1 acyl group of phosphatidylcholine to CRBP-bound retinol.
plain_language
A membrane choline phospholipid supplies the fatty-acid group used to store vitamin A.
primary_references
[va-macdonald-1988] A lecithin:retinol acyltransferase activity in human and rat liver (1988). https://pubmed.ncbi.nlm.nih.gov/3178828/ DOI: 10.1016/S0006-291X(88)80818-0
tissue_or_cell_type
Liver microsomes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 317–330
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human and rat liver microsomes supplied phosphatidylcholine and CRBP-bound retinol. · source_derived_draft · unverified_draft
### va-lrat-phosphatidylcholine-donor Human and rat liver LRAT activity transferred the sn-1 acyl group of phosphatidylcholine to CRBP-bound retinol. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A membrane choline phospholipid supplies the fatty-acid group used to store vitamin A. organism: Homo sapiens and Rattus norvegicus tissue_or_cell_type: Liver microsomes experimental_model: Human and rat liver microsomes supplied phosphatidylcholine and CRBP-bound retinol. limitations: Biochemical donor requirement; dietary choline deficiency was not tested. exposure: Exogenous phosphatidylcholine plus CRBP-bound retinol. outcome: Human and rat liver LRAT activity transferred the sn-1 acyl group of phosphatidylcholine to CRBP-bound retinol. evidence_location: Abstract cross_nutrient: Phosphatidylcholine-dependent retinol storage links retinoid metabolism to choline-containing phospholipid availability. [va-macdonald-1988] A lecithin:retinol acyltransferase activity in human and rat liver (1988). https://pubmed.ncbi.nlm.nih.gov/3178828/ DOI: 10.1016/S0006-291X(88)80818-0
Complete structured claim and evidence
Lrat-null mice still secreted chylomicron retinyl esters whose acyl composition reflected the gavage oil.
Lecithin:retinol acyltransferase / LRAT → Chylomicron retinoid delivery source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Figure 3
experimental_model
Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet.
exposure
6 micrograms retinol in peanut oil; P-407 clearance blockade; sampling at three hours.
limitations
Clearance was pharmacologically blocked; remaining enzyme identity was not established here.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Lrat-null mice still secreted chylomicron retinyl esters whose acyl composition reflected the gavage oil.
plain_language
Alternative esterification partly handles absorbed retinol when LRAT is missing.
primary_references
[va-obyrne-2005] Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT) (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC1352312/ DOI: 10.1074/jbc.M507924200
tissue_or_cell_type
Intestine and isolated chylomicrons
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 346–358
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet. · source_derived_draft · unverified_draft
### va-lrat-chylomicron-retinoids Lrat-null mice still secreted chylomicron retinyl esters whose acyl composition reflected the gavage oil. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Alternative esterification partly handles absorbed retinol when LRAT is missing. organism: Mus musculus tissue_or_cell_type: Intestine and isolated chylomicrons experimental_model: Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet. limitations: Clearance was pharmacologically blocked; remaining enzyme identity was not established here. exposure: 6 micrograms retinol in peanut oil; P-407 clearance blockade; sampling at three hours. outcome: Lrat-null mice still secreted chylomicron retinyl esters whose acyl composition reflected the gavage oil. evidence_location: Figure 3 [va-obyrne-2005] Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT) (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC1352312/ DOI: 10.1074/jbc.M507924200
Complete structured claim and evidence
One month of dietary retinoid withdrawal lowered serum retinol in Lrat-null mice, with no comparable fall in wild type.
Lecithin:retinol acyltransferase / LRAT → Serum retinol concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_location
Figure 6
experimental_model
Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet.
exposure
Three-month-old males and females; one month of retinoid-free diet.
limitations
Combined genetic and dietary perturbation; not a human depletion timetable.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
One month of dietary retinoid withdrawal lowered serum retinol in Lrat-null mice, with no comparable fall in wild type.
plain_language
Poor storage made dietary vitamin A withdrawal affect blood retinol sooner.
primary_references
[va-obyrne-2005] Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT) (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC1352312/ DOI: 10.1074/jbc.M507924200
tissue_or_cell_type
Serum
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 360–372
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet. · source_derived_draft · unverified_draft
### va-lrat-dietary-depletion-retinol One month of dietary retinoid withdrawal lowered serum retinol in Lrat-null mice, with no comparable fall in wild type. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Poor storage made dietary vitamin A withdrawal affect blood retinol sooner. organism: Mus musculus tissue_or_cell_type: Serum experimental_model: Lrat-knockout mice; retinol gavage and one-month retinoid-deficient diet. limitations: Combined genetic and dietary perturbation; not a human depletion timetable. exposure: Three-month-old males and females; one month of retinoid-free diet. outcome: One month of dietary retinoid withdrawal lowered serum retinol in Lrat-null mice, with no comparable fall in wild type. evidence_location: Figure 6 [va-obyrne-2005] Retinoid Absorption and Storage Is Impaired in Mice Lacking Lecithin:Retinol Acyltransferase (LRAT) (2005). https://pmc.ncbi.nlm.nih.gov/articles/PMC1352312/ DOI: 10.1074/jbc.M507924200
Complete structured claim and evidence
Rbp4-null mice acquired hepatic vitamin A stores but could not mobilize them normally.
Retinol-binding protein 4 / RBP4 → Hepatic retinol mobilization source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Abstract
experimental_model
Rbp4-knockout mice on vitamin A-sufficient and deficient diets.
exposure
Rbp4 knockout under sufficient and deficient feeding.
limitations
Alternative delivery operates with adequate intake; RBP4 is not the sole tissue supply route.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Rbp4-null mice acquired hepatic vitamin A stores but could not mobilize them normally.
plain_language
Stored vitamin A can remain inaccessible when its transport protein is absent.
primary_references
[va-quadro-1999] Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein (1999). https://pmc.ncbi.nlm.nih.gov/articles/PMC1171537/ DOI: 10.1093/emboj/18.17.4633
tissue_or_cell_type
Liver and circulation
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 374–386
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rbp4-knockout mice on vitamin A-sufficient and deficient diets. · source_derived_draft · unverified_draft
### va-rbp4-store-mobilization Rbp4-null mice acquired hepatic vitamin A stores but could not mobilize them normally. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Stored vitamin A can remain inaccessible when its transport protein is absent. organism: Mus musculus tissue_or_cell_type: Liver and circulation experimental_model: Rbp4-knockout mice on vitamin A-sufficient and deficient diets. limitations: Alternative delivery operates with adequate intake; RBP4 is not the sole tissue supply route. exposure: Rbp4 knockout under sufficient and deficient feeding. outcome: Rbp4-null mice acquired hepatic vitamin A stores but could not mobilize them normally. evidence_location: Abstract [va-quadro-1999] Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein (1999). https://pmc.ncbi.nlm.nih.gov/articles/PMC1171537/ DOI: 10.1093/emboj/18.17.4633
Complete structured claim and evidence
Circulating retinol became undetectable after one week of vitamin A-deficient feeding in adult Rbp4-null mice.
Retinol-binding protein 4 / RBP4 → Serum retinol concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_location
Abstract
experimental_model
Rbp4-knockout mice on vitamin A-sufficient and deficient diets.
exposure
Adult Rbp4-null mice placed on vitamin A-deficient diet.
limitations
Assay undetectability is model-specific, not a universal cellular threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Circulating retinol became undetectable after one week of vitamin A-deficient feeding in adult Rbp4-null mice.
plain_language
Dietary supply could no longer compensate for lost transport from stores.
primary_references
[va-quadro-1999] Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein (1999). https://pmc.ncbi.nlm.nih.gov/articles/PMC1171537/ DOI: 10.1093/emboj/18.17.4633
tissue_or_cell_type
Serum
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 388–400
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rbp4-knockout mice on vitamin A-sufficient and deficient diets. · source_derived_draft · unverified_draft
### va-rbp4-dietary-withdrawal Circulating retinol became undetectable after one week of vitamin A-deficient feeding in adult Rbp4-null mice. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Dietary supply could no longer compensate for lost transport from stores. organism: Mus musculus tissue_or_cell_type: Serum experimental_model: Rbp4-knockout mice on vitamin A-sufficient and deficient diets. limitations: Assay undetectability is model-specific, not a universal cellular threshold. exposure: Adult Rbp4-null mice placed on vitamin A-deficient diet. outcome: Circulating retinol became undetectable after one week of vitamin A-deficient feeding in adult Rbp4-null mice. evidence_location: Abstract [va-quadro-1999] Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein (1999). https://pmc.ncbi.nlm.nih.gov/articles/PMC1171537/ DOI: 10.1093/emboj/18.17.4633
Complete structured claim and evidence
Ttr-null mice had plasma retinol averaging about 6% of wild type.
Transthyretin / TTR → Plasma retinol concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Abstract
experimental_model
Ttr-knockout mice; circulating and tissue retinoid assays.
exposure
Ttr knockout; pooled plasma comparison.
limitations
Not evidence that every tissue was depleted; the mechanism of the plasma fall was incompletely resolved.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Ttr-null mice had plasma retinol averaging about 6% of wild type.
plain_language
Loss of the RBP-associated carrier strongly lowers the blood measurement.
primary_references
[va-wei-1995] Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination (1995). https://pubmed.ncbi.nlm.nih.gov/7822324/ DOI: 10.1074/jbc.270.2.866
tissue_or_cell_type
Plasma
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 402–414
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ttr-knockout mice; circulating and tissue retinoid assays. · source_derived_draft · unverified_draft
### va-ttr-plasma-retinol Ttr-null mice had plasma retinol averaging about 6% of wild type. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of the RBP-associated carrier strongly lowers the blood measurement. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Ttr-knockout mice; circulating and tissue retinoid assays. limitations: Not evidence that every tissue was depleted; the mechanism of the plasma fall was incompletely resolved. exposure: Ttr knockout; pooled plasma comparison. outcome: Ttr-null mice had plasma retinol averaging about 6% of wild type. evidence_location: Abstract [va-wei-1995] Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination (1995). https://pubmed.ncbi.nlm.nih.gov/7822324/ DOI: 10.1074/jbc.270.2.866
Complete structured claim and evidence
Ttr-null mice maintained normal retinol/retinyl-ester levels in the tested liver and extrahepatic tissues despite low plasma retinol.
Transthyretin / TTR → Tissue retinoid stores source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_location
Abstract
experimental_model
Ttr-knockout mice; circulating and tissue retinoid assays.
exposure
Ttr knockout tissue assays.
limitations
Normal tissue pools do not establish every cell function or long-term diet-independent adequacy.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
outcome
Ttr-null mice maintained normal retinol/retinyl-ester levels in the tested liver and extrahepatic tissues despite low plasma retinol.
plain_language
Low blood retinol did not mean low stores in these sampled tissues.
primary_references
[va-wei-1995] Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination (1995). https://pubmed.ncbi.nlm.nih.gov/7822324/ DOI: 10.1074/jbc.270.2.866
tissue_or_cell_type
Liver, testis, kidney, spleen and eye cups
trigger_kind
biomarker_context Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 416–428
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ttr-knockout mice; circulating and tissue retinoid assays. · source_derived_draft · unverified_draft
### va-ttr-tissue-pool-boundary Ttr-null mice maintained normal retinol/retinyl-ester levels in the tested liver and extrahepatic tissues despite low plasma retinol. Condition category: biomarker_context nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low blood retinol did not mean low stores in these sampled tissues. organism: Mus musculus tissue_or_cell_type: Liver, testis, kidney, spleen and eye cups experimental_model: Ttr-knockout mice; circulating and tissue retinoid assays. limitations: Normal tissue pools do not establish every cell function or long-term diet-independent adequacy. exposure: Ttr knockout tissue assays. outcome: Ttr-null mice maintained normal retinol/retinyl-ester levels in the tested liver and extrahepatic tissues despite low plasma retinol. evidence_location: Abstract [va-wei-1995] Studies on the metabolism of retinol and retinol-binding protein in transthyretin-deficient mice produced by homologous recombination (1995). https://pubmed.ncbi.nlm.nih.gov/7822324/ DOI: 10.1074/jbc.270.2.866
Complete structured claim and evidence
STRA6 was identified as a high-affinity membrane receptor for retinol-binding protein.
Retinol uptake receptor STRA6 → Retinol-loaded RBP4 source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Receptor isolation from bovine retinal pigment epithelium and cellular uptake assays.
exposure
RBP-binding purification and receptor-expression assays.
limitations
Identification in RPE does not make STRA6 mandatory for every tissue.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus receptor-isolation material and transfected cells
outcome
STRA6 was identified as a high-affinity membrane receptor for retinol-binding protein.
plain_language
Cells recognize circulating retinol through its carrier protein.
primary_references
[va-kawaguchi-2007] A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A (2007). https://pubmed.ncbi.nlm.nih.gov/17255476/ DOI: 10.1126/science.1136244
tissue_or_cell_type
Retinal pigment epithelium and plasma membrane
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 430–442
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Receptor isolation from bovine retinal pigment epithelium and cellular uptake assays. · source_derived_draft · unverified_draft
### va-stra6-rbp-binding STRA6 was identified as a high-affinity membrane receptor for retinol-binding protein. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells recognize circulating retinol through its carrier protein. organism: Bos taurus receptor-isolation material and transfected cells tissue_or_cell_type: Retinal pigment epithelium and plasma membrane experimental_model: Receptor isolation from bovine retinal pigment epithelium and cellular uptake assays. limitations: Identification in RPE does not make STRA6 mandatory for every tissue. exposure: RBP-binding purification and receptor-expression assays. outcome: STRA6 was identified as a high-affinity membrane receptor for retinol-binding protein. evidence_location: Abstract [va-kawaguchi-2007] A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A (2007). https://pubmed.ncbi.nlm.nih.gov/17255476/ DOI: 10.1126/science.1136244
Complete structured claim and evidence
STRA6 accelerated retinol release from extracellular RBP in real-time assays.
Retinol uptake receptor STRA6 → All-trans-retinol source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Transfected-cell radioretinol uptake and real-time retinol-release assays.
exposure
Retinol-loaded RBP and STRA6 expression.
limitations
In vitro transport mechanism; no organism-wide flux estimate. Cell-line species were not resolved in the retrieved abstract/figure evidence; no species-specific extension is asserted.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mammalian transfected-cell preparations
outcome
STRA6 accelerated retinol release from extracellular RBP in real-time assays.
plain_language
The receptor unloads retinol from its blood carrier.
primary_references
[va-kawaguchi-2011] Receptor-mediated cellular uptake mechanism that couples to intracellular storage (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3199320/ DOI: 10.1021/cb200178w
tissue_or_cell_type
Plasma membrane
transport_direction
extracellular holo-RBP4 to membrane/cell
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 444–457
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected-cell radioretinol uptake and real-time retinol-release assays. · source_derived_draft · unverified_draft
### va-stra6-retinol-release STRA6 accelerated retinol release from extracellular RBP in real-time assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The receptor unloads retinol from its blood carrier. organism: Mammalian transfected-cell preparations tissue_or_cell_type: Plasma membrane experimental_model: Transfected-cell radioretinol uptake and real-time retinol-release assays. limitations: In vitro transport mechanism; no organism-wide flux estimate. Cell-line species were not resolved in the retrieved abstract/figure evidence; no species-specific extension is asserted. exposure: Retinol-loaded RBP and STRA6 expression. outcome: STRA6 accelerated retinol release from extracellular RBP in real-time assays. evidence_location: Abstract transport_direction: extracellular holo-RBP4 to membrane/cell [va-kawaguchi-2011] Receptor-mediated cellular uptake mechanism that couples to intracellular storage (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3199320/ DOI: 10.1021/cb200178w
Complete structured claim and evidence
Coexpression of LRAT enhanced STRA6-mediated retinol uptake by coupling transport to ester storage.
Lecithin:retinol acyltransferase / LRAT → STRA6-mediated retinol uptake source_derived_draftungraded
Experimental context and source evidence
evidence_location
Figure 1
experimental_model
Transfected-cell radioretinol uptake and real-time retinol-release assays.
exposure
STRA6 with or without LRAT; radiolabeled holo-RBP uptake.
limitations
No single intracellular protein was absolutely required for STRA6 activity. Cell-line species were not resolved in the retrieved abstract/figure evidence; no species-specific extension is asserted.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mammalian transfected cells
outcome
Coexpression of LRAT enhanced STRA6-mediated retinol uptake by coupling transport to ester storage.
plain_language
Retinol esterification helps keep inward uptake moving.
primary_references
[va-kawaguchi-2011] Receptor-mediated cellular uptake mechanism that couples to intracellular storage (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3199320/ DOI: 10.1021/cb200178w
tissue_or_cell_type
Plasma membrane and intracellular retinoid compartment
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 459–471
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected-cell radioretinol uptake and real-time retinol-release assays. · source_derived_draft · unverified_draft
### va-lrat-couples-stra6 Coexpression of LRAT enhanced STRA6-mediated retinol uptake by coupling transport to ester storage. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Retinol esterification helps keep inward uptake moving. organism: Mammalian transfected cells tissue_or_cell_type: Plasma membrane and intracellular retinoid compartment experimental_model: Transfected-cell radioretinol uptake and real-time retinol-release assays. limitations: No single intracellular protein was absolutely required for STRA6 activity. Cell-line species were not resolved in the retrieved abstract/figure evidence; no species-specific extension is asserted. exposure: STRA6 with or without LRAT; radiolabeled holo-RBP uptake. outcome: Coexpression of LRAT enhanced STRA6-mediated retinol uptake by coupling transport to ester storage. evidence_location: Figure 1 [va-kawaguchi-2011] Receptor-mediated cellular uptake mechanism that couples to intracellular storage (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3199320/ DOI: 10.1021/cb200178w
Complete structured claim and evidence
Cellular RBP1 enhanced STRA6-mediated uptake of RBP-bound retinol.
Cellular retinol-binding protein 1 / RBP1 → STRA6-mediated retinol uptake source_derived_draftungraded
Experimental context and source evidence
evidence_location
Figure 1
experimental_model
Transfected-cell radioretinol uptake and real-time retinol-release assays.
exposure
STRA6 plus CRBP-I compared with STRA6 alone.
limitations
Coupling is supported, but absolute RBP1 dependence is not. Cell-line species were not resolved in the retrieved abstract/figure evidence; no species-specific extension is asserted.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mammalian transfected cells
outcome
Cellular RBP1 enhanced STRA6-mediated uptake of RBP-bound retinol.
plain_language
An intracellular retinol-binding protein helps retain delivered vitamin A.
primary_references
[va-kawaguchi-2011] Receptor-mediated cellular uptake mechanism that couples to intracellular storage (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3199320/ DOI: 10.1021/cb200178w
tissue_or_cell_type
Plasma membrane and cytoplasm
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 473–485
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected-cell radioretinol uptake and real-time retinol-release assays. · source_derived_draft · unverified_draft
### va-rbp1-couples-stra6 Cellular RBP1 enhanced STRA6-mediated uptake of RBP-bound retinol. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An intracellular retinol-binding protein helps retain delivered vitamin A. organism: Mammalian transfected cells tissue_or_cell_type: Plasma membrane and cytoplasm experimental_model: Transfected-cell radioretinol uptake and real-time retinol-release assays. limitations: Coupling is supported, but absolute RBP1 dependence is not. Cell-line species were not resolved in the retrieved abstract/figure evidence; no species-specific extension is asserted. exposure: STRA6 plus CRBP-I compared with STRA6 alone. outcome: Cellular RBP1 enhanced STRA6-mediated uptake of RBP-bound retinol. evidence_location: Figure 1 [va-kawaguchi-2011] Receptor-mediated cellular uptake mechanism that couples to intracellular storage (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3199320/ DOI: 10.1021/cb200178w
Complete structured claim and evidence
Silencing endogenous RDH10 reduced retinoic-acid production from retinol in human cells.
Retinol dehydrogenase 10 / RDH10 → All-trans-retinoic-acid biosynthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Experimental Procedures: siRNA-mediated Knockdowns; Results: endogenous SDR silencing
experimental_model
Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells.
exposure
RDH10 siRNA at 100 nanomolar, two transfections 24 hours apart; 10 micromolar retinol for 24 hours after silencing.
limitations
Residual activity and other enzymes prevent an exclusive RDH10 interpretation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
outcome
Silencing endogenous RDH10 reduced retinoic-acid production from retinol in human cells.
plain_language
Reducing precursor oxidation lowered downstream active retinoid production.
primary_references
[va-belyaeva-2008] Kinetic Analysis of Human Enzyme RDH10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2459273/ DOI: 10.1074/jbc.M800019200
tissue_or_cell_type
HEK293 cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 502–514
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells. · source_derived_draft · unverified_draft
### va-rdh10-silencing-ra Silencing endogenous RDH10 reduced retinoic-acid production from retinol in human cells. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing precursor oxidation lowered downstream active retinoid production. organism: Homo sapiens tissue_or_cell_type: HEK293 cells experimental_model: Human RDH10 in Sf9 microsomes and siRNA perturbation in human cells. limitations: Residual activity and other enzymes prevent an exclusive RDH10 interpretation. exposure: RDH10 siRNA at 100 nanomolar, two transfections 24 hours apart; 10 micromolar retinol for 24 hours after silencing. outcome: Silencing endogenous RDH10 reduced retinoic-acid production from retinol in human cells. evidence_location: Experimental Procedures: siRNA-mediated Knockdowns; Results: endogenous SDR silencing [va-belyaeva-2008] Kinetic Analysis of Human Enzyme RDH10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2459273/ DOI: 10.1074/jbc.M800019200
Complete structured claim and evidence
RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH.
Dehydrogenase/reductase 3 / DHRS3 → All-trans-retinol source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
NADPH supports a retinoid buffering reaction.
evidence_location
Figure 5 and Table 1
experimental_model
Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos.
exposure
DHRS3 coexpressed with RDH10; retinal plus NADPH.
limitations
Cofactor dependency is not a dietary niacin intervention.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens proteins in Sf9 and HEK293 systems
outcome
RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH.
plain_language
This reverse step restrains retinal available for acid production.
primary_references
[va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257
tissue_or_cell_type
Microsomal/cellular retinoid system
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 516–529
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. · source_derived_draft · unverified_draft
### va-dhrs3-retinal-reduction RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This reverse step restrains retinal available for acid production. organism: Homo sapiens proteins in Sf9 and HEK293 systems tissue_or_cell_type: Microsomal/cellular retinoid system experimental_model: Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. limitations: Cofactor dependency is not a dietary niacin intervention. exposure: DHRS3 coexpressed with RDH10; retinal plus NADPH. outcome: RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH. evidence_location: Figure 5 and Table 1 cross_nutrient: NADPH supports a retinoid buffering reaction. [va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257
Complete structured claim and evidence
RDH10 coexpression increased DHRS3 retinaldehyde reductase activity even when RDH10 itself was catalytically inactive.
Retinol dehydrogenase 10 / RDH10 → Dehydrogenase/reductase 3 / DHRS3 source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos.
exposure
Coexpression including inactive RDH10 constructs.
limitations
Does not identify an exact complex stoichiometry or require substrate channeling.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant proteins
outcome
RDH10 coexpression increased DHRS3 retinaldehyde reductase activity even when RDH10 itself was catalytically inactive.
plain_language
The partner enzyme also acts through a noncatalytic interaction.
primary_references
[va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257
tissue_or_cell_type
Sf9 microsomes and HEK293 cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 531–543
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. · source_derived_draft · unverified_draft
### va-rdh10-activates-dhrs3 RDH10 coexpression increased DHRS3 retinaldehyde reductase activity even when RDH10 itself was catalytically inactive. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The partner enzyme also acts through a noncatalytic interaction. organism: Homo sapiens recombinant proteins tissue_or_cell_type: Sf9 microsomes and HEK293 cells experimental_model: Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. limitations: Does not identify an exact complex stoichiometry or require substrate channeling. exposure: Coexpression including inactive RDH10 constructs. outcome: RDH10 coexpression increased DHRS3 retinaldehyde reductase activity even when RDH10 itself was catalytically inactive. evidence_location: Abstract [va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257
Complete structured claim and evidence
DHRS3 coexpression enhanced RDH10 retinol dehydrogenase activity independently of DHRS3 catalytic activity.
Dehydrogenase/reductase 3 / DHRS3 → Retinol dehydrogenase 10 / RDH10 source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos.
exposure
Coexpression including inactive DHRS3 constructs.
limitations
Net retinoic-acid output depends on both opposing reactions and cellular conditions.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant proteins
outcome
DHRS3 coexpression enhanced RDH10 retinol dehydrogenase activity independently of DHRS3 catalytic activity.
plain_language
The two enzymes mutually stimulate one another.
primary_references
[va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257
tissue_or_cell_type
Sf9 microsomes and HEK293 cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 545–557
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. · source_derived_draft · unverified_draft
### va-dhrs3-activates-rdh10 DHRS3 coexpression enhanced RDH10 retinol dehydrogenase activity independently of DHRS3 catalytic activity. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two enzymes mutually stimulate one another. organism: Homo sapiens recombinant proteins tissue_or_cell_type: Sf9 microsomes and HEK293 cells experimental_model: Human RDH10/DHRS3 coexpression in HEK293 and Sf9 cells, plus Dhrs3-null embryos. limitations: Net retinoic-acid output depends on both opposing reactions and cellular conditions. exposure: Coexpression including inactive DHRS3 constructs. outcome: DHRS3 coexpression enhanced RDH10 retinol dehydrogenase activity independently of DHRS3 catalytic activity. evidence_location: Abstract [va-adams-2014] The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4031538/ DOI: 10.1074/jbc.M114.552257
Complete structured claim and evidence
Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.
Aldehyde dehydrogenase 1A1 / ALDH1A1 → All-trans-retinoic acid source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays.
exposure
Side-by-side retinaldehyde kinetic measurements by HPLC.
limitations
In vitro catalytic efficiency does not specify its contribution in a particular tissue.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein
outcome
Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.
plain_language
This independently identified enzyme supplies the acid form used for signaling.
primary_references
[va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 559–571
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. · source_derived_draft · unverified_draft
### va-aldh1a1-retinal-oxidation Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified enzyme supplies the acid form used for signaling. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. limitations: In vitro catalytic efficiency does not specify its contribution in a particular tissue. exposure: Side-by-side retinaldehyde kinetic measurements by HPLC. outcome: Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. evidence_location: Abstract [va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256
Complete structured claim and evidence
Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.
Aldehyde dehydrogenase 1A2 / ALDH1A2 → All-trans-retinoic acid source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays.
exposure
Side-by-side retinaldehyde kinetic measurements by HPLC.
limitations
In vitro catalytic efficiency does not specify its contribution in a particular tissue.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein
outcome
Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.
plain_language
This independently identified enzyme supplies the acid form used for signaling.
primary_references
[va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 573–585
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. · source_derived_draft · unverified_draft
### va-aldh1a2-retinal-oxidation Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified enzyme supplies the acid form used for signaling. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. limitations: In vitro catalytic efficiency does not specify its contribution in a particular tissue. exposure: Side-by-side retinaldehyde kinetic measurements by HPLC. outcome: Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. evidence_location: Abstract [va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256
Complete structured claim and evidence
Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.
Aldehyde dehydrogenase 1A3 / ALDH1A3 → All-trans-retinoic acid source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays.
exposure
Side-by-side retinaldehyde kinetic measurements by HPLC.
limitations
In vitro catalytic efficiency does not specify its contribution in a particular tissue.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein
outcome
Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.
plain_language
This independently identified enzyme supplies the acid form used for signaling.
primary_references
[va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256
tissue_or_cell_type
Cell-free enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 587–599
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. · source_derived_draft · unverified_draft
### va-aldh1a3-retinal-oxidation Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This independently identified enzyme supplies the acid form used for signaling. organism: Homo sapiens recombinant protein tissue_or_cell_type: Cell-free enzyme experimental_model: Side-by-side recombinant human ALDH1A1, ALDH1A2 and ALDH1A3 kinetic assays. limitations: In vitro catalytic efficiency does not specify its contribution in a particular tissue. exposure: Side-by-side retinaldehyde kinetic measurements by HPLC. outcome: Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays. evidence_location: Abstract [va-pequerul-2020] Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis (2020). https://pubmed.ncbi.nlm.nih.gov/31923393/ DOI: 10.1016/j.abb.2020.108256
Complete structured claim and evidence
Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid.
Cytochrome P450 26A1 / CYP26A1 → 4-Hydroxy-all-trans-retinoic acid source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
NADPH and heme-containing P450 machinery support retinoid oxidation; nutritional deficiency was not tested.
evidence_location
Abstract
experimental_model
Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays.
exposure
All-trans-retinoic-acid concentration series with P450 reductase and NADPH.
limitations
Assay kinetics are not whole-body clearance; hydroxylated products are not assumed biologically inert.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein in insect cells
outcome
Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid.
plain_language
This P450 begins oxidative removal of the signaling retinoid.
primary_references
[va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007
tissue_or_cell_type
Reconstituted enzyme/microsomes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 601–614
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. · source_derived_draft · unverified_draft
### va-cyp26a1-primary-hydroxylation Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This P450 begins oxidative removal of the signaling retinoid. organism: Homo sapiens recombinant protein in insect cells tissue_or_cell_type: Reconstituted enzyme/microsomes experimental_model: Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. limitations: Assay kinetics are not whole-body clearance; hydroxylated products are not assumed biologically inert. exposure: All-trans-retinoic-acid concentration series with P450 reductase and NADPH. outcome: Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid. evidence_location: Abstract cross_nutrient: NADPH and heme-containing P450 machinery support retinoid oxidation; nutritional deficiency was not tested. [va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007
Complete structured claim and evidence
CYP26A1 further metabolized 4-hydroxy-all-trans-retinoic acid.
Cytochrome P450 26A1 / CYP26A1 → Oxidative clearance of retinoic-acid metabolites source_derived_draftungraded
Experimental context and source evidence
evidence_location
Abstract
experimental_model
Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays.
exposure
Incubation with 4-hydroxy-all-trans-retinoic acid.
limitations
This assay does not assign every downstream metabolite a structure or biological inactivity.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens recombinant protein
outcome
CYP26A1 further metabolized 4-hydroxy-all-trans-retinoic acid.
plain_language
Oxidation continues beyond the first hydroxylated product.
primary_references
[va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007
tissue_or_cell_type
Reconstituted enzyme
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 630–642
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. · source_derived_draft · unverified_draft
### va-cyp26a1-secondary-metabolism CYP26A1 further metabolized 4-hydroxy-all-trans-retinoic acid. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Oxidation continues beyond the first hydroxylated product. organism: Homo sapiens recombinant protein tissue_or_cell_type: Reconstituted enzyme experimental_model: Human CYP26A1/CYP26B1 expressed in insect cells; purified/reconstituted metabolism and tissue assays. limitations: This assay does not assign every downstream metabolite a structure or biological inactivity. exposure: Incubation with 4-hydroxy-all-trans-retinoic acid. outcome: CYP26A1 further metabolized 4-hydroxy-all-trans-retinoic acid. evidence_location: Abstract [va-topletz-2012] Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases (2012). https://pubmed.ncbi.nlm.nih.gov/22020119/ DOI: 10.1016/j.bcp.2011.10.007
Complete structured claim and evidence
Bovine rhodopsin crystallography identifies 11-cis-retinal within the inactive seven-helix receptor.
11-cis-retinal → Rhodopsin source_derived_draftungraded
Experimental context and source evidence
experimental_model
2.8-angstrom crystal structure
limitations
A static ground-state structure does not measure dietary requirements.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
The cis retinal isomer is the rod pigment chromophore.
primary_references
[palczewski-2000] Crystal structure of rhodopsin: A G protein-coupled receptor (2000). https://pubmed.ncbi.nlm.nih.gov/10926528/ DOI: 10.1126/science.289.5480.739
tissue_or_cell_type
Rod photopigment
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 644–653
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 2.8-angstrom crystal structure · source_derived_draft · unverified_draft
### a-vision-chromophore Bovine rhodopsin crystallography identifies 11-cis-retinal within the inactive seven-helix receptor. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cis retinal isomer is the rod pigment chromophore. organism: Bos taurus tissue_or_cell_type: Rod photopigment experimental_model: 2.8-angstrom crystal structure limitations: A static ground-state structure does not measure dietary requirements. [palczewski-2000] Crystal structure of rhodopsin: A G protein-coupled receptor (2000). https://pubmed.ncbi.nlm.nih.gov/10926528/ DOI: 10.1126/science.289.5480.739
Complete structured claim and evidence
Light activation changes rhodopsin-bound 11-cis-retinal into its all-trans geometry, coupled to receptor activation.
11-cis-retinal → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
experimental_model
Solid-state NMR before/after illumination
limitations
Bound chromophore conversion precedes release of free retinal.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
A photon changes the bound retinoid shape and starts the signal.
primary_references
[grobner-2000] Observations of light-induced structural changes of retinal within rhodopsin (2000). https://www.nature.com/articles/35015604 DOI: 10.1038/35015604
tissue_or_cell_type
Purified rhodopsin
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 655–664
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Solid-state NMR before/after illumination · source_derived_draft · unverified_draft
### a-vision-photoisomerization Light activation changes rhodopsin-bound 11-cis-retinal into its all-trans geometry, coupled to receptor activation. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A photon changes the bound retinoid shape and starts the signal. organism: Bos taurus tissue_or_cell_type: Purified rhodopsin experimental_model: Solid-state NMR before/after illumination limitations: Bound chromophore conversion precedes release of free retinal. [grobner-2000] Observations of light-induced structural changes of retinal within rhodopsin (2000). https://www.nature.com/articles/35015604 DOI: 10.1038/35015604
Complete structured claim and evidence
ZnCl2 did not restore isomerohydrolase activity after metal chelation in the bovine RPE assay, whereas FeSO4 did.
Zinc(II) ion → RPE65 retinoid isomerohydrolase source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Iron and zinc are not interchangeable RPE65 cofactors in the tested preparation.
experimental_model
Metal-rescue comparison
limitations
Does not test systemic zinc status or other zinc-dependent visual functions.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
Zinc could not replace iron in this enzyme assay.
primary_references
[moiseyev-2006] RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle (2006). https://pubmed.ncbi.nlm.nih.gov/16319067/ DOI: 10.1074/jbc.M508903200
tissue_or_cell_type
RPE microsomes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 689–699
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metal-rescue comparison · source_derived_draft · unverified_draft
### a-vision-rpe65-zinc-not-substitute ZnCl2 did not restore isomerohydrolase activity after metal chelation in the bovine RPE assay, whereas FeSO4 did. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc could not replace iron in this enzyme assay. organism: Bos taurus tissue_or_cell_type: RPE microsomes experimental_model: Metal-rescue comparison limitations: Does not test systemic zinc status or other zinc-dependent visual functions. cross_nutrient: Iron and zinc are not interchangeable RPE65 cofactors in the tested preparation. [moiseyev-2006] RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle (2006). https://pubmed.ncbi.nlm.nih.gov/16319067/ DOI: 10.1074/jbc.M508903200
Complete structured claim and evidence
Lrat deletion severely depleted the ocular all-trans-retinyl ester pool in mice.
LRAT loss → All-trans-retinyl esters source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Lrat knockout versus controls
limitations
Other tissues and dietary deficiency are separate questions.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Without LRAT, the eye cannot maintain its normal ester reserve.
primary_references
[batten-2004] Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver (2004). https://pubmed.ncbi.nlm.nih.gov/14684738/ DOI: 10.1074/jbc.M312410200
tissue_or_cell_type
Eye/RPE
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 701–710
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lrat knockout versus controls · source_derived_draft · unverified_draft
### a-vision-lrat-esters Lrat deletion severely depleted the ocular all-trans-retinyl ester pool in mice. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Without LRAT, the eye cannot maintain its normal ester reserve. organism: Mus musculus tissue_or_cell_type: Eye/RPE experimental_model: Lrat knockout versus controls limitations: Other tissues and dietary deficiency are separate questions. [batten-2004] Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver (2004). https://pubmed.ncbi.nlm.nih.gov/14684738/ DOI: 10.1074/jbc.M312410200
Complete structured claim and evidence
Lrat-null mice had severely attenuated rod and cone visual function by electroretinography and pupil-response testing.
LRAT loss → Visual sensitivity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Electroretinography and pupillary constriction
limitations
The phenotype tests a genetic esterification defect.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Loss of retinol esterification impaired measured vision.
primary_references
[batten-2004] Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver (2004). https://pubmed.ncbi.nlm.nih.gov/14684738/ DOI: 10.1074/jbc.M312410200
tissue_or_cell_type
Eye
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 712–721
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electroretinography and pupillary constriction · source_derived_draft · unverified_draft
### a-vision-lrat-visual-function Lrat-null mice had severely attenuated rod and cone visual function by electroretinography and pupil-response testing. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of retinol esterification impaired measured vision. organism: Mus musculus tissue_or_cell_type: Eye experimental_model: Electroretinography and pupillary constriction limitations: The phenotype tests a genetic esterification defect. [batten-2004] Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver (2004). https://pubmed.ncbi.nlm.nih.gov/14684738/ DOI: 10.1074/jbc.M312410200
Complete structured claim and evidence
RDH5 variants segregating with fundus albipunctatus showed lower recombinant enzyme activity than wild type.
Pathogenic RDH5 variants → 11-cis-retinol dehydrogenase / RDH5 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Patient genetics and recombinant enzyme assay
limitations
Variants were evaluated in a small number of families.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
The inherited protein changes weaken the recycling reaction.
primary_references
[yamamoto-1999] Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus (1999). https://pubmed.ncbi.nlm.nih.gov/10369264/ DOI: 10.1038/9707
tissue_or_cell_type
RPE enzyme model
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 734–743
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient genetics and recombinant enzyme assay · source_derived_draft · unverified_draft
### a-vision-rdh5-mutant-activity RDH5 variants segregating with fundus albipunctatus showed lower recombinant enzyme activity than wild type. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The inherited protein changes weaken the recycling reaction. organism: Homo sapiens tissue_or_cell_type: RPE enzyme model experimental_model: Patient genetics and recombinant enzyme assay limitations: Variants were evaluated in a small number of families. [yamamoto-1999] Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus (1999). https://pubmed.ncbi.nlm.nih.gov/10369264/ DOI: 10.1038/9707
Complete structured claim and evidence
The RDH5-associated fundus albipunctatus phenotype included delayed visual-pigment regeneration and night blindness.
Pathogenic RDH5 variants → Rod dark adaptation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Clinical phenotype and family segregation
limitations
Genetic association plus enzyme evidence; not a supplementation trial.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
A recycling defect can delay vision recovery in darkness despite a different cause from dietary deficiency.
primary_references
[yamamoto-1999] Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus (1999). https://pubmed.ncbi.nlm.nih.gov/10369264/ DOI: 10.1038/9707
tissue_or_cell_type
Retina
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 745–754
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical phenotype and family segregation · source_derived_draft · unverified_draft
### a-vision-rdh5-night-adaptation The RDH5-associated fundus albipunctatus phenotype included delayed visual-pigment regeneration and night blindness. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A recycling defect can delay vision recovery in darkness despite a different cause from dietary deficiency. organism: Homo sapiens tissue_or_cell_type: Retina experimental_model: Clinical phenotype and family segregation limitations: Genetic association plus enzyme evidence; not a supplementation trial. [yamamoto-1999] Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus (1999). https://pubmed.ncbi.nlm.nih.gov/10369264/ DOI: 10.1038/9707
Complete structured claim and evidence
Single-cell knockout comparisons showed RDH8 supplies most reduction of bleach-generated all-trans-retinal in mouse rod outer segments.
Retinol dehydrogenase 8 / RDH8 → All-trans-retinol source_derived_draftungraded
Experimental context and source evidence
experimental_model
Wild-type/Rdh8-null/Rdh12-null rod fluorescence
limitations
Residual reductases exist; this does not establish an exclusive enzyme.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RDH8 converts the aldehyde photoproduct back to retinol in the outer segment.
primary_references
[chen-2012] Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12 (2012). https://pubmed.ncbi.nlm.nih.gov/22621924/ DOI: 10.1074/jbc.M112.354514
tissue_or_cell_type
Rod outer segment
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 756–765
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Wild-type/Rdh8-null/Rdh12-null rod fluorescence · source_derived_draft · unverified_draft
### a-vision-rdh8-reduction Single-cell knockout comparisons showed RDH8 supplies most reduction of bleach-generated all-trans-retinal in mouse rod outer segments. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RDH8 converts the aldehyde photoproduct back to retinol in the outer segment. organism: Mus musculus tissue_or_cell_type: Rod outer segment experimental_model: Wild-type/Rdh8-null/Rdh12-null rod fluorescence limitations: Residual reductases exist; this does not establish an exclusive enzyme. [chen-2012] Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12 (2012). https://pubmed.ncbi.nlm.nih.gov/22621924/ DOI: 10.1074/jbc.M112.354514
Complete structured claim and evidence
Mouse rod imaging identified RDH12-dependent reduction of retinaldehyde entering inner segments from the outer segment or extracellular medium.
Retinol dehydrogenase 12 / RDH12 → Photoreceptor retinaldehyde reduction source_derived_draftungraded
Experimental context and source evidence
experimental_model
Knockout rod imaging and exogenous retinal challenge
limitations
The inferred protection of organelles is not itself a clinical outcome.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RDH12 helps clear retinal that reaches the cell interior.
primary_references
[chen-2012] Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12 (2012). https://pubmed.ncbi.nlm.nih.gov/22621924/ DOI: 10.1074/jbc.M112.354514
tissue_or_cell_type
Rod inner segment
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 767–776
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Knockout rod imaging and exogenous retinal challenge · source_derived_draft · unverified_draft
### a-vision-rdh12-reduction Mouse rod imaging identified RDH12-dependent reduction of retinaldehyde entering inner segments from the outer segment or extracellular medium. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RDH12 helps clear retinal that reaches the cell interior. organism: Mus musculus tissue_or_cell_type: Rod inner segment experimental_model: Knockout rod imaging and exogenous retinal challenge limitations: The inferred protection of organelles is not itself a clinical outcome. [chen-2012] Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12 (2012). https://pubmed.ncbi.nlm.nih.gov/22621924/ DOI: 10.1074/jbc.M112.354514
Complete structured claim and evidence
Purified human RDH12 used NADPH for retinal reduction and had much lower apparent cofactor Km for NADP(H) than NAD(H).
NADPH → Retinol dehydrogenase 12 / RDH12 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified-enzyme cofactor/substrate kinetics
limitations
Biochemical cofactor preference does not demonstrate a dietary niacin-deficiency visual phenotype.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens protein
plain_language
The reductase uses NADPH reducing power to convert retinal into retinol.
primary_references
[belyaeva-2005] Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids (2005). https://pubmed.ncbi.nlm.nih.gov/15865448/ DOI: 10.1021/bi050226k
tissue_or_cell_type
Recombinant enzyme preparation
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 778–787
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified-enzyme cofactor/substrate kinetics · source_derived_draft · unverified_draft
### a-vision-rdh12-nadph Purified human RDH12 used NADPH for retinal reduction and had much lower apparent cofactor Km for NADP(H) than NAD(H). Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The reductase uses NADPH reducing power to convert retinal into retinol. organism: Homo sapiens protein tissue_or_cell_type: Recombinant enzyme preparation experimental_model: Purified-enzyme cofactor/substrate kinetics limitations: Biochemical cofactor preference does not demonstrate a dietary niacin-deficiency visual phenotype. [belyaeva-2005] Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids (2005). https://pubmed.ncbi.nlm.nih.gov/15865448/ DOI: 10.1021/bi050226k
Complete structured claim and evidence
IRBP at at least 10 micromolar increased all-trans-retinol release from bleached isolated toad retina during dark incubation.
Interphotoreceptor retinoid-binding protein / IRBP → Retinal all-trans-retinol release source_derived_draftungraded
Experimental context and source evidence
experimental_model
2-90 micromolar IRBP; 5-180-minute incubation; HPLC
limitations
Measures release, not the entire in vivo round trip to RPE.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bufo marinus
plain_language
Extracellular IRBP helps remove retinol from the bleached retina.
primary_references
[qtaishat-2005] Interphotoreceptor retinoid-binding protein (IRBP) promotes the release of all-trans retinol from the isolated retina following rhodopsin bleaching illumination (2005). https://pubmed.ncbi.nlm.nih.gov/15935345/ DOI: 10.1016/j.exer.2005.03.005
tissue_or_cell_type
Isolated retina and extracellular medium
transport_direction
retina to extracellular medium
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 789–799
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 2-90 micromolar IRBP; 5-180-minute incubation; HPLC · source_derived_draft · unverified_draft
### a-vision-irbp-retinol-release IRBP at at least 10 micromolar increased all-trans-retinol release from bleached isolated toad retina during dark incubation. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extracellular IRBP helps remove retinol from the bleached retina. organism: Bufo marinus tissue_or_cell_type: Isolated retina and extracellular medium experimental_model: 2-90 micromolar IRBP; 5-180-minute incubation; HPLC limitations: Measures release, not the entire in vivo round trip to RPE. transport_direction: retina to extracellular medium [qtaishat-2005] Interphotoreceptor retinoid-binding protein (IRBP) promotes the release of all-trans retinol from the isolated retina following rhodopsin bleaching illumination (2005). https://pubmed.ncbi.nlm.nih.gov/15935345/ DOI: 10.1016/j.exer.2005.03.005
Complete structured claim and evidence
ABCA4 drove ATP-dependent transport of retinal-PE adduct from the disc lumen-facing leaflet toward the cytoplasmic leaflet.
ABCA4 retinoid transporter → N-retinylidene-phosphatidylethanolamine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Proteoliposomes and native disc transport assays
limitations
The assayed substrate is the adduct, not a requirement for free retinal diffusion.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bovine/mouse discs; recombinant transporter
plain_language
ABCA4 moves the trapped retinal-lipid adduct to the disposal side of the disc.
primary_references
[quazi-2012] ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3871175/ DOI: 10.1038/ncomms1927
tissue_or_cell_type
Photoreceptor disc membrane
transport_direction
disc lumen leaflet to cytoplasmic leaflet
transport_effect
raises Recorded as ATP-dependent transport from the disc lumen-facing leaflet toward the cytoplasmic leaflet.
transport_pool
the cytoplasmic leaflet of the disc membrane Recorded as ATP-dependent transport from the disc lumen-facing leaflet toward the cytoplasmic leaflet.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 801–811
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Proteoliposomes and native disc transport assays · source_derived_draft · unverified_draft
### a-vision-abca4-retinoid-flip ABCA4 drove ATP-dependent transport of retinal-PE adduct from the disc lumen-facing leaflet toward the cytoplasmic leaflet. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: ABCA4 moves the trapped retinal-lipid adduct to the disposal side of the disc. organism: Bovine/mouse discs; recombinant transporter tissue_or_cell_type: Photoreceptor disc membrane experimental_model: Proteoliposomes and native disc transport assays limitations: The assayed substrate is the adduct, not a requirement for free retinal diffusion. transport_direction: disc lumen leaflet to cytoplasmic leaflet [quazi-2012] ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3871175/ DOI: 10.1038/ncomms1927
Complete structured claim and evidence
Reconstituted ABCA4 also transported phosphatidylethanolamine in the import orientation.
ABCA4 retinoid transporter → Phosphatidylethanolamine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Fluorescent lipid transport
limitations
Lipid transport alone does not prove the complete visual-cycle flux.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Purified/reconstituted transporter
plain_language
The transporter can move PE as well as its retinal adduct.
primary_references
[quazi-2012] ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3871175/ DOI: 10.1038/ncomms1927
tissue_or_cell_type
Model membranes
transport_direction
lumen-equivalent leaflet to cytoplasmic-equivalent leaflet
transport_effect
raises Recorded as transport in the import orientation in the reconstituted system.
transport_pool
the cytoplasmic leaflet of the disc membrane Recorded as transport in the import orientation in the reconstituted system.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 813–823
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fluorescent lipid transport · source_derived_draft · unverified_draft
### a-vision-abca4-pe-flip Reconstituted ABCA4 also transported phosphatidylethanolamine in the import orientation. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The transporter can move PE as well as its retinal adduct. organism: Purified/reconstituted transporter tissue_or_cell_type: Model membranes experimental_model: Fluorescent lipid transport limitations: Lipid transport alone does not prove the complete visual-cycle flux. transport_direction: lumen-equivalent leaflet to cytoplasmic-equivalent leaflet [quazi-2012] ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3871175/ DOI: 10.1038/ncomms1927
Complete structured claim and evidence
Abca4/Rdh8 double-knockout mice developed early RPE/photoreceptor dystrophy in the retinal-clearance study.
Combined RDH8 and ABCA4 loss → Retinal degeneration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Double-knockout retinoid and retinal phenotype
limitations
Light and genetic background influence phenotype; the experiment does not isolate A2E as sole cause.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Removing both disposal routes made the retina vulnerable.
primary_references
[maeda-2008] Retinopathy in mice induced by disrupted all-trans-retinal clearance (2008). https://pubmed.ncbi.nlm.nih.gov/18658157/ DOI: 10.1074/jbc.M804505200
tissue_or_cell_type
RPE and photoreceptors
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 825–834
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-knockout retinoid and retinal phenotype · source_derived_draft · unverified_draft
### a-vision-clearance-retinopathy Abca4/Rdh8 double-knockout mice developed early RPE/photoreceptor dystrophy in the retinal-clearance study. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing both disposal routes made the retina vulnerable. organism: Mus musculus tissue_or_cell_type: RPE and photoreceptors experimental_model: Double-knockout retinoid and retinal phenotype limitations: Light and genetic background influence phenotype; the experiment does not isolate A2E as sole cause. [maeda-2008] Retinopathy in mice induced by disrupted all-trans-retinal clearance (2008). https://pubmed.ncbi.nlm.nih.gov/18658157/ DOI: 10.1074/jbc.M804505200
Complete structured claim and evidence
Single, double and triple Rdh8/Rdh12/Abca4 knockout comparisons showed greater age-dependent ocular A2E accumulation than wild type.
RDH8/RDH12/ABCA4 knockout genotypes → A2E bisretinoid source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
HPLC at 3 and 6 months
limitations
Genotypes differ in severity; accumulation is not equivalent to demonstrated cell death.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Defects in retinal disposal increase a bisretinoid by-product.
primary_references
[maeda-2009] Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina (2009). https://pubmed.ncbi.nlm.nih.gov/19553623/ DOI: 10.1167/iovs.09-3944
tissue_or_cell_type
Whole eye
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 836–845
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HPLC at 3 and 6 months · source_derived_draft · unverified_draft
### a-vision-clearance-a2e Single, double and triple Rdh8/Rdh12/Abca4 knockout comparisons showed greater age-dependent ocular A2E accumulation than wild type. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Defects in retinal disposal increase a bisretinoid by-product. organism: Mus musculus tissue_or_cell_type: Whole eye experimental_model: HPLC at 3 and 6 months limitations: Genotypes differ in severity; accumulation is not equivalent to demonstrated cell death. [maeda-2009] Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina (2009). https://pubmed.ncbi.nlm.nih.gov/19553623/ DOI: 10.1167/iovs.09-3944
Complete structured claim and evidence
Vitamin A-supplemented diets increased ocular A2E/bisretinoid accumulation in wild-type and Abca4-null mice relative to control diets.
Vitamin A → A2E bisretinoid source_derived_draftungraded
Experimental context and source evidence
experimental_model
Dietary supplementation versus control; biochemical and morphologic endpoints
exposure
dietary vitamin A excess/supplementation
genotype
wild type and Abca4-null
limitations
Mouse exposure; no human dose or treatment recommendation follows. Degeneration depended on pigmentation and occurred on both diets.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Extra vitamin A increased visual-cycle by-products in these mice.
primary_references
[radu-2008] Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation (2008). https://pubmed.ncbi.nlm.nih.gov/18515570/ DOI: 10.1167/iovs.07-1470
tissue_or_cell_type
Eye/RPE
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 847–858
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary supplementation versus control; biochemical and morphologic endpoints · source_derived_draft · unverified_draft
### a-vision-excess-bisretinoids Vitamin A-supplemented diets increased ocular A2E/bisretinoid accumulation in wild-type and Abca4-null mice relative to control diets. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra vitamin A increased visual-cycle by-products in these mice. organism: Mus musculus tissue_or_cell_type: Eye/RPE experimental_model: Dietary supplementation versus control; biochemical and morphologic endpoints limitations: Mouse exposure; no human dose or treatment recommendation follows. Degeneration depended on pigmentation and occurred on both diets. exposure: dietary vitamin A excess/supplementation genotype: wild type and Abca4-null [radu-2008] Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation (2008). https://pubmed.ncbi.nlm.nih.gov/18515570/ DOI: 10.1167/iovs.07-1470
Complete structured claim and evidence
RPE-selective CRALBP knockout markedly delayed mouse rod dark adaptation after bleaching.
RPE-selective CRALBP loss → Rod dark adaptation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
ERG recovery after bleaching
limitations
Same machinery perturbation as the retinoid measurements.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The slowed recycling is accompanied by slow rod recovery.
primary_references
[bassetto-2024] Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors (2024). https://pubmed.ncbi.nlm.nih.gov/38676924/ DOI: 10.1016/j.celrep.2024.114143
tissue_or_cell_type
Rod retina with RPE-selective mutation
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 871–880
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ERG recovery after bleaching · source_derived_draft · unverified_draft
### a-vision-rpe-cralbp-rods RPE-selective CRALBP knockout markedly delayed mouse rod dark adaptation after bleaching. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The slowed recycling is accompanied by slow rod recovery. organism: Mus musculus tissue_or_cell_type: Rod retina with RPE-selective mutation experimental_model: ERG recovery after bleaching limitations: Same machinery perturbation as the retinoid measurements. [bassetto-2024] Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors (2024). https://pubmed.ncbi.nlm.nih.gov/38676924/ DOI: 10.1016/j.celrep.2024.114143
Complete structured claim and evidence
Müller-glia-selective CRALBP knockout mildly affected cone pigment regeneration, while bulk chromophore regeneration remained normal.
Müller-glia-selective CRALBP loss → Cone dark adaptation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Timed Müller-glia-selective deletion
limitations
Different preparation from global-knockout rescue; relative route contributions depend on experimental context.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
In this cell-specific model, the RPE supplied most measured chromophore renewal.
primary_references
[bassetto-2024] Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors (2024). https://pubmed.ncbi.nlm.nih.gov/38676924/ DOI: 10.1016/j.celrep.2024.114143
tissue_or_cell_type
Müller glia and retina
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 894–903
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Timed Müller-glia-selective deletion · source_derived_draft · unverified_draft
### a-vision-muller-cralbp-qualified Müller-glia-selective CRALBP knockout mildly affected cone pigment regeneration, while bulk chromophore regeneration remained normal. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this cell-specific model, the RPE supplied most measured chromophore renewal. organism: Mus musculus tissue_or_cell_type: Müller glia and retina experimental_model: Timed Müller-glia-selective deletion limitations: Different preparation from global-knockout rescue; relative route contributions depend on experimental context. [bassetto-2024] Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors (2024). https://pubmed.ncbi.nlm.nih.gov/38676924/ DOI: 10.1016/j.celrep.2024.114143
Complete structured claim and evidence
Photoactivated rhodopsin catalyzed GDP-to-GTP nucleotide exchange on transducin in reconstituted bovine rod preparations.
Photoactivated rhodopsin → Rod transducin heterotrimer source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified protein reconstitution
limitations
Biochemical amplification is not a nutritional dose response.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
Activated pigment switches transducin into its signaling state.
primary_references
[fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152
tissue_or_cell_type
Rod outer-segment protein system
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 905–914
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified protein reconstitution · source_derived_draft · unverified_draft
### a-vision-transducin-exchange Photoactivated rhodopsin catalyzed GDP-to-GTP nucleotide exchange on transducin in reconstituted bovine rod preparations. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Activated pigment switches transducin into its signaling state. organism: Bos taurus tissue_or_cell_type: Rod outer-segment protein system experimental_model: Purified protein reconstitution limitations: Biochemical amplification is not a nutritional dose response. [fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152
Complete structured claim and evidence
Activated transducin stimulated rod cyclic-GMP phosphodiesterase in the reconstituted signaling system.
GTP-bound rod transducin alpha → Rod PDE6 complex source_derived_draftungraded
Experimental context and source evidence
experimental_model
Reconstituted transducin/PDE assays
limitations
Rod PDE6 complex identity is kept separate from cone PDE6.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
Transducin turns on the enzyme that removes cGMP.
primary_references
[fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152
tissue_or_cell_type
Rod outer-segment proteins
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 916–925
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transducin/PDE assays · source_derived_draft · unverified_draft
### a-vision-transducin-pde6 Activated transducin stimulated rod cyclic-GMP phosphodiesterase in the reconstituted signaling system. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Transducin turns on the enzyme that removes cGMP. organism: Bos taurus tissue_or_cell_type: Rod outer-segment proteins experimental_model: Reconstituted transducin/PDE assays limitations: Rod PDE6 complex identity is kept separate from cone PDE6. [fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152
Complete structured claim and evidence
Activated rod phosphodiesterase hydrolyzed cyclic GMP in the phototransduction reconstitution.
Rod PDE6 complex → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Biochemical phosphodiesterase assay
limitations
The channel step was tested in a separate experiment.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
cGMP destruction passes the light signal toward channel closure.
primary_references
[fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152
tissue_or_cell_type
Rod outer-segment proteins
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 927–936
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical phosphodiesterase assay · source_derived_draft · unverified_draft
### a-vision-pde6-cgmp Activated rod phosphodiesterase hydrolyzed cyclic GMP in the phototransduction reconstitution. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: cGMP destruction passes the light signal toward channel closure. organism: Bos taurus tissue_or_cell_type: Rod outer-segment proteins experimental_model: Biochemical phosphodiesterase assay limitations: The channel step was tested in a separate experiment. [fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152
Complete structured claim and evidence
Cytoplasmic-side cGMP reversibly increased cation conductance in excised rod outer-segment patches without nucleoside triphosphates.
Cyclic guanosine monophosphate → Rod cyclic nucleotide-gated channel source_derived_draftungraded
Experimental context and source evidence
experimental_model
Inside-out patch; cGMP EC50 about 30 micromolar
limitations
The historical experiment measured conductance before modern channel-subunit assignment.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rana temporaria
plain_language
cGMP directly keeps the rod cation channel open.
primary_references
[fesenko-1985] Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment (1985). https://pubmed.ncbi.nlm.nih.gov/2578616/ DOI: 10.1038/313310a0
tissue_or_cell_type
Rod outer-segment plasma membrane
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 938–947
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Inside-out patch; cGMP EC50 about 30 micromolar · source_derived_draft · unverified_draft
### a-vision-cgmp-channel Cytoplasmic-side cGMP reversibly increased cation conductance in excised rod outer-segment patches without nucleoside triphosphates. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: cGMP directly keeps the rod cation channel open. organism: Rana temporaria tissue_or_cell_type: Rod outer-segment plasma membrane experimental_model: Inside-out patch; cGMP EC50 about 30 micromolar limitations: The historical experiment measured conductance before modern channel-subunit assignment. [fesenko-1985] Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment (1985). https://pubmed.ncbi.nlm.nih.gov/2578616/ DOI: 10.1038/313310a0
Complete structured claim and evidence
Rod calcium-flux recordings showed that illumination reduces outer-segment free calcium as entry falls while extrusion continues.
Photoactivated rhodopsin → Rod outer-segment free calcium concentration source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
The vitamin A chromophore-initiated electrical response changes calcium signaling inside the rod.
experimental_model
Calcium influx/efflux measurements during illumination
limitations
Not a claim that dietary calcium intake determines rod calcium transients.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bufo marinus
plain_language
The light response lowers intracellular calcium, providing a recovery signal.
primary_references
[yau-1985] Light-induced reduction of cytoplasmic free calcium in retinal rod outer segment (1985). https://pubmed.ncbi.nlm.nih.gov/2578628/ DOI: 10.1038/313579a0
tissue_or_cell_type
Rod outer segment
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 949–959
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Calcium influx/efflux measurements during illumination · source_derived_draft · unverified_draft
### a-vision-light-calcium Rod calcium-flux recordings showed that illumination reduces outer-segment free calcium as entry falls while extrusion continues. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The light response lowers intracellular calcium, providing a recovery signal. organism: Bufo marinus tissue_or_cell_type: Rod outer segment experimental_model: Calcium influx/efflux measurements during illumination limitations: Not a claim that dietary calcium intake determines rod calcium transients. cross_nutrient: The vitamin A chromophore-initiated electrical response changes calcium signaling inside the rod. [yau-1985] Light-induced reduction of cytoplasmic free calcium in retinal rod outer segment (1985). https://pubmed.ncbi.nlm.nih.gov/2578628/ DOI: 10.1038/313579a0
Complete structured claim and evidence
Removing GCAP1 and GCAP2 abolished calcium dependence of retinal guanylyl cyclase activity in mouse assays.
Rod GCAP1 and GCAP2 → Retinal guanylyl cyclases source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Calcium-sensitive GCAPs regulate recovery downstream of the vitamin A photopigment.
experimental_model
Retinal homogenate cyclase activity at low versus high free calcium
limitations
Evidence for intracellular feedback, not calcium intake or blood-calcium thresholds.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
GCAP sensors connect calcium changes to cGMP synthesis.
primary_references
[mendez-2001] Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC55558/ DOI: 10.1073/pnas.171308998
tissue_or_cell_type
Retina
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 961–971
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retinal homogenate cyclase activity at low versus high free calcium · source_derived_draft · unverified_draft
### a-vision-calcium-cyclase-feedback Removing GCAP1 and GCAP2 abolished calcium dependence of retinal guanylyl cyclase activity in mouse assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: GCAP sensors connect calcium changes to cGMP synthesis. organism: Mus musculus tissue_or_cell_type: Retina experimental_model: Retinal homogenate cyclase activity at low versus high free calcium limitations: Evidence for intracellular feedback, not calcium intake or blood-calcium thresholds. cross_nutrient: Calcium-sensitive GCAPs regulate recovery downstream of the vitamin A photopigment. [mendez-2001] Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC55558/ DOI: 10.1073/pnas.171308998
Complete structured claim and evidence
Magnesium-bound GCAP1, rather than metal-free GCAP1, activated RetGC1 under low-calcium assay conditions.
Mg2+ → GCAP1 / GUCA1A source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Mg2+ and Ca2+ regulate a sensor in vitamin A-dependent phototransduction recovery.
experimental_model
Purified protein metal-binding and cyclase assays
limitations
No dietary magnesium deficiency or human night-vision outcome was measured.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant protein biochemical system
plain_language
Magnesium occupancy lets the calcium sensor stimulate cGMP recovery.
primary_references
[peshenko-2006] Ca2+ and Mg2+ binding properties of GCAP-1. Evidence that Mg2+-bound form is the physiological activator of photoreceptor guanylyl cyclase (2006). https://pubmed.ncbi.nlm.nih.gov/16793776/ DOI: 10.1074/jbc.M600257200
tissue_or_cell_type
Photoreceptor-protein model
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 973–983
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified protein metal-binding and cyclase assays · source_derived_draft · unverified_draft
### a-vision-magnesium-gcap1 Magnesium-bound GCAP1, rather than metal-free GCAP1, activated RetGC1 under low-calcium assay conditions. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium occupancy lets the calcium sensor stimulate cGMP recovery. organism: Recombinant protein biochemical system tissue_or_cell_type: Photoreceptor-protein model experimental_model: Purified protein metal-binding and cyclase assays limitations: No dietary magnesium deficiency or human night-vision outcome was measured. cross_nutrient: Mg2+ and Ca2+ regulate a sensor in vitamin A-dependent phototransduction recovery. [peshenko-2006] Ca2+ and Mg2+ binding properties of GCAP-1. Evidence that Mg2+-bound form is the physiological activator of photoreceptor guanylyl cyclase (2006). https://pubmed.ncbi.nlm.nih.gov/16793776/ DOI: 10.1074/jbc.M600257200
Complete structured claim and evidence
GCAP-null mouse rods showed larger and slower dark-adapted flash responses than wild-type rods.
Combined GCAP1 and GCAP2 loss → Rod electrical light response source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Loss of calcium feedback changes a vitamin A-initiated response without proving nutrient deficiency.
experimental_model
Single-rod suction-electrode recordings
limitations
GCAP2 restoration did not fully restore normal kinetics; isoforms are not interchangeable.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Without these calcium sensors, rod responses last longer.
primary_references
[mendez-2001] Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC55558/ DOI: 10.1073/pnas.171308998
tissue_or_cell_type
Rod photoreceptors
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 985–995
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-rod suction-electrode recordings · source_derived_draft · unverified_draft
### a-vision-gcap-response GCAP-null mouse rods showed larger and slower dark-adapted flash responses than wild-type rods. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Without these calcium sensors, rod responses last longer. organism: Mus musculus tissue_or_cell_type: Rod photoreceptors experimental_model: Single-rod suction-electrode recordings limitations: GCAP2 restoration did not fully restore normal kinetics; isoforms are not interchangeable. cross_nutrient: Loss of calcium feedback changes a vitamin A-initiated response without proving nutrient deficiency. [mendez-2001] Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC55558/ DOI: 10.1073/pnas.171308998
Complete structured claim and evidence
In three vitamin A-deficient patients, slow rod dark adaptation accompanied abnormally slow rhodopsin regeneration.
Vitamin A → Rhodopsin regeneration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Adaptometry and fundus reflectometry
limitations
Disease-associated deficiency; no general threshold or intake estimate.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Pigment recovery slowed when vitamin A was depleted.
primary_references
[kemp-1988] Visual function and rhodopsin levels in humans with vitamin A deficiency (1988). https://pubmed.ncbi.nlm.nih.gov/3350064/ DOI: 10.1016/S0014-4835(88)80076-9
tissue_or_cell_type
Mid-peripheral retina
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 997–1006
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adaptometry and fundus reflectometry · source_derived_draft · unverified_draft
### a-vision-deficiency-rhodopsin In three vitamin A-deficient patients, slow rod dark adaptation accompanied abnormally slow rhodopsin regeneration. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Pigment recovery slowed when vitamin A was depleted. organism: Homo sapiens tissue_or_cell_type: Mid-peripheral retina experimental_model: Adaptometry and fundus reflectometry limitations: Disease-associated deficiency; no general threshold or intake estimate. [kemp-1988] Visual function and rhodopsin levels in humans with vitamin A deficiency (1988). https://pubmed.ncbi.nlm.nih.gov/3350064/ DOI: 10.1016/S0014-4835(88)80076-9
Complete structured claim and evidence
All three deficient patients initially lacked measurable rod function and had delayed cone adaptation.
Vitamin A → Visual sensitivity source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Baseline visual function
limitations
Clinical series of three, not a population effect size.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Severe depletion impaired night vision and also slowed cone recovery.
primary_references
[kemp-1988] Visual function and rhodopsin levels in humans with vitamin A deficiency (1988). https://pubmed.ncbi.nlm.nih.gov/3350064/ DOI: 10.1016/S0014-4835(88)80076-9
tissue_or_cell_type
Retina
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1008–1017
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baseline visual function · source_derived_draft · unverified_draft
### a-vision-deficiency-sensitivity All three deficient patients initially lacked measurable rod function and had delayed cone adaptation. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Severe depletion impaired night vision and also slowed cone recovery. organism: Homo sapiens tissue_or_cell_type: Retina experimental_model: Baseline visual function limitations: Clinical series of three, not a population effect size. [kemp-1988] Visual function and rhodopsin levels in humans with vitamin A deficiency (1988). https://pubmed.ncbi.nlm.nih.gov/3350064/ DOI: 10.1016/S0014-4835(88)80076-9
Complete structured claim and evidence
Visual function normalized within eight days of vitamin A treatment in the three reported deficient patients.
Vitamin A → Visual sensitivity source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Before/after repletion follow-up
limitations
Uncontrolled treatment observation; no dose recommendation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Repletion reversed the measured visual deficit in this series.
primary_references
[kemp-1988] Visual function and rhodopsin levels in humans with vitamin A deficiency (1988). https://pubmed.ncbi.nlm.nih.gov/3350064/ DOI: 10.1016/S0014-4835(88)80076-9
tissue_or_cell_type
Retina
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1019–1028
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Before/after repletion follow-up · source_derived_draft · unverified_draft
### a-vision-deficiency-repletion Visual function normalized within eight days of vitamin A treatment in the three reported deficient patients. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Repletion reversed the measured visual deficit in this series. organism: Homo sapiens tissue_or_cell_type: Retina experimental_model: Before/after repletion follow-up limitations: Uncontrolled treatment observation; no dose recommendation. [kemp-1988] Visual function and rhodopsin levels in humans with vitamin A deficiency (1988). https://pubmed.ncbi.nlm.nih.gov/3350064/ DOI: 10.1016/S0014-4835(88)80076-9
Complete structured claim and evidence
All-trans RA bound the tested RAR alpha, beta and gamma preparations with high affinity.
All-trans-retinoic acid → Retinoic acid receptor family source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters.
exposure
Radioligand competition
limitations
Binding affinity is not a dietary threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant receptors in African green monkey COS-1 cells
plain_language
The all-trans isomer directly engages RAR proteins.
primary_references
[va-allenby-1993] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids (1993). https://pubmed.ncbi.nlm.nih.gov/8380496/ DOI: 10.1073/pnas.90.1.30
tissue_or_cell_type
Nuclear extracts
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1030–1041
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters. · source_derived_draft · unverified_draft
### va-sig-atra-rar-binding All-trans RA bound the tested RAR alpha, beta and gamma preparations with high affinity. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The all-trans isomer directly engages RAR proteins. organism: Recombinant receptors in African green monkey COS-1 cells tissue_or_cell_type: Nuclear extracts experimental_model: Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters. limitations: Binding affinity is not a dietary threshold. evidence_locator: Abstract exposure: Radioligand competition [va-allenby-1993] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids (1993). https://pubmed.ncbi.nlm.nih.gov/8380496/ DOI: 10.1073/pnas.90.1.30
Complete structured claim and evidence
9-cis RA also bound RAR alpha, beta and gamma; it was not RXR-selective.
9-cis-retinoic acid → Retinoic acid receptor family source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters.
exposure
Isomer competition
limitations
Does not establish endogenous tissue concentrations.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant receptors in COS-1 cells
plain_language
An RXR-binding retinoid can also activate RAR pathways.
primary_references
[va-allenby-1993] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids (1993). https://pubmed.ncbi.nlm.nih.gov/8380496/ DOI: 10.1073/pnas.90.1.30
tissue_or_cell_type
Nuclear extracts
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1043–1054
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters. · source_derived_draft · unverified_draft
### va-sig-9cis-rar-binding 9-cis RA also bound RAR alpha, beta and gamma; it was not RXR-selective. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An RXR-binding retinoid can also activate RAR pathways. organism: Recombinant receptors in COS-1 cells tissue_or_cell_type: Nuclear extracts experimental_model: Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters. limitations: Does not establish endogenous tissue concentrations. evidence_locator: Abstract exposure: Isomer competition [va-allenby-1993] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids (1993). https://pubmed.ncbi.nlm.nih.gov/8380496/ DOI: 10.1073/pnas.90.1.30
Complete structured claim and evidence
All-trans RA did not effectively compete for RXR binding in the tested isomer assay.
All-trans-retinoic acid → Retinoid X receptor family source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters.
exposure
Isomer competition
limitations
Cell metabolism can alter apparent reporter responses.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant receptors in COS-1 cells
plain_language
RAR and RXR cannot be treated as interchangeable RA receptors.
primary_references
[va-allenby-1993] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids (1993). https://pubmed.ncbi.nlm.nih.gov/8380496/ DOI: 10.1073/pnas.90.1.30
tissue_or_cell_type
Nuclear extracts
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1056–1067
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters. · source_derived_draft · unverified_draft
### va-sig-atra-rxr-selectivity All-trans RA did not effectively compete for RXR binding in the tested isomer assay. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RAR and RXR cannot be treated as interchangeable RA receptors. organism: Recombinant receptors in COS-1 cells tissue_or_cell_type: Nuclear extracts experimental_model: Transfected COS-1 nucleosol; ligand competition and chimeric receptor reporters. limitations: Cell metabolism can alter apparent reporter responses. evidence_locator: Abstract exposure: Isomer competition [va-allenby-1993] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids (1993). https://pubmed.ncbi.nlm.nih.gov/8380496/ DOI: 10.1073/pnas.90.1.30
Complete structured claim and evidence
9-cis RA bound the tested RXR preparation with high affinity and activated RXR-dependent reporter responses.
9-cis-retinoic acid → Retinoid X receptor family source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Receptor binding and cell transfection assays.
exposure
9-cis RA exposure
limitations
Its biochemical activity does not establish a universal physiological RXR ligand pool.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant/cultured-cell system
plain_language
The 9-cis isomer supplies a direct experimental RXR ligand.
primary_references
[va-heyman-1992] 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor (1992). https://pubmed.ncbi.nlm.nih.gov/1310260/ DOI: 10.1016/0092-8674(92)90479-v
tissue_or_cell_type
Receptor-binding preparations
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1069–1080
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Receptor binding and cell transfection assays. · source_derived_draft · unverified_draft
### va-sig-9cis-rxr-binding 9-cis RA bound the tested RXR preparation with high affinity and activated RXR-dependent reporter responses. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The 9-cis isomer supplies a direct experimental RXR ligand. organism: Recombinant/cultured-cell system tissue_or_cell_type: Receptor-binding preparations experimental_model: Receptor binding and cell transfection assays. limitations: Its biochemical activity does not establish a universal physiological RXR ligand pool. evidence_locator: Abstract exposure: 9-cis RA exposure [va-heyman-1992] 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor (1992). https://pubmed.ncbi.nlm.nih.gov/1310260/ DOI: 10.1016/0092-8674(92)90479-v
Complete structured claim and evidence
RXRA associated with RARA and cooperatively bound retinoid response DNA.
Retinoid X receptor alpha → Retinoic acid receptor alpha source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Figure 2
experimental_model
Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters.
exposure
Receptor coexpression/reconstitution
limitations
Synthetic response elements; not every genomic site.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant receptors
plain_language
Two distinct receptor proteins assemble a DNA-binding complex.
primary_references
[va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0
tissue_or_cell_type
Cell-free DNA-binding assay
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1082–1093
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. · source_derived_draft · unverified_draft
### va-sig-rara-rxra-cooperative-binding RXRA associated with RARA and cooperatively bound retinoid response DNA. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two distinct receptor proteins assemble a DNA-binding complex. organism: Recombinant receptors tissue_or_cell_type: Cell-free DNA-binding assay experimental_model: Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. limitations: Synthetic response elements; not every genomic site. evidence_locator: Figure 2 exposure: Receptor coexpression/reconstitution [va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0
Complete structured claim and evidence
RXRA formed a VDR complex and enhanced binding to the osteopontin vitamin D response element.
Retinoid X receptor alpha → Vitamin D receptor / VDR source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin A-vitamin D: shared receptor partner; no supplementation or deficiency rescue tested.
evidence_locator
Figure 3
experimental_model
Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters.
exposure
Reconstituted VDR/RXRA
limitations
Does not prove vitamin A intake enhances calcium absorption.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant receptors
plain_language
Vitamin D signaling shares RXRA receptor machinery with retinoid pathways.
primary_references
[va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0
tissue_or_cell_type
Cell-free DNA-binding assay
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1095–1107
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. · source_derived_draft · unverified_draft
### va-sig-rxra-vdr-partnership RXRA formed a VDR complex and enhanced binding to the osteopontin vitamin D response element. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin D signaling shares RXRA receptor machinery with retinoid pathways. organism: Recombinant receptors tissue_or_cell_type: Cell-free DNA-binding assay experimental_model: Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. limitations: Does not prove vitamin A intake enhances calcium absorption. evidence_locator: Figure 3 cross_nutrient: Vitamin A-vitamin D: shared receptor partner; no supplementation or deficiency rescue tested. exposure: Reconstituted VDR/RXRA [va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0
Complete structured claim and evidence
RXRA complexed with TR beta and enhanced thyroid-response-element binding.
Retinoid X receptor alpha → Thyroid hormone receptor beta source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin A-iodine: shared receptor machinery for an iodine-containing hormone; not evidence of iodine repletion.
evidence_locator
Figure 3
experimental_model
Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters.
exposure
Reconstituted TR beta/RXRA
limitations
No iodine nutritional manipulation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Recombinant receptors
plain_language
A receptor used by retinoids also supports thyroid-hormone DNA recognition.
primary_references
[va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0
tissue_or_cell_type
Cell-free DNA-binding assay
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1109–1121
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. · source_derived_draft · unverified_draft
### va-sig-rxra-thrb-partnership RXRA complexed with TR beta and enhanced thyroid-response-element binding. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A receptor used by retinoids also supports thyroid-hormone DNA recognition. organism: Recombinant receptors tissue_or_cell_type: Cell-free DNA-binding assay experimental_model: Recombinant receptors, gel shifts, coimmunoprecipitation and CV-1 reporters. limitations: No iodine nutritional manipulation. evidence_locator: Figure 3 cross_nutrient: Vitamin A-iodine: shared receptor machinery for an iodine-containing hormone; not evidence of iodine repletion. exposure: Reconstituted TR beta/RXRA [va-kliewer-1992] Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling (1992). https://pubmed.ncbi.nlm.nih.gov/1310351/ DOI: 10.1038/355446a0
Complete structured claim and evidence
RXRA enhanced RAR-mediated transcription at RA concentrations insufficient to substantially activate RXRA itself.
Retinoid X receptor alpha → Retinoic-acid-responsive transcription source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Receptor interaction, DNA binding and transfection experiments.
exposure
Receptor cotransfection and RA
limitations
Reporter-system dependence; no nutrient dose response.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Engineered cellular receptor system
plain_language
RXRA can assist RAR signaling without equivalent activation of both partners.
primary_references
[va-zhang-1992] Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors (1992). https://pubmed.ncbi.nlm.nih.gov/1310350/ DOI: 10.1038/355441a0
tissue_or_cell_type
Transfection reporters
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1123–1134
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Receptor interaction, DNA binding and transfection experiments. · source_derived_draft · unverified_draft
### va-sig-rxra-rar-transactivation RXRA enhanced RAR-mediated transcription at RA concentrations insufficient to substantially activate RXRA itself. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RXRA can assist RAR signaling without equivalent activation of both partners. organism: Engineered cellular receptor system tissue_or_cell_type: Transfection reporters experimental_model: Receptor interaction, DNA binding and transfection experiments. limitations: Reporter-system dependence; no nutrient dose response. evidence_locator: Abstract exposure: Receptor cotransfection and RA [va-zhang-1992] Retinoid X receptor is an auxiliary protein for thyroid hormone and retinoic acid receptors (1992). https://pubmed.ncbi.nlm.nih.gov/1310350/ DOI: 10.1038/355441a0
Complete structured claim and evidence
SMRT associated with retinoid receptors and mediated transcriptional silencing in engineered assays.
Nuclear receptor corepressor 2 / SMRT → Retinoic-acid-responsive transcription source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Biochemical interactions and engineered cellular transcription reporters.
exposure
Unliganded receptor and SMRT
limitations
Not a claim that all unliganded RAR targets are repressed.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Biochemical and cellular reporter systems
plain_language
Corepressor proteins help keep selected receptor-controlled genes quiet.
primary_references
[va-chen-1995] A transcriptional co-repressor that interacts with nuclear hormone receptors (1995). https://pubmed.ncbi.nlm.nih.gov/7566127/ DOI: 10.1038/377454a0
tissue_or_cell_type
Receptor complexes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1136–1147
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical interactions and engineered cellular transcription reporters. · source_derived_draft · unverified_draft
### va-sig-smrt-repression SMRT associated with retinoid receptors and mediated transcriptional silencing in engineered assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Corepressor proteins help keep selected receptor-controlled genes quiet. organism: Biochemical and cellular reporter systems tissue_or_cell_type: Receptor complexes experimental_model: Biochemical interactions and engineered cellular transcription reporters. limitations: Not a claim that all unliganded RAR targets are repressed. evidence_locator: Abstract exposure: Unliganded receptor and SMRT [va-chen-1995] A transcriptional co-repressor that interacts with nuclear hormone receptors (1995). https://pubmed.ncbi.nlm.nih.gov/7566127/ DOI: 10.1038/377454a0
Complete structured claim and evidence
Ligand destabilized SMRT association with retinoid receptor complexes, including DNA-bound receptors.
All-trans-retinoic acid → Nuclear receptor corepressor 2 / SMRT source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Biochemical interactions and engineered cellular transcription reporters.
exposure
Ligand addition
limitations
Cofactor exchange varies by promoter and cell.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Biochemical receptor system
plain_language
Ligand binding can release a transcriptional brake.
primary_references
[va-chen-1995] A transcriptional co-repressor that interacts with nuclear hormone receptors (1995). https://pubmed.ncbi.nlm.nih.gov/7566127/ DOI: 10.1038/377454a0
tissue_or_cell_type
Receptor complexes
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1149–1160
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical interactions and engineered cellular transcription reporters. · source_derived_draft · unverified_draft
### va-sig-ligand-smrt-release Ligand destabilized SMRT association with retinoid receptor complexes, including DNA-bound receptors. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Ligand binding can release a transcriptional brake. organism: Biochemical receptor system tissue_or_cell_type: Receptor complexes experimental_model: Biochemical interactions and engineered cellular transcription reporters. limitations: Cofactor exchange varies by promoter and cell. evidence_locator: Abstract exposure: Ligand addition [va-chen-1995] A transcriptional co-repressor that interacts with nuclear hormone receptors (1995). https://pubmed.ncbi.nlm.nih.gov/7566127/ DOI: 10.1038/377454a0
Complete structured claim and evidence
The agonist-bound RAR ligand-binding domain interacted with TIF2 in an AF-2-dependent manner.
Retinoic acid receptor alpha → Nuclear receptor coactivator 2 / TIF2 source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Human TIF2 cloning; in vitro receptor-domain interactions and cellular reporters.
exposure
Agonist versus control; AF-2 mutants
limitations
Domain assays do not resolve every endogenous chromatin complex.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Human TIF2 and engineered receptor domains
plain_language
An activated receptor gains a binding surface for a transcriptional coactivator.
primary_references
[va-voegel-1996] TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors (1996). https://pubmed.ncbi.nlm.nih.gov/8670870/ DOI: 10.1002/j.1460-2075.1996.tb00736.x
tissue_or_cell_type
Cell-free and cellular interaction assays
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1162–1173
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human TIF2 cloning; in vitro receptor-domain interactions and cellular reporters. · source_derived_draft · unverified_draft
### va-sig-rara-tif2-recruitment The agonist-bound RAR ligand-binding domain interacted with TIF2 in an AF-2-dependent manner. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An activated receptor gains a binding surface for a transcriptional coactivator. organism: Human TIF2 and engineered receptor domains tissue_or_cell_type: Cell-free and cellular interaction assays experimental_model: Human TIF2 cloning; in vitro receptor-domain interactions and cellular reporters. limitations: Domain assays do not resolve every endogenous chromatin complex. evidence_locator: Abstract exposure: Agonist versus control; AF-2 mutants [va-voegel-1996] TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors (1996). https://pubmed.ncbi.nlm.nih.gov/8670870/ DOI: 10.1002/j.1460-2075.1996.tb00736.x
Complete structured claim and evidence
RA during mouse T-cell activation increased CCR9 expression.
All-trans-retinoic acid → C-C chemokine receptor 9 source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice.
exposure
Added RA
limitations
Receptor expression is distinct from clinical infection protection.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Activated cells acquire a receptor associated with gut entry.
primary_references
[va-iwata-2004] Retinoic acid imprints gut-homing specificity on T cells (2004). https://pubmed.ncbi.nlm.nih.gov/15485630/ DOI: 10.1016/j.immuni.2004.08.011
tissue_or_cell_type
Activated T cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1175–1186
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice. · source_derived_draft · unverified_draft
### va-sig-ra-ccr9 RA during mouse T-cell activation increased CCR9 expression. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Activated cells acquire a receptor associated with gut entry. organism: Mus musculus tissue_or_cell_type: Activated T cells experimental_model: Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice. limitations: Receptor expression is distinct from clinical infection protection. evidence_locator: Abstract exposure: Added RA [va-iwata-2004] Retinoic acid imprints gut-homing specificity on T cells (2004). https://pubmed.ncbi.nlm.nih.gov/15485630/ DOI: 10.1016/j.immuni.2004.08.011
Complete structured claim and evidence
RA during T-cell activation increased the alpha4beta7 gut-homing integrin.
All-trans-retinoic acid → Integrin alpha4beta7 source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice.
exposure
Added RA
limitations
Does not establish independent transcriptional induction of each subunit.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RA helps activated T cells acquire an intestinal adhesion complex.
primary_references
[va-iwata-2004] Retinoic acid imprints gut-homing specificity on T cells (2004). https://pubmed.ncbi.nlm.nih.gov/15485630/ DOI: 10.1016/j.immuni.2004.08.011
tissue_or_cell_type
Activated T cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1188–1199
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice. · source_derived_draft · unverified_draft
### va-sig-ra-alpha4beta7 RA during T-cell activation increased the alpha4beta7 gut-homing integrin. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RA helps activated T cells acquire an intestinal adhesion complex. organism: Mus musculus tissue_or_cell_type: Activated T cells experimental_model: Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice. limitations: Does not establish independent transcriptional induction of each subunit. evidence_locator: Abstract exposure: Added RA [va-iwata-2004] Retinoic acid imprints gut-homing specificity on T cells (2004). https://pubmed.ncbi.nlm.nih.gov/15485630/ DOI: 10.1016/j.immuni.2004.08.011
Complete structured claim and evidence
Vitamin A-deficient mice had depleted intestinal lamina propria T cells.
Vitamin A → Intestinal T-cell abundance source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_locator
Abstract
experimental_model
Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice.
exposure
Vitamin A-deficient diet
limitations
Does not isolate trafficking from all other deficiency effects.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Dietary depletion changed the intestinal T-cell compartment.
primary_references
[va-iwata-2004] Retinoic acid imprints gut-homing specificity on T cells (2004). https://pubmed.ncbi.nlm.nih.gov/15485630/ DOI: 10.1016/j.immuni.2004.08.011
tissue_or_cell_type
Intestinal lamina propria
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1201–1212
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice. · source_derived_draft · unverified_draft
### va-sig-deficient-intestinal-t-cells Vitamin A-deficient mice had depleted intestinal lamina propria T cells. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Dietary depletion changed the intestinal T-cell compartment. organism: Mus musculus tissue_or_cell_type: Intestinal lamina propria experimental_model: Mouse activated T cells, gut dendritic cells and vitamin A-deficient mice. limitations: Does not isolate trafficking from all other deficiency effects. evidence_locator: Abstract exposure: Vitamin A-deficient diet [va-iwata-2004] Retinoic acid imprints gut-homing specificity on T cells (2004). https://pubmed.ncbi.nlm.nih.gov/15485630/ DOI: 10.1016/j.immuni.2004.08.011
Complete structured claim and evidence
Dendritic-cell-derived RA conferred gut tropism on activated B cells.
All-trans-retinoic acid → B-cell gut homing source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice.
exposure
Gut dendritic-cell-derived RA
limitations
Gut tropism alone is not IgA secretion.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RA helps route antibody-producing cell precursors to the intestine.
primary_references
[va-mora-2006] Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells (2006). https://pubmed.ncbi.nlm.nih.gov/17110582/ DOI: 10.1126/science.1132742
tissue_or_cell_type
B-cell cultures
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1214–1225
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice. · source_derived_draft · unverified_draft
### va-sig-ra-b-cell-homing Dendritic-cell-derived RA conferred gut tropism on activated B cells. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RA helps route antibody-producing cell precursors to the intestine. organism: Mus musculus tissue_or_cell_type: B-cell cultures experimental_model: Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice. limitations: Gut tropism alone is not IgA secretion. evidence_locator: Abstract exposure: Gut dendritic-cell-derived RA [va-mora-2006] Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells (2006). https://pubmed.ncbi.nlm.nih.gov/17110582/ DOI: 10.1126/science.1132742
Complete structured claim and evidence
RA alone was insufficient for IgA secretion but cooperated with IL-6 or IL-5 to induce it.
All-trans-retinoic acid → Immunoglobulin A source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice.
exposure
RA with IL-6 or IL-5
limitations
Cannot generalize to every IgA-switching pathway.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
IgA output required additional immune signals in this experiment.
primary_references
[va-mora-2006] Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells (2006). https://pubmed.ncbi.nlm.nih.gov/17110582/ DOI: 10.1126/science.1132742
tissue_or_cell_type
B-cell cultures
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1227–1238
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice. · source_derived_draft · unverified_draft
### va-sig-ra-cytokine-iga RA alone was insufficient for IgA secretion but cooperated with IL-6 or IL-5 to induce it. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: IgA output required additional immune signals in this experiment. organism: Mus musculus tissue_or_cell_type: B-cell cultures experimental_model: Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice. limitations: Cannot generalize to every IgA-switching pathway. evidence_locator: Abstract exposure: RA with IL-6 or IL-5 [va-mora-2006] Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells (2006). https://pubmed.ncbi.nlm.nih.gov/17110582/ DOI: 10.1126/science.1132742
Complete structured claim and evidence
Vitamin A-deficient mice lacked IgA-secreting cells in the small intestine.
Vitamin A → Intestinal IgA-secreting cell abundance source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_locator
Abstract
experimental_model
Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice.
exposure
Vitamin A-deficient diet
limitations
Migration and differentiation contributions are not interchangeable.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Depletion reduced the local antibody-secreting cell compartment.
primary_references
[va-mora-2006] Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells (2006). https://pubmed.ncbi.nlm.nih.gov/17110582/ DOI: 10.1126/science.1132742
tissue_or_cell_type
Small intestine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1240–1251
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice. · source_derived_draft · unverified_draft
### va-sig-deficient-intestinal-iga Vitamin A-deficient mice lacked IgA-secreting cells in the small intestine. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Depletion reduced the local antibody-secreting cell compartment. organism: Mus musculus tissue_or_cell_type: Small intestine experimental_model: Mouse B-cell/dendritic-cell systems and vitamin A-deficient mice. limitations: Migration and differentiation contributions are not interchangeable. evidence_locator: Abstract exposure: Vitamin A-deficient diet [va-mora-2006] Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells (2006). https://pubmed.ncbi.nlm.nih.gov/17110582/ DOI: 10.1126/science.1132742
Complete structured claim and evidence
RA promoted regulatory T-cell differentiation under the tested TGF-beta-dependent conditions.
All-trans-retinoic acid → FOXP3-positive regulatory T cell source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse naive T-cell differentiation under TGF-beta and inflammatory cytokine conditions.
exposure
Added RA in TGF-beta-driven differentiation
limitations
Not an unconditional anti-inflammatory effect or human dietary outcome.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RA can cooperate with TGF-beta to favor regulatory cells.
primary_references
[va-mucida-2007] Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid (2007). https://pubmed.ncbi.nlm.nih.gov/17569825/ DOI: 10.1126/science.1145697
tissue_or_cell_type
Naive T-cell cultures
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1253–1264
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse naive T-cell differentiation under TGF-beta and inflammatory cytokine conditions. · source_derived_draft · unverified_draft
### va-sig-ra-tgfb-foxp3 RA promoted regulatory T-cell differentiation under the tested TGF-beta-dependent conditions. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RA can cooperate with TGF-beta to favor regulatory cells. organism: Mus musculus tissue_or_cell_type: Naive T-cell cultures experimental_model: Mouse naive T-cell differentiation under TGF-beta and inflammatory cytokine conditions. limitations: Not an unconditional anti-inflammatory effect or human dietary outcome. evidence_locator: Abstract exposure: Added RA in TGF-beta-driven differentiation [va-mucida-2007] Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid (2007). https://pubmed.ncbi.nlm.nih.gov/17569825/ DOI: 10.1126/science.1145697
Complete structured claim and evidence
Added RA inhibited IL-6-driven Th17 induction in the tested TGF-beta context.
All-trans-retinoic acid → Th17 differentiation source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse naive T-cell differentiation under TGF-beta and inflammatory cytokine conditions.
exposure
RA with IL-6/TGF-beta
limitations
New lineage induction differs from established intestinal Th17 effector function.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The cytokine environment determines which T-cell differentiation program RA modifies.
primary_references
[va-mucida-2007] Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid (2007). https://pubmed.ncbi.nlm.nih.gov/17569825/ DOI: 10.1126/science.1145697
tissue_or_cell_type
Naive T-cell cultures
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1266–1277
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse naive T-cell differentiation under TGF-beta and inflammatory cytokine conditions. · source_derived_draft · unverified_draft
### va-sig-ra-th17-differentiation Added RA inhibited IL-6-driven Th17 induction in the tested TGF-beta context. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cytokine environment determines which T-cell differentiation program RA modifies. organism: Mus musculus tissue_or_cell_type: Naive T-cell cultures experimental_model: Mouse naive T-cell differentiation under TGF-beta and inflammatory cytokine conditions. limitations: New lineage induction differs from established intestinal Th17 effector function. evidence_locator: Abstract exposure: RA with IL-6/TGF-beta [va-mucida-2007] Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid (2007). https://pubmed.ncbi.nlm.nih.gov/17569825/ DOI: 10.1126/science.1145697
Complete structured claim and evidence
Rara-deficient or RAR-antagonized T cells proliferated less efficiently after stimulation.
Retinoic acid receptor alpha → CD4 T-cell proliferation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_locator
Discussion and T-cell activation experiments
experimental_model
Vitamin A-insufficient and Rara-deficient mice; stimulated CD4 T cells.
exposure
Rara loss or RAR antagonism
limitations
Does not negate RA effects on Treg differentiation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Loss of receptor signaling can weaken effector-cell expansion.
primary_references
[va-hall-2011] Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3415227/ DOI: 10.1016/j.immuni.2011.03.003
tissue_or_cell_type
CD4 T cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1279–1290
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Vitamin A-insufficient and Rara-deficient mice; stimulated CD4 T cells. · source_derived_draft · unverified_draft
### va-sig-rara-t-cell-proliferation Rara-deficient or RAR-antagonized T cells proliferated less efficiently after stimulation. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of receptor signaling can weaken effector-cell expansion. organism: Mus musculus tissue_or_cell_type: CD4 T cells experimental_model: Vitamin A-insufficient and Rara-deficient mice; stimulated CD4 T cells. limitations: Does not negate RA effects on Treg differentiation. evidence_locator: Discussion and T-cell activation experiments exposure: Rara loss or RAR antagonism [va-hall-2011] Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha (2011). https://pmc.ncbi.nlm.nih.gov/articles/PMC3415227/ DOI: 10.1016/j.immuni.2011.03.003
Complete structured claim and evidence
RA with IL-15 promoted dendritic-cell IL-12p70 release.
All-trans-retinoic acid → Interleukin-12 p70 source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract and Figure 3
experimental_model
Mouse dendritic-cell/T-cell experiments and IL-15-rich intestinal models.
exposure
RA plus IL-15
limitations
No claim that dietary vitamin A causes coeliac disease.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
An inflammatory cytokine can redirect RA-associated immune signaling.
primary_references
[va-depaolo-2011] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens (2011). https://www.nature.com/articles/nature09849 DOI: 10.1038/nature09849
tissue_or_cell_type
Dendritic cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1292–1303
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse dendritic-cell/T-cell experiments and IL-15-rich intestinal models. · source_derived_draft · unverified_draft
### va-sig-ra-il15-il12 RA with IL-15 promoted dendritic-cell IL-12p70 release. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An inflammatory cytokine can redirect RA-associated immune signaling. organism: Mus musculus tissue_or_cell_type: Dendritic cells experimental_model: Mouse dendritic-cell/T-cell experiments and IL-15-rich intestinal models. limitations: No claim that dietary vitamin A causes coeliac disease. evidence_locator: Abstract and Figure 3 exposure: RA plus IL-15 [va-depaolo-2011] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens (2011). https://www.nature.com/articles/nature09849 DOI: 10.1038/nature09849
Complete structured claim and evidence
RA with IL-15 promoted dendritic-cell IL-23 release.
All-trans-retinoic acid → Interleukin-23 source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract and Figure 3
experimental_model
Mouse dendritic-cell/T-cell experiments and IL-15-rich intestinal models.
exposure
RA plus IL-15
limitations
Different context from isolated naive T-cell induction.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RA participates in a proinflammatory response in this cytokine setting.
primary_references
[va-depaolo-2011] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens (2011). https://www.nature.com/articles/nature09849 DOI: 10.1038/nature09849
tissue_or_cell_type
Dendritic cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1305–1316
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse dendritic-cell/T-cell experiments and IL-15-rich intestinal models. · source_derived_draft · unverified_draft
### va-sig-ra-il15-il23 RA with IL-15 promoted dendritic-cell IL-23 release. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RA participates in a proinflammatory response in this cytokine setting. organism: Mus musculus tissue_or_cell_type: Dendritic cells experimental_model: Mouse dendritic-cell/T-cell experiments and IL-15-rich intestinal models. limitations: Different context from isolated naive T-cell induction. evidence_locator: Abstract and Figure 3 exposure: RA plus IL-15 [va-depaolo-2011] Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens (2011). https://www.nature.com/articles/nature09849 DOI: 10.1038/nature09849
Complete structured claim and evidence
RAR beta occupied the mouse Saa3 promoter; mutation of RARE -224 abolished reporter activity.
Retinoic acid receptor beta → Mouse Saa3 gene source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Figure 2; Methods
experimental_model
Mouse MODE-K cells and intestinal epithelial Rarb deletion.
exposure
100 nM retinol plus 100 ng/mL LPS for 24 h
limitations
Direct binding to Saa1/Saa2 was predicted, not demonstrated here.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Epithelial retinoid sensing directly controls this mouse immune gene.
primary_references
[va-gattu-2019] Epithelial retinoic acid receptor beta regulates serum amyloid A expression and vitamin A-dependent intestinal immunity (2019). https://pmc.ncbi.nlm.nih.gov/articles/PMC6561173/ DOI: 10.1073/pnas.1812069116
tissue_or_cell_type
MODE-K intestinal epithelial cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1318–1329
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse MODE-K cells and intestinal epithelial Rarb deletion. · source_derived_draft · unverified_draft
### va-sig-rarb-saa3-promoter RAR beta occupied the mouse Saa3 promoter; mutation of RARE -224 abolished reporter activity. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Epithelial retinoid sensing directly controls this mouse immune gene. organism: Mus musculus tissue_or_cell_type: MODE-K intestinal epithelial cells experimental_model: Mouse MODE-K cells and intestinal epithelial Rarb deletion. limitations: Direct binding to Saa1/Saa2 was predicted, not demonstrated here. evidence_locator: Figure 2; Methods exposure: 100 nM retinol plus 100 ng/mL LPS for 24 h [va-gattu-2019] Epithelial retinoic acid receptor beta regulates serum amyloid A expression and vitamin A-dependent intestinal immunity (2019). https://pmc.ncbi.nlm.nih.gov/articles/PMC6561173/ DOI: 10.1073/pnas.1812069116
Complete structured claim and evidence
Epithelial Rarb deletion reduced intestinal Th17 IL-17A production without reducing overall Th17 frequency.
Retinoic acid receptor beta → Interleukin 17A source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_locator
Figure 4A-D
experimental_model
Mouse MODE-K cells and intestinal epithelial Rarb deletion.
exposure
Epithelial Rarb deletion
limitations
Does not establish a complete retinol-transfer chain.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
A receptor in epithelial cells helps neighboring immune cells function.
primary_references
[va-gattu-2019] Epithelial retinoic acid receptor beta regulates serum amyloid A expression and vitamin A-dependent intestinal immunity (2019). https://pmc.ncbi.nlm.nih.gov/articles/PMC6561173/ DOI: 10.1073/pnas.1812069116
tissue_or_cell_type
Intestinal lamina propria
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1331–1342
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse MODE-K cells and intestinal epithelial Rarb deletion. · source_derived_draft · unverified_draft
### va-sig-rarb-th17-effector Epithelial Rarb deletion reduced intestinal Th17 IL-17A production without reducing overall Th17 frequency. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A receptor in epithelial cells helps neighboring immune cells function. organism: Mus musculus tissue_or_cell_type: Intestinal lamina propria experimental_model: Mouse MODE-K cells and intestinal epithelial Rarb deletion. limitations: Does not establish a complete retinol-transfer chain. evidence_locator: Figure 4A-D exposure: Epithelial Rarb deletion [va-gattu-2019] Epithelial retinoic acid receptor beta regulates serum amyloid A expression and vitamin A-dependent intestinal immunity (2019). https://pmc.ncbi.nlm.nih.gov/articles/PMC6561173/ DOI: 10.1073/pnas.1812069116
Complete structured claim and evidence
Recombinant SAA1 restored impaired Th17 cytokine output in cultured lamina propria cells from epithelial Rarb mutants.
Serum amyloid A1 → Interleukin 17A source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_locator
Figure 4E
experimental_model
Mouse MODE-K cells and intestinal epithelial Rarb deletion.
exposure
rSAA1 during 4-hour stimulation
limitations
Rescue does not establish delivery of retinol to Th17 cells.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Adding an epithelial-associated mediator rescued the measured immune output.
primary_references
[va-gattu-2019] Epithelial retinoic acid receptor beta regulates serum amyloid A expression and vitamin A-dependent intestinal immunity (2019). https://pmc.ncbi.nlm.nih.gov/articles/PMC6561173/ DOI: 10.1073/pnas.1812069116
tissue_or_cell_type
Ex vivo intestinal lamina propria cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1344–1355
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse MODE-K cells and intestinal epithelial Rarb deletion. · source_derived_draft · unverified_draft
### va-sig-saa1-rescue-th17 Recombinant SAA1 restored impaired Th17 cytokine output in cultured lamina propria cells from epithelial Rarb mutants. Condition category: machinery_impairment nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding an epithelial-associated mediator rescued the measured immune output. organism: Mus musculus tissue_or_cell_type: Ex vivo intestinal lamina propria cells experimental_model: Mouse MODE-K cells and intestinal epithelial Rarb deletion. limitations: Rescue does not establish delivery of retinol to Th17 cells. evidence_locator: Figure 4E exposure: rSAA1 during 4-hour stimulation [va-gattu-2019] Epithelial retinoic acid receptor beta regulates serum amyloid A expression and vitamin A-dependent intestinal immunity (2019). https://pmc.ncbi.nlm.nih.gov/articles/PMC6561173/ DOI: 10.1073/pnas.1812069116
Complete structured claim and evidence
RAR alpha-selective pharmacology supported RAR alpha-mediated induction of airway mucin transcripts, including MUC5AC.
Retinoic acid receptor alpha → MUC5AC gene source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Normal human tracheobronchial epithelial cultures with receptor-selective agonists/antagonists.
exposure
Receptor-selective agonists/antagonists
limitations
Transcript changes do not establish improved mucus clearance.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
RAR signaling helps cultured airway cells adopt a mucus-producing program.
primary_references
[va-koo-1999] Role of retinoid receptors in the regulation of mucin gene expression by retinoic acid in human tracheobronchial epithelial cells (1999). https://pubmed.ncbi.nlm.nih.gov/10024510/ DOI: 10.1042/bj3380351
tissue_or_cell_type
Normal tracheobronchial epithelial cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1357–1368
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Normal human tracheobronchial epithelial cultures with receptor-selective agonists/antagonists. · source_derived_draft · unverified_draft
### va-sig-rara-airway-mucin RAR alpha-selective pharmacology supported RAR alpha-mediated induction of airway mucin transcripts, including MUC5AC. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RAR signaling helps cultured airway cells adopt a mucus-producing program. organism: Homo sapiens tissue_or_cell_type: Normal tracheobronchial epithelial cells experimental_model: Normal human tracheobronchial epithelial cultures with receptor-selective agonists/antagonists. limitations: Transcript changes do not establish improved mucus clearance. evidence_locator: Abstract exposure: Receptor-selective agonists/antagonists [va-koo-1999] Role of retinoid receptors in the regulation of mucin gene expression by retinoic acid in human tracheobronchial epithelial cells (1999). https://pubmed.ncbi.nlm.nih.gov/10024510/ DOI: 10.1042/bj3380351
Complete structured claim and evidence
An RXR-selective agonist alone failed to induce mucin transcripts but enhanced a suboptimal RAR agonist response.
Retinoid X receptor family → Retinoic acid receptor family source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Normal human tracheobronchial epithelial cultures with receptor-selective agonists/antagonists.
exposure
Selective receptor agonists
limitations
No inference that 9-cis RA improves airway disease.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Both partners can cooperate, with RAR activation required in this assay.
primary_references
[va-koo-1999] Role of retinoid receptors in the regulation of mucin gene expression by retinoic acid in human tracheobronchial epithelial cells (1999). https://pubmed.ncbi.nlm.nih.gov/10024510/ DOI: 10.1042/bj3380351
tissue_or_cell_type
Normal tracheobronchial epithelial cells
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1370–1381
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Normal human tracheobronchial epithelial cultures with receptor-selective agonists/antagonists. · source_derived_draft · unverified_draft
### va-sig-rxr-airway-cooperation An RXR-selective agonist alone failed to induce mucin transcripts but enhanced a suboptimal RAR agonist response. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both partners can cooperate, with RAR activation required in this assay. organism: Homo sapiens tissue_or_cell_type: Normal tracheobronchial epithelial cells experimental_model: Normal human tracheobronchial epithelial cultures with receptor-selective agonists/antagonists. limitations: No inference that 9-cis RA improves airway disease. evidence_locator: Abstract exposure: Selective receptor agonists [va-koo-1999] Role of retinoid receptors in the regulation of mucin gene expression by retinoic acid in human tracheobronchial epithelial cells (1999). https://pubmed.ncbi.nlm.nih.gov/10024510/ DOI: 10.1042/bj3380351
Complete structured claim and evidence
Removing RA from airway epithelial culture medium sharply reduced mucin secretion.
All-trans-retinoic acid → Airway epithelial mucin secretion source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_locator
Abstract
experimental_model
Human normal tracheobronchial epithelial air-liquid interface cultures.
exposure
RA withdrawal
limitations
Does not demonstrate airway infection protection.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
RA availability helps maintain the secretory phenotype in cultured airway cells.
primary_references
[va-yoon-1997] Regulation of the secretory phenotype of human airway epithelium by retinoic acid, triiodothyronine, and extracellular matrix (1997). https://pubmed.ncbi.nlm.nih.gov/9191474/ DOI: 10.1165/ajrcmb.16.6.9191474
tissue_or_cell_type
Normal tracheobronchial epithelial air-liquid interface culture
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1383–1394
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human normal tracheobronchial epithelial air-liquid interface cultures. · source_derived_draft · unverified_draft
### va-sig-ra-airway-secretion Removing RA from airway epithelial culture medium sharply reduced mucin secretion. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: RA availability helps maintain the secretory phenotype in cultured airway cells. organism: Homo sapiens tissue_or_cell_type: Normal tracheobronchial epithelial air-liquid interface culture experimental_model: Human normal tracheobronchial epithelial air-liquid interface cultures. limitations: Does not demonstrate airway infection protection. evidence_locator: Abstract exposure: RA withdrawal [va-yoon-1997] Regulation of the secretory phenotype of human airway epithelium by retinoic acid, triiodothyronine, and extracellular matrix (1997). https://pubmed.ncbi.nlm.nih.gov/9191474/ DOI: 10.1165/ajrcmb.16.6.9191474
Complete structured claim and evidence
A conserved Hoxb1 enhancer containing a RARE mediated RA responsiveness and early neuroectodermal expression.
All-trans-retinoic acid → Early neuroectodermal Hoxb1 expression source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Mouse Hoxb1 enhancer transgenes; homologous chicken and pufferfish elements.
exposure
Enhancer transgenes and RA exposure
limitations
Enhancer behavior is not a maternal serum-retinol threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus; comparative chicken/pufferfish enhancer sequences
plain_language
Embryonic RA signaling connects to a spatial developmental gene program.
primary_references
[va-marshall-1994] A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1 (1994). https://www.nature.com/articles/370567a0 DOI: 10.1038/370567a0
tissue_or_cell_type
Early embryonic neuroectoderm
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1396–1407
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Hoxb1 enhancer transgenes; homologous chicken and pufferfish elements. · source_derived_draft · unverified_draft
### va-sig-hoxb1-ra-enhancer A conserved Hoxb1 enhancer containing a RARE mediated RA responsiveness and early neuroectodermal expression. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Embryonic RA signaling connects to a spatial developmental gene program. organism: Mus musculus; comparative chicken/pufferfish enhancer sequences tissue_or_cell_type: Early embryonic neuroectoderm experimental_model: Mouse Hoxb1 enhancer transgenes; homologous chicken and pufferfish elements. limitations: Enhancer behavior is not a maternal serum-retinol threshold. evidence_locator: Abstract exposure: Enhancer transgenes and RA exposure [va-marshall-1994] A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1 (1994). https://www.nature.com/articles/370567a0 DOI: 10.1038/370567a0
Complete structured claim and evidence
FRET sensors visualized an endogenous RA concentration gradient during zebrafish gastrulation and somitogenesis.
All-trans-retinoic acid → Embryonic retinoic acid concentration gradient source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
Genetically encoded FRET RA sensors in living zebrafish embryos.
exposure
Genetically encoded RA sensors
limitations
Sensor affinity, developmental stage and model constrain interpretation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Danio rerio
plain_language
Embryonic cells encounter different local amounts of signaling RA.
primary_references
[va-shimozono-2013] Visualization of an endogenous retinoic acid gradient across embryonic development (2013). https://pubmed.ncbi.nlm.nih.gov/23563268/ DOI: 10.1038/nature12037
tissue_or_cell_type
Living early embryos
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1409–1420
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genetically encoded FRET RA sensors in living zebrafish embryos. · source_derived_draft · unverified_draft
### va-sig-embryonic-ra-gradient FRET sensors visualized an endogenous RA concentration gradient during zebrafish gastrulation and somitogenesis. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Embryonic cells encounter different local amounts of signaling RA. organism: Danio rerio tissue_or_cell_type: Living early embryos experimental_model: Genetically encoded FRET RA sensors in living zebrafish embryos. limitations: Sensor affinity, developmental stage and model constrain interpretation. evidence_locator: Abstract exposure: Genetically encoded RA sensors [va-shimozono-2013] Visualization of an endogenous retinoic acid gradient across embryonic development (2013). https://pubmed.ncbi.nlm.nih.gov/23563268/ DOI: 10.1038/nature12037
Complete structured claim and evidence
Preheadfold RA exposure altered segmental Hoxb1 reporter expression in mouse hindbrain.
All-trans-retinoic acid → Hoxb1 gene source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
RA-exposed preheadfold transgenic mouse embryos; lacZ and anatomy.
exposure
Experimental excess RA exposure
limitations
Timing-specific teratogenic experiment, not ordinary dietary intake.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Excess RA can shift where an embryonic patterning gene is active.
primary_references
[va-marshall-1992] Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity (1992). https://www.nature.com/articles/360737a0 DOI: 10.1038/360737a0
tissue_or_cell_type
Preheadfold embryos/hindbrain
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1422–1433
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RA-exposed preheadfold transgenic mouse embryos; lacZ and anatomy. · source_derived_draft · unverified_draft
### va-sig-excess-ra-hox-pattern Preheadfold RA exposure altered segmental Hoxb1 reporter expression in mouse hindbrain. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Excess RA can shift where an embryonic patterning gene is active. organism: Mus musculus tissue_or_cell_type: Preheadfold embryos/hindbrain experimental_model: RA-exposed preheadfold transgenic mouse embryos; lacZ and anatomy. limitations: Timing-specific teratogenic experiment, not ordinary dietary intake. evidence_locator: Abstract exposure: Experimental excess RA exposure [va-marshall-1992] Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity (1992). https://www.nature.com/articles/360737a0 DOI: 10.1038/360737a0
Complete structured claim and evidence
The exposed embryos showed rhombomere 2/3 transformation toward 4/5 identity with matching anatomical changes.
All-trans-retinoic acid → Hindbrain segment identity source_derived_draftungraded
Experimental context and source evidence
evidence_locator
Abstract
experimental_model
RA-exposed preheadfold transgenic mouse embryos; lacZ and anatomy.
exposure
Experimental excess RA exposure
limitations
Not a quantitative human teratogenic threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Excess developmental signaling changed segment identity.
primary_references
[va-marshall-1992] Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity (1992). https://www.nature.com/articles/360737a0 DOI: 10.1038/360737a0
tissue_or_cell_type
Embryonic hindbrain
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1435–1446
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RA-exposed preheadfold transgenic mouse embryos; lacZ and anatomy. · source_derived_draft · unverified_draft
### va-sig-excess-ra-hindbrain-identity The exposed embryos showed rhombomere 2/3 transformation toward 4/5 identity with matching anatomical changes. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Excess developmental signaling changed segment identity. organism: Mus musculus tissue_or_cell_type: Embryonic hindbrain experimental_model: RA-exposed preheadfold transgenic mouse embryos; lacZ and anatomy. limitations: Not a quantitative human teratogenic threshold. evidence_locator: Abstract exposure: Experimental excess RA exposure [va-marshall-1992] Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity (1992). https://www.nature.com/articles/360737a0 DOI: 10.1038/360737a0
Complete structured claim and evidence
Combined vitamin A and iron produced the largest hemoglobin response in the factorial pregnancy trial.
Vitamin A → Blood hemoglobin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin A/iron -> hemoglobin response.
experimental_model
Eight-week randomized trial.
limitations
Combined benefit does not prove a biochemical synergy or specify the cellular mediator.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Correcting more than one shortage improved the measured response in this population.
primary_references
[va-suharno1993] Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia (1993). https://pubmed.ncbi.nlm.nih.gov/7901636/ DOI: 10.1016/0140-6736(93)92246-p
tissue_or_cell_type
Blood
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1448–1458
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight-week randomized trial. · source_derived_draft · unverified_draft
### va-iron-combined-hemoglobin Combined vitamin A and iron produced the largest hemoglobin response in the factorial pregnancy trial. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Correcting more than one shortage improved the measured response in this population. organism: Homo sapiens tissue_or_cell_type: Blood experimental_model: Eight-week randomized trial. limitations: Combined benefit does not prove a biochemical synergy or specify the cellular mediator. cross_nutrient: Vitamin A/iron -> hemoglobin response. [va-suharno1993] Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia (1993). https://pubmed.ncbi.nlm.nih.gov/7901636/ DOI: 10.1016/0140-6736(93)92246-p
Complete structured claim and evidence
Vitamin A increased circulating EPO and hemoglobin in schoolchildren with poor nutrient status.
Vitamin A → Circulating erythropoietin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin A -> EPO/iron use.
experimental_model
Randomized ten-month follow-up.
limitations
EPO was measured, not blocked; its mediation of the hemoglobin response remains inferred.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Vitamin A can influence the signal that supports red-cell production.
primary_references
[va-zimmermann2006-iron] Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron (2006). https://pubmed.ncbi.nlm.nih.gov/16960172/ DOI: 10.1093/ajcn/84.3.580
tissue_or_cell_type
Blood
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1460–1470
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized ten-month follow-up. · source_derived_draft · unverified_draft
### va-repletion-erythropoietin Vitamin A increased circulating EPO and hemoglobin in schoolchildren with poor nutrient status. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A can influence the signal that supports red-cell production. organism: Homo sapiens tissue_or_cell_type: Blood experimental_model: Randomized ten-month follow-up. limitations: EPO was measured, not blocked; its mediation of the hemoglobin response remains inferred. cross_nutrient: Vitamin A -> EPO/iron use. [va-zimmermann2006-iron] Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron (2006). https://pubmed.ncbi.nlm.nih.gov/16960172/ DOI: 10.1093/ajcn/84.3.580
Complete structured claim and evidence
Ferritin fell while calculated total-body iron remained unchanged in the same trial, consistent with redistribution of existing iron.
Vitamin A → Serum ferritin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Ferritin/transferrin-receptor-based estimates.
limitations
Redistribution is an interpretation; liver iron was not directly biopsied.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
A better blood count did not require a measured increase in total-body iron.
primary_references
[va-zimmermann2006-iron] Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron (2006). https://pubmed.ncbi.nlm.nih.gov/16960172/ DOI: 10.1093/ajcn/84.3.580
tissue_or_cell_type
Blood; inferred storage
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1472–1481
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ferritin/transferrin-receptor-based estimates. · source_derived_draft · unverified_draft
### va-repletion-iron-store-redistribution Ferritin fell while calculated total-body iron remained unchanged in the same trial, consistent with redistribution of existing iron. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A better blood count did not require a measured increase in total-body iron. organism: Homo sapiens tissue_or_cell_type: Blood; inferred storage experimental_model: Ferritin/transferrin-receptor-based estimates. limitations: Redistribution is an interpretation; liver iron was not directly biopsied. [va-zimmermann2006-iron] Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron (2006). https://pubmed.ncbi.nlm.nih.gov/16960172/ DOI: 10.1093/ajcn/84.3.580
Complete structured claim and evidence
Zinc increased plasma retinol and transthyretin versus placebo; the RBP increase was not significant.
Zinc → Plasma retinol concentration source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Zinc -> vitamin A biomarkers.
experimental_model
Six-month preschool trial.
limitations
No direct proof of restored liver release or increased RBP synthesis.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Zinc status can influence vitamin A transport-related blood measurements.
primary_references
[va-munoz2000] Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers (2000). https://pubmed.ncbi.nlm.nih.gov/10702174/ DOI: 10.1093/ajcn/71.3.789
tissue_or_cell_type
Plasma
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1483–1493
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six-month preschool trial. · source_derived_draft · unverified_draft
### va-zinc-improves-retinol-marker Zinc increased plasma retinol and transthyretin versus placebo; the RBP increase was not significant. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc status can influence vitamin A transport-related blood measurements. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Six-month preschool trial. limitations: No direct proof of restored liver release or increased RBP synthesis. cross_nutrient: Zinc -> vitamin A biomarkers. [va-munoz2000] Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers (2000). https://pubmed.ncbi.nlm.nih.gov/10702174/ DOI: 10.1093/ajcn/71.3.789
Complete structured claim and evidence
Iron increased plasma retinol, RBP and transthyretin; the combined iron/zinc arm increased retinol without significant carrier-protein increases.
Iron → Plasma retinol concentration source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Iron/zinc -> retinoid transport markers.
experimental_model
Same factorial trial.
limitations
Measured biomarkers do not prove the molecular mechanism.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
The two minerals did not produce identical carrier-protein responses.
primary_references
[va-munoz2000] Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers (2000). https://pubmed.ncbi.nlm.nih.gov/10702174/ DOI: 10.1093/ajcn/71.3.789
tissue_or_cell_type
Plasma
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1495–1505
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same factorial trial. · source_derived_draft · unverified_draft
### va-iron-improves-retinol-marker Iron increased plasma retinol, RBP and transthyretin; the combined iron/zinc arm increased retinol without significant carrier-protein increases. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two minerals did not produce identical carrier-protein responses. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Same factorial trial. limitations: Measured biomarkers do not prove the molecular mechanism. cross_nutrient: Iron/zinc -> retinoid transport markers. [va-munoz2000] Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers (2000). https://pubmed.ncbi.nlm.nih.gov/10702174/ DOI: 10.1093/ajcn/71.3.789
Complete structured claim and evidence
In women with low initial zinc, vitamin A plus zinc improved night-vision recovery versus double placebo; zinc alone did not.
Zinc → Night vision source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Zinc/vitamin A -> dark-adaptation response.
experimental_model
Three-week zinc randomization, existing vitamin A allocation.
limitations
Not a universal zinc requirement; relative estimate had a wide confidence interval.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
An additional shortage may limit the response, but this result was subgroup-specific.
primary_references
[va-christian2001] Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women (2001). https://pubmed.ncbi.nlm.nih.gov/11382658/ DOI: 10.1093/ajcn/73.6.1045
tissue_or_cell_type
Human visual function
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1507–1517
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Three-week zinc randomization, existing vitamin A allocation. · source_derived_draft · unverified_draft
### va-zinc-night-vision-subgroup In women with low initial zinc, vitamin A plus zinc improved night-vision recovery versus double placebo; zinc alone did not. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: An additional shortage may limit the response, but this result was subgroup-specific. organism: Homo sapiens tissue_or_cell_type: Human visual function experimental_model: Three-week zinc randomization, existing vitamin A allocation. limitations: Not a universal zinc requirement; relative estimate had a wide confidence interval. cross_nutrient: Zinc/vitamin A -> dark-adaptation response. [va-christian2001] Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women (2001). https://pubmed.ncbi.nlm.nih.gov/11382658/ DOI: 10.1093/ajcn/73.6.1045
Complete structured claim and evidence
Zinc-deficient rats had lower hepatic retinol-oxidizing ADH activity and greater hepatic vitamin A content.
Zinc → Hepatic retinol-oxidizing ADH activity source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Zinc -> hepatic retinoid metabolism.
experimental_model
Pair-feeding controls; three weeks.
limitations
Does not show that every retinol dehydrogenase is a zinc enzyme.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
Zinc depletion changed retinoid handling in the liver.
primary_references
[va-kim1988] Effect of zinc deficiency on hepatic enzymes regulating vitamin A status (1988). https://pubmed.ncbi.nlm.nih.gov/3404291/ DOI: 10.1093/jn/118.8.995
tissue_or_cell_type
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1519–1529
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pair-feeding controls; three weeks. · source_derived_draft · unverified_draft
### va-zinc-deficiency-adh-decrease Zinc-deficient rats had lower hepatic retinol-oxidizing ADH activity and greater hepatic vitamin A content. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Zinc depletion changed retinoid handling in the liver. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Pair-feeding controls; three weeks. limitations: Does not show that every retinol dehydrogenase is a zinc enzyme. cross_nutrient: Zinc -> hepatic retinoid metabolism. [va-kim1988] Effect of zinc deficiency on hepatic enzymes regulating vitamin A status (1988). https://pubmed.ncbi.nlm.nih.gov/3404291/ DOI: 10.1093/jn/118.8.995
Complete structured claim and evidence
The same zinc-deficient rats showed increased retinal oxidase activity, with no detected REH/ARAT activity changes.
Zinc → Hepatic retinal oxidase activity source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Same hepatic activity assays.
limitations
Activity is not whole-body flux or proof of a direct zinc-binding requirement.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
Vitamin A processing did not simply stop at every step.
primary_references
[va-kim1988] Effect of zinc deficiency on hepatic enzymes regulating vitamin A status (1988). https://pubmed.ncbi.nlm.nih.gov/3404291/ DOI: 10.1093/jn/118.8.995
tissue_or_cell_type
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1531–1540
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same hepatic activity assays. · source_derived_draft · unverified_draft
### va-zinc-deficiency-retinal-oxidation-increase The same zinc-deficient rats showed increased retinal oxidase activity, with no detected REH/ARAT activity changes. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A processing did not simply stop at every step. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Same hepatic activity assays. limitations: Activity is not whole-body flux or proof of a direct zinc-binding requirement. [va-kim1988] Effect of zinc deficiency on hepatic enzymes regulating vitamin A status (1988). https://pubmed.ncbi.nlm.nih.gov/3404291/ DOI: 10.1093/jn/118.8.995
Complete structured claim and evidence
Vitamin A and beta-carotene increased labelled nonheme iron absorption from tested cereal meals.
Vitamin A → Nonheme iron absorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin A/carotene -> iron absorption; contested.
experimental_model
Six human cereal-meal studies.
limitations
Not consistently replicated; the claimed iron-complex mechanism was proposed rather than structurally demonstrated.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
This study found that the meal additives made more iron available.
primary_references
[va-garciacasal1998] Vitamin A and beta-carotene can improve nonheme iron absorption from rice, wheat and corn by humans (1998). https://pubmed.ncbi.nlm.nih.gov/9482776/ DOI: 10.1093/jn/128.3.646
tissue_or_cell_type
Intestinal absorption
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1542–1552
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six human cereal-meal studies. · source_derived_draft · unverified_draft
### va-iron-absorption-positive1998 Vitamin A and beta-carotene increased labelled nonheme iron absorption from tested cereal meals. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: This study found that the meal additives made more iron available. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Six human cereal-meal studies. limitations: Not consistently replicated; the claimed iron-complex mechanism was proposed rather than structurally demonstrated. cross_nutrient: Vitamin A/carotene -> iron absorption; contested. [va-garciacasal1998] Vitamin A and beta-carotene can improve nonheme iron absorption from rice, wheat and corn by humans (1998). https://pubmed.ncbi.nlm.nih.gov/9482776/ DOI: 10.1093/jn/128.3.646
Complete structured claim and evidence
Adding beta-carotene or vitamin A retained more iron in solution when the assay pH rose from acidic toward near-neutral.
All-trans-beta-carotene → Iron solubility source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Retinoid/iron chemistry; hypothesis boundary retained.
experimental_model
Cell-free pH-shift experiment.
limitations
Solubility alone neither proves a defined retinoid-iron complex nor absorption in vivo.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
A laboratory solubility result supported a proposed explanation for the meal findings.
primary_references
[va-garciacasal1998] Vitamin A and beta-carotene can improve nonheme iron absorption from rice, wheat and corn by humans (1998). https://pubmed.ncbi.nlm.nih.gov/9482776/ DOI: 10.1093/jn/128.3.646
tissue_or_cell_type
Cell-free chemistry
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1554–1564
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free pH-shift experiment. · source_derived_draft · unverified_draft
### va-retinoid-iron-solubility-assay Adding beta-carotene or vitamin A retained more iron in solution when the assay pH rose from acidic toward near-neutral. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A laboratory solubility result supported a proposed explanation for the meal findings. organism: Homo sapiens tissue_or_cell_type: Cell-free chemistry experimental_model: Cell-free pH-shift experiment. limitations: Solubility alone neither proves a defined retinoid-iron complex nor absorption in vivo. cross_nutrient: Retinoid/iron chemistry; hypothesis boundary retained. [va-garciacasal1998] Vitamin A and beta-carotene can improve nonheme iron absorption from rice, wheat and corn by humans (1998). https://pubmed.ncbi.nlm.nih.gov/9482776/ DOI: 10.1093/jn/128.3.646
Complete structured claim and evidence
Five isotope studies did not confirm enhanced iron absorption after adding retinyl palmitate to corn-bread meals.
All-trans-retinyl palmitate → Nonheme iron absorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin A/iron absorption replication disagreement.
experimental_model
Water/coffee meal conditions; stable and radioisotope methods.
limitations
Possible effect modification by poor vitamin A status remained unresolved; beta-carotene was not directly retested.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Follow-up experiments did not reproduce the earlier positive result.
primary_references
[va-walczyk2003] No enhancing effect of vitamin A on iron absorption in humans (2003). https://pubmed.ncbi.nlm.nih.gov/12499334/ DOI: 10.1093/ajcn/77.1.144
tissue_or_cell_type
Intestinal absorption
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1566–1576
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Water/coffee meal conditions; stable and radioisotope methods. · source_derived_draft · unverified_draft
### va-iron-absorption-no-enhancement2003 Five isotope studies did not confirm enhanced iron absorption after adding retinyl palmitate to corn-bread meals. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Follow-up experiments did not reproduce the earlier positive result. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption experimental_model: Water/coffee meal conditions; stable and radioisotope methods. limitations: Possible effect modification by poor vitamin A status remained unresolved; beta-carotene was not directly retested. cross_nutrient: Vitamin A/iron absorption replication disagreement. [va-walczyk2003] No enhancing effect of vitamin A on iron absorption in humans (2003). https://pubmed.ncbi.nlm.nih.gov/12499334/ DOI: 10.1093/ajcn/77.1.144
Complete structured claim and evidence
Vitamin A without iodine supplementation lowered TSH in the iodine-deficient study setting.
All-trans-retinyl palmitate → Serum TSH concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin A/iodine -> thyroid feedback.
experimental_model
404 children; factorial trial.
limitations
TSH-beta transcriptional suppression is an explanation, not a directly measured step in these children.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Vitamin A status affected how strongly the thyroid was being stimulated.
primary_references
[va-zimmermann2007-iodine] Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate (2007). https://pubmed.ncbi.nlm.nih.gov/17921382/ DOI: 10.1093/ajcn/86.4.1040
tissue_or_cell_type
Pituitary-thyroid axis
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1578–1588
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 404 children; factorial trial. · source_derived_draft · unverified_draft
### va-iodine-context-lowers-tsh Vitamin A without iodine supplementation lowered TSH in the iodine-deficient study setting. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A status affected how strongly the thyroid was being stimulated. organism: Homo sapiens tissue_or_cell_type: Pituitary-thyroid axis experimental_model: 404 children; factorial trial. limitations: TSH-beta transcriptional suppression is an explanation, not a directly measured step in these children. cross_nutrient: Vitamin A/iodine -> thyroid feedback. [va-zimmermann2007-iodine] Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate (2007). https://pubmed.ncbi.nlm.nih.gov/17921382/ DOI: 10.1093/ajcn/86.4.1040
Complete structured claim and evidence
Thyroid volume and thyroglobulin decreased with vitamin A alone; total T4 showed no significant treatment-interaction effect.
All-trans-retinyl palmitate → Thyroid volume source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Same trial.
limitations
Iodine treatment remained effective; nutrient roles are not interchangeable.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Reduced thyroid enlargement did not establish a universal rise in thyroid hormone.
primary_references
[va-zimmermann2007-iodine] Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate (2007). https://pubmed.ncbi.nlm.nih.gov/17921382/ DOI: 10.1093/ajcn/86.4.1040
tissue_or_cell_type
Thyroid
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1590–1599
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same trial. · source_derived_draft · unverified_draft
### va-iodine-context-thyroid-volume Thyroid volume and thyroglobulin decreased with vitamin A alone; total T4 showed no significant treatment-interaction effect. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reduced thyroid enlargement did not establish a universal rise in thyroid hormone. organism: Homo sapiens tissue_or_cell_type: Thyroid experimental_model: Same trial. limitations: Iodine treatment remained effective; nutrient roles are not interchangeable. [va-zimmermann2007-iodine] Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate (2007). https://pubmed.ncbi.nlm.nih.gov/17921382/ DOI: 10.1093/ajcn/86.4.1040
Complete structured claim and evidence
Retinyl palmitate attenuated the serum-calcium rise after calcitriol in the small crossover.
All-trans-retinyl palmitate → Serum calcium concentration source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Retinyl ester/calcitriol/calcium interaction.
experimental_model
Nine adults; acute blinded crossover.
exposure
15 mg retinyl palmitate and/or 2 micrograms calcitriol; historical experiment, not advice.
limitations
Serum response is not a direct isotope absorption measurement, long-term fracture outcome or universal vitamin A:D ratio.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Vitamin A form and exposure changed a measured vitamin D/calcium response.
primary_references
[va-johansson2001] Vitamin A antagonizes calcium response to vitamin D in man (2001). https://pubmed.ncbi.nlm.nih.gov/11585356/ DOI: 10.1359/jbmr.2001.16.10.1899
tissue_or_cell_type
Serum
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1601–1612
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine adults; acute blinded crossover. · source_derived_draft · unverified_draft
### va-retinyl-palmitate-calcitriol-calcium Retinyl palmitate attenuated the serum-calcium rise after calcitriol in the small crossover. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A form and exposure changed a measured vitamin D/calcium response. organism: Homo sapiens tissue_or_cell_type: Serum experimental_model: Nine adults; acute blinded crossover. limitations: Serum response is not a direct isotope absorption measurement, long-term fracture outcome or universal vitamin A:D ratio. cross_nutrient: Retinyl ester/calcitriol/calcium interaction. exposure: 15 mg retinyl palmitate and/or 2 micrograms calcitriol; historical experiment, not advice. [va-johansson2001] Vitamin A antagonizes calcium response to vitamin D in man (2001). https://pubmed.ncbi.nlm.nih.gov/11585356/ DOI: 10.1359/jbmr.2001.16.10.1899
Complete structured claim and evidence
Retinoic acid increased RANKL and the RANKL/OPG ratio in mouse calvarial cultures; receptor-selective results implicated RARalpha.
All-trans-retinoic acid → RANK ligand / TNFSF11 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Retinoid signaling -> calcium-store remodeling.
experimental_model
Neonatal mouse bone organ culture.
limitations
Receptor pharmacology is not proof of a human dietary effect.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
A vitamin A metabolite increased a signal that promotes bone resorption.
primary_references
[va-conaway2011] Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor (2011). https://pubmed.ncbi.nlm.nih.gov/21715325/ DOI: 10.1074/jbc.m111.247734
tissue_or_cell_type
Calvarial bone
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1614–1624
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Neonatal mouse bone organ culture. · source_derived_draft · unverified_draft
### va-rar-alpha-rankl-bone Retinoic acid increased RANKL and the RANKL/OPG ratio in mouse calvarial cultures; receptor-selective results implicated RARalpha. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A vitamin A metabolite increased a signal that promotes bone resorption. organism: Mus musculus tissue_or_cell_type: Calvarial bone experimental_model: Neonatal mouse bone organ culture. limitations: Receptor pharmacology is not proof of a human dietary effect. cross_nutrient: Retinoid signaling -> calcium-store remodeling. [va-conaway2011] Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor (2011). https://pubmed.ncbi.nlm.nih.gov/21715325/ DOI: 10.1074/jbc.m111.247734
Complete structured claim and evidence
Exogenous OPG blocked retinoic-acid-stimulated labelled calcium release from calvarial bone.
Osteoprotegerin / TNFRSF11B / OPG → Osteoclastic bone resorption source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin A/RANKL -> calcium release.
experimental_model
Same organ culture.
limitations
Preparation-specific causal intervention.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Blocking the RANKL signal interrupted the measured resorption response.
primary_references
[va-conaway2011] Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor (2011). https://pubmed.ncbi.nlm.nih.gov/21715325/ DOI: 10.1074/jbc.m111.247734
tissue_or_cell_type
Bone
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1626–1636
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same organ culture. · source_derived_draft · unverified_draft
### va-opg-blocks-retinoid-calcium-release Exogenous OPG blocked retinoic-acid-stimulated labelled calcium release from calvarial bone. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking the RANKL signal interrupted the measured resorption response. organism: Mus musculus tissue_or_cell_type: Bone experimental_model: Same organ culture. limitations: Preparation-specific causal intervention. cross_nutrient: Vitamin A/RANKL -> calcium release. [va-conaway2011] Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor (2011). https://pubmed.ncbi.nlm.nih.gov/21715325/ DOI: 10.1074/jbc.m111.247734
Complete structured claim and evidence
Retinoic acid suppressed RANK and RANKL-driven osteoclast differentiation in progenitor cultures.
All-trans-retinoic acid → Receptor activator of NF-kappa-B / TNFRSF11A / RANK source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Retinoid/bone-cell stage-dependent response.
experimental_model
Human and mouse osteoclast progenitors.
limitations
Does not negate whole-bone resorption results; cell stage and neighboring cells differ.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens; Mus musculus
plain_language
The response differs when the experiment starts with isolated precursor cells.
primary_references
[va-hu2010] Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK (2010). https://pubmed.ncbi.nlm.nih.gov/20949013/ DOI: 10.1371/journal.pone.0013305
tissue_or_cell_type
Osteoclast precursors
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1638–1648
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human and mouse osteoclast progenitors. · source_derived_draft · unverified_draft
### va-retinoic-acid-precursor-rank Retinoic acid suppressed RANK and RANKL-driven osteoclast differentiation in progenitor cultures. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The response differs when the experiment starts with isolated precursor cells. organism: Homo sapiens; Mus musculus tissue_or_cell_type: Osteoclast precursors experimental_model: Human and mouse osteoclast progenitors. limitations: Does not negate whole-bone resorption results; cell stage and neighboring cells differ. cross_nutrient: Retinoid/bone-cell stage-dependent response. [va-hu2010] Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK (2010). https://pubmed.ncbi.nlm.nih.gov/20949013/ DOI: 10.1371/journal.pone.0013305
Complete structured claim and evidence
Retinoic acid reduced mineralization in human and murine osteoblast models through RAR-linked effects.
All-trans-retinoic acid → Osteoblast mineralization source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Retinoid signaling -> calcium/phosphate mineralization.
experimental_model
Primary human osteoblasts and MC3T3-E1 cells.
limitations
Pharmacology and culture exposure do not define a safe dietary threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens; Mus musculus
plain_language
Too much local retinoid signaling can impair mineral deposition in these models.
primary_references
[va-lind2013] Vitamin a is a negative regulator of osteoblast mineralization (2013). https://pubmed.ncbi.nlm.nih.gov/24340023/ DOI: 10.1371/journal.pone.0082388
tissue_or_cell_type
Osteoblasts
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1650–1660
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human osteoblasts and MC3T3-E1 cells. · source_derived_draft · unverified_draft
### va-retinoic-acid-mineralization Retinoic acid reduced mineralization in human and murine osteoblast models through RAR-linked effects. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Too much local retinoid signaling can impair mineral deposition in these models. organism: Homo sapiens; Mus musculus tissue_or_cell_type: Osteoblasts experimental_model: Primary human osteoblasts and MC3T3-E1 cells. limitations: Pharmacology and culture exposure do not define a safe dietary threshold. cross_nutrient: Retinoid signaling -> calcium/phosphate mineralization. [va-lind2013] Vitamin a is a negative regulator of osteoblast mineralization (2013). https://pubmed.ncbi.nlm.nih.gov/24340023/ DOI: 10.1371/journal.pone.0082388
Complete structured claim and evidence
RA-treated osteoblasts had reduced alkaline phosphatase and osteocalcin, with lower RUNX2/SP7 protein and PHEX expression.
All-trans-retinoic acid → Tissue-nonspecific alkaline phosphatase ALPL / TNAP source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Vitamin A -> shared ALPL node already linked to zinc, magnesium and calcium.
experimental_model
Same culture experiments.
limitations
Parallel marker changes do not prove each mediates the mineralization loss.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens; Mus musculus
plain_language
Several components of the bone-building program changed together.
primary_references
[va-lind2013] Vitamin a is a negative regulator of osteoblast mineralization (2013). https://pubmed.ncbi.nlm.nih.gov/24340023/ DOI: 10.1371/journal.pone.0082388
tissue_or_cell_type
Osteoblasts
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1662–1672
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same culture experiments. · source_derived_draft · unverified_draft
### va-retinoic-acid-osteoblast-markers RA-treated osteoblasts had reduced alkaline phosphatase and osteocalcin, with lower RUNX2/SP7 protein and PHEX expression. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several components of the bone-building program changed together. organism: Homo sapiens; Mus musculus tissue_or_cell_type: Osteoblasts experimental_model: Same culture experiments. limitations: Parallel marker changes do not prove each mediates the mineralization loss. cross_nutrient: Vitamin A -> shared ALPL node already linked to zinc, magnesium and calcium. [va-lind2013] Vitamin a is a negative regulator of osteoblast mineralization (2013). https://pubmed.ncbi.nlm.nih.gov/24340023/ DOI: 10.1371/journal.pone.0082388
Complete structured claim and evidence
LPS lowered circulating retinol without a detected decrease in liver or kidney retinol in vitamin A-sufficient rats.
Lipopolysaccharide → Plasma retinol concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
LPS versus saline with food withdrawal.
limitations
Acute rat model; not every inflammatory illness follows the same kinetics.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
A low blood value did not mean the measured tissue stores had been emptied.
primary_references
[va-rosales1996] Effects of acute inflammation on plasma retinol, retinol-binding protein, and its mRNA in the liver and kidneys of vitamin A-sufficient rats (1996). https://pubmed.ncbi.nlm.nih.gov/8725149/ DOI: 10.1016/s0022-2275(20)42007-3
tissue_or_cell_type
Plasma, liver and kidney
trigger_kind
biomarker_context Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1674–1683
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · LPS versus saline with food withdrawal. · source_derived_draft · unverified_draft
### va-lps-lowers-retinol-with-stores LPS lowered circulating retinol without a detected decrease in liver or kidney retinol in vitamin A-sufficient rats. Condition category: biomarker_context nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A low blood value did not mean the measured tissue stores had been emptied. organism: Rattus norvegicus tissue_or_cell_type: Plasma, liver and kidney experimental_model: LPS versus saline with food withdrawal. limitations: Acute rat model; not every inflammatory illness follows the same kinetics. [va-rosales1996] Effects of acute inflammation on plasma retinol, retinol-binding protein, and its mRNA in the liver and kidneys of vitamin A-sufficient rats (1996). https://pubmed.ncbi.nlm.nih.gov/8725149/ DOI: 10.1016/s0022-2275(20)42007-3
Complete structured claim and evidence
Inflammation reduced hepatic RBP mRNA and circulating transport proteins in the same rat study.
Lipopolysaccharide → RBP4 mRNA source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Hepatic RNA and RBP/TTR assays.
limitations
Reduced secretion is inferred from the combined measurements, not measured as a complete flux chain.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
Transport regulation helps explain why blood retinol can fall during illness.
primary_references
[va-rosales1996] Effects of acute inflammation on plasma retinol, retinol-binding protein, and its mRNA in the liver and kidneys of vitamin A-sufficient rats (1996). https://pubmed.ncbi.nlm.nih.gov/8725149/ DOI: 10.1016/s0022-2275(20)42007-3
tissue_or_cell_type
Liver and plasma
trigger_kind
biomarker_context Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1685–1694
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Hepatic RNA and RBP/TTR assays. · source_derived_draft · unverified_draft
### va-lps-reduces-rbp-transcript Inflammation reduced hepatic RBP mRNA and circulating transport proteins in the same rat study. Condition category: biomarker_context nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Transport regulation helps explain why blood retinol can fall during illness. organism: Rattus norvegicus tissue_or_cell_type: Liver and plasma experimental_model: Hepatic RNA and RBP/TTR assays. limitations: Reduced secretion is inferred from the combined measurements, not measured as a complete flux chain. [va-rosales1996] Effects of acute inflammation on plasma retinol, retinol-binding protein, and its mRNA in the liver and kidneys of vitamin A-sufficient rats (1996). https://pubmed.ncbi.nlm.nih.gov/8725149/ DOI: 10.1016/s0022-2275(20)42007-3
Complete structured claim and evidence
Serum-retinol and isotope-modelled liver-store classifications disagreed in Thai and Zambian children; inflammation adjustment reduced false positives in the latter.
Serum retinol concentration → Vitamin A status classification source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
37 Thai and 128 Zambian children.
limitations
Isotope-derived liver reserves are model estimates; these data do not establish universal diagnostic performance.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Neither a normal nor a low serum result fully described reserves in these cohorts.
primary_references
[va-suri2015] Serum retinol concentrations demonstrate high specificity after correcting for inflammation but questionable sensitivity compared with liver stores calculated from isotope dilution in determining vitamin A deficiency in Thai and Zambian children (2015). https://pubmed.ncbi.nlm.nih.gov/26447158/ DOI: 10.3945/ajcn.115.113050
tissue_or_cell_type
Serum and inferred liver stores
trigger_kind
biomarker_context Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1696–1705
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 37 Thai and 128 Zambian children. · source_derived_draft · unverified_draft
### va-serum-versus-isotope-classification Serum-retinol and isotope-modelled liver-store classifications disagreed in Thai and Zambian children; inflammation adjustment reduced false positives in the latter. Condition category: biomarker_context nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Neither a normal nor a low serum result fully described reserves in these cohorts. organism: Homo sapiens tissue_or_cell_type: Serum and inferred liver stores experimental_model: 37 Thai and 128 Zambian children. limitations: Isotope-derived liver reserves are model estimates; these data do not establish universal diagnostic performance. [va-suri2015] Serum retinol concentrations demonstrate high specificity after correcting for inflammation but questionable sensitivity compared with liver stores calculated from isotope dilution in determining vitamin A deficiency in Thai and Zambian children (2015). https://pubmed.ncbi.nlm.nih.gov/26447158/ DOI: 10.3945/ajcn.115.113050
Complete structured claim and evidence
Vitamin A reduced the combined risk of death or major complications during severe-measles hospitalization in the trial.
All-trans-retinyl palmitate → Major complications or death during measles hospitalization source_derived_draftungraded
Experimental context and source evidence
experimental_model
189 hospitalized children; randomized trial.
limitations
No specific immune pathway was proven as mediator; not evidence for preventing all infections or replacing vaccination.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
A clinical benefit was demonstrated in a defined illness setting.
primary_references
[va-hussey1990] A randomized, controlled trial of vitamin A in children with severe measles (1990). https://pubmed.ncbi.nlm.nih.gov/2194128/ DOI: 10.1056/nejm199007193230304
tissue_or_cell_type
Clinical outcome
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1707–1716
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 189 hospitalized children; randomized trial. · source_derived_draft · unverified_draft
### va-measles-clinical-endpoint Vitamin A reduced the combined risk of death or major complications during severe-measles hospitalization in the trial. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A clinical benefit was demonstrated in a defined illness setting. organism: Homo sapiens tissue_or_cell_type: Clinical outcome experimental_model: 189 hospitalized children; randomized trial. limitations: No specific immune pathway was proven as mediator; not evidence for preventing all infections or replacing vaccination. [va-hussey1990] A randomized, controlled trial of vitamin A in children with severe measles (1990). https://pubmed.ncbi.nlm.nih.gov/2194128/ DOI: 10.1056/nejm199007193230304
Complete structured claim and evidence
Beta-carotene increased lung-cancer incidence in the male-smoker trial; alpha-tocopherol did not show a significant interaction with this effect.
All-trans-beta-carotene → Lung cancer incidence source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Carotene/vitamin E/tobacco context.
experimental_model
29,133 male smokers; factorial randomized trial.
exposure
20 mg/day beta-carotene, 5-8 years; study exposure only.
limitations
Supplement exposure is not equivalent to eating carotenoid-rich foods; the molecular cause was not isolated.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
The proposed antioxidant benefit did not predict the actual outcome.
primary_references
[va-atbc1994] The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers (1994). https://pubmed.ncbi.nlm.nih.gov/8127329/ DOI: 10.1056/nejm199404143301501
tissue_or_cell_type
Clinical lung-cancer incidence
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1718–1729
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 29,133 male smokers; factorial randomized trial. · source_derived_draft · unverified_draft
### va-atbc-carotene-lung-cancer Beta-carotene increased lung-cancer incidence in the male-smoker trial; alpha-tocopherol did not show a significant interaction with this effect. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The proposed antioxidant benefit did not predict the actual outcome. organism: Homo sapiens tissue_or_cell_type: Clinical lung-cancer incidence experimental_model: 29,133 male smokers; factorial randomized trial. limitations: Supplement exposure is not equivalent to eating carotenoid-rich foods; the molecular cause was not isolated. cross_nutrient: Carotene/vitamin E/tobacco context. exposure: 20 mg/day beta-carotene, 5-8 years; study exposure only. [va-atbc1994] The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers (1994). https://pubmed.ncbi.nlm.nih.gov/8127329/ DOI: 10.1056/nejm199404143301501
Complete structured claim and evidence
CARET found increased lung-cancer incidence with beta-carotene plus retinyl palmitate versus placebo (relative risk 1.28).
All-trans-retinyl palmitate → Lung cancer incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
18,314 high-risk participants; mean four years.
exposure
30 mg/day beta-carotene plus 25,000 IU/day preformed vitamin A; trial stopped early.
limitations
Combined intervention cannot separate the contribution of each ingredient or establish their biochemical interaction.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Combining the two forms did not produce the hoped-for protection.
primary_references
[va-omenn1996] Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease (1996). https://pubmed.ncbi.nlm.nih.gov/8602180/ DOI: 10.1056/nejm199605023341802
tissue_or_cell_type
Clinical lung-cancer incidence
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1731–1741
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 18,314 high-risk participants; mean four years. · source_derived_draft · unverified_draft
### va-caret-combination-lung-cancer CARET found increased lung-cancer incidence with beta-carotene plus retinyl palmitate versus placebo (relative risk 1.28). Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Combining the two forms did not produce the hoped-for protection. organism: Homo sapiens tissue_or_cell_type: Clinical lung-cancer incidence experimental_model: 18,314 high-risk participants; mean four years. limitations: Combined intervention cannot separate the contribution of each ingredient or establish their biochemical interaction. exposure: 30 mg/day beta-carotene plus 25,000 IU/day preformed vitamin A; trial stopped early. [va-omenn1996] Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease (1996). https://pubmed.ncbi.nlm.nih.gov/8602180/ DOI: 10.1056/nejm199605023341802
Complete structured claim and evidence
Vitamin A-deficient rats had more splenic iron but lower serum iron and transferrin saturation.
Vitamin A → Splenic iron storage source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin A deficiency -> iron distribution.
experimental_model
Controlled rat dietary groups.
limitations
Erythrophagocytosis is a proposed explanation, not a fully isolated causal sequence.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
Iron could be retained in one tissue while circulating availability fell.
primary_references
[va-cunha2014] Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis (2014). https://pubmed.ncbi.nlm.nih.gov/24998947/ DOI: 10.1016/j.jnutbio.2014.05.005
tissue_or_cell_type
Spleen and serum
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1743–1753
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled rat dietary groups. · source_derived_draft · unverified_draft
### va-deficiency-iron-sequestration Vitamin A-deficient rats had more splenic iron but lower serum iron and transferrin saturation. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Iron could be retained in one tissue while circulating availability fell. organism: Rattus norvegicus tissue_or_cell_type: Spleen and serum experimental_model: Controlled rat dietary groups. limitations: Erythrophagocytosis is a proposed explanation, not a fully isolated causal sequence. cross_nutrient: Vitamin A deficiency -> iron distribution. [va-cunha2014] Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis (2014). https://pubmed.ncbi.nlm.nih.gov/24998947/ DOI: 10.1016/j.jnutbio.2014.05.005
Complete structured claim and evidence
Vitamin A deficiency reduced renal Epo mRNA in the rat experiment.
Vitamin A → EPO mRNA source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Renal gene-expression assay.
limitations
Does not by itself measure circulating EPO or prove ineffective erythropoiesis mediation.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
A shortage affected expression of an erythropoietic signal.
primary_references
[va-cunha2014] Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis (2014). https://pubmed.ncbi.nlm.nih.gov/24998947/ DOI: 10.1016/j.jnutbio.2014.05.005
tissue_or_cell_type
Kidney
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1755–1764
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Renal gene-expression assay. · source_derived_draft · unverified_draft
### va-deficiency-epo-transcript Vitamin A deficiency reduced renal Epo mRNA in the rat experiment. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: A shortage affected expression of an erythropoietic signal. organism: Rattus norvegicus tissue_or_cell_type: Kidney experimental_model: Renal gene-expression assay. limitations: Does not by itself measure circulating EPO or prove ineffective erythropoiesis mediation. [va-cunha2014] Vitamin A deficiency modulates iron metabolism via ineffective erythropoiesis (2014). https://pubmed.ncbi.nlm.nih.gov/24998947/ DOI: 10.1016/j.jnutbio.2014.05.005
Complete structured claim and evidence
Vitamin A-deficient rats showed lower hepatic Hamp transcripts despite increased Bmp6 and Hfe2 transcripts.
Vitamin A → HAMP mRNA source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Vitamin A/iron -> hepcidin regulation.
experimental_model
Dietary comparison; hepatic mRNA.
limitations
Not a direct demonstration of BMP signaling flux or circulating hepcidin.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
The measured regulatory signals did not all move in the same direction.
primary_references
[va-cunha2016] Vitamin A deficiency modulates iron metabolism independent of hemojuvelin (Hfe2) and bone morphogenetic protein 6 (Bmp6) transcript levels (2016). https://pubmed.ncbi.nlm.nih.gov/27551308/ DOI: 10.1186/s12263-016-0519-4
tissue_or_cell_type
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1766–1776
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary comparison; hepatic mRNA. · source_derived_draft · unverified_draft
### va-deficiency-hepcidin-transcript Vitamin A-deficient rats showed lower hepatic Hamp transcripts despite increased Bmp6 and Hfe2 transcripts. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured regulatory signals did not all move in the same direction. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Dietary comparison; hepatic mRNA. limitations: Not a direct demonstration of BMP signaling flux or circulating hepcidin. cross_nutrient: Vitamin A/iron -> hepcidin regulation. [va-cunha2016] Vitamin A deficiency modulates iron metabolism independent of hemojuvelin (Hfe2) and bone morphogenetic protein 6 (Bmp6) transcript levels (2016). https://pubmed.ncbi.nlm.nih.gov/27551308/ DOI: 10.1186/s12263-016-0519-4
Complete structured claim and evidence
Vitamin A deficiency reduced intestinal Fpn1 transcripts in the same rat study.
Vitamin A → SLC40A1 mRNA source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Intestinal mRNA assay.
limitations
Does not quantify ferroportin membrane protein or iron-export flux.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Rattus norvegicus
plain_language
Expression of an iron-export component changed alongside systemic signals.
primary_references
[va-cunha2016] Vitamin A deficiency modulates iron metabolism independent of hemojuvelin (Hfe2) and bone morphogenetic protein 6 (Bmp6) transcript levels (2016). https://pubmed.ncbi.nlm.nih.gov/27551308/ DOI: 10.1186/s12263-016-0519-4
tissue_or_cell_type
Small intestine
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1778–1787
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intestinal mRNA assay. · source_derived_draft · unverified_draft
### va-deficiency-ferroportin-transcript Vitamin A deficiency reduced intestinal Fpn1 transcripts in the same rat study. Condition category: nutrient_deficiency nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Expression of an iron-export component changed alongside systemic signals. organism: Rattus norvegicus tissue_or_cell_type: Small intestine experimental_model: Intestinal mRNA assay. limitations: Does not quantify ferroportin membrane protein or iron-export flux. [va-cunha2016] Vitamin A deficiency modulates iron metabolism independent of hemojuvelin (Hfe2) and bone morphogenetic protein 6 (Bmp6) transcript levels (2016). https://pubmed.ncbi.nlm.nih.gov/27551308/ DOI: 10.1186/s12263-016-0519-4
Complete structured claim and evidence
The 2023 study reported direct radical-trapping activity for retinol, retinal and ATRA alongside ferroptosis protection.
All-trans-retinoic acid → Lipid radical trapping source_derived_draftungraded
Experimental context and source evidence
experimental_model
Cell-free assay and cell lines.
limitations
ATRA direct activity was not reproduced in the 2024 assays; no clinical or nutrient-replacement inference.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Different vitamin A forms were protective in the tested systems.
primary_references
[va-jakaria2023] Vitamin A metabolites inhibit ferroptosis (2023). https://pubmed.ncbi.nlm.nih.gov/37236031/ DOI: 10.1016/j.biopha.2023.114930
tissue_or_cell_type
Cell-free chemistry and cell cultures
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1789–1798
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free assay and cell lines. · source_derived_draft · unverified_draft
### va-atra-direct-radical-trapping2023 The 2023 study reported direct radical-trapping activity for retinol, retinal and ATRA alongside ferroptosis protection. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different vitamin A forms were protective in the tested systems. organism: Homo sapiens tissue_or_cell_type: Cell-free chemistry and cell cultures experimental_model: Cell-free assay and cell lines. limitations: ATRA direct activity was not reproduced in the 2024 assays; no clinical or nutrient-replacement inference. [va-jakaria2023] Vitamin A metabolites inhibit ferroptosis (2023). https://pubmed.ncbi.nlm.nih.gov/37236031/ DOI: 10.1016/j.biopha.2023.114930
Complete structured claim and evidence
ATRA showed no direct activity in AAPH/C11-BODIPY and DPPH assays; retinol and retinal were active in the AAPH assay.
All-trans-retinoic acid → Lipid radical trapping source_derived_draftungraded
Experimental context and source evidence
experimental_model
Cell-free assays.
limitations
Does not establish universal absence of antioxidant chemistry.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Chemical form and assay conditions matter.
primary_references
[va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1
tissue_or_cell_type
Cell-free chemistry
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1800–1809
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-free assays. · source_derived_draft · unverified_draft
### va-atra-no-direct-radical-trapping2024 ATRA showed no direct activity in AAPH/C11-BODIPY and DPPH assays; retinol and retinal were active in the AAPH assay. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Chemical form and assay conditions matter. organism: Homo sapiens tissue_or_cell_type: Cell-free chemistry experimental_model: Cell-free assays. limitations: Does not establish universal absence of antioxidant chemistry. [va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1
Complete structured claim and evidence
ATRA increased GPX4/FSP1 protein and GCH1 transcripts; RAR blockade suppressed the transcript responses.
All-trans-retinoic acid → GPX4 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Shared GPX4 connects retinoid signaling to the selenium collection; no proven supplementation synergy.
experimental_model
HT-1080 cells; pharmacological ATRA.
limitations
Direct promoter binding and dietary selenium replacement were not tested.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Retinoid signaling reached existing ferroptosis-defense machinery.
primary_references
[va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1
tissue_or_cell_type
Human cell line
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1811–1821
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HT-1080 cells; pharmacological ATRA. · source_derived_draft · unverified_draft
### va-atra-ferroptosis-regulators ATRA increased GPX4/FSP1 protein and GCH1 transcripts; RAR blockade suppressed the transcript responses. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Retinoid signaling reached existing ferroptosis-defense machinery. organism: Homo sapiens tissue_or_cell_type: Human cell line experimental_model: HT-1080 cells; pharmacological ATRA. limitations: Direct promoter binding and dietary selenium replacement were not tested. cross_nutrient: Shared GPX4 connects retinoid signaling to the selenium collection; no proven supplementation synergy. [va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1
Complete structured claim and evidence
ATRA or ferrostatin-1 rescued differentiation under antioxidant-deprived neuronal culture conditions.
All-trans-retinoic acid → Cortical neuronal differentiation source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human stem-cell neurons/organoids.
limitations
No dietary recommendation or evidence that vitamin A replaces vitamin E in humans.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Suppressing ferroptosis supported this developmental model.
primary_references
[va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1
tissue_or_cell_type
Human neural cultures
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1823–1832
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human stem-cell neurons/organoids. · source_derived_draft · unverified_draft
### va-atra-neuronal-ferroptosis-rescue ATRA or ferrostatin-1 rescued differentiation under antioxidant-deprived neuronal culture conditions. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Suppressing ferroptosis supported this developmental model. organism: Homo sapiens tissue_or_cell_type: Human neural cultures experimental_model: Human stem-cell neurons/organoids. limitations: No dietary recommendation or evidence that vitamin A replaces vitamin E in humans. [va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1
Complete structured claim and evidence
Chronic vitamin A hepatotoxicity cases included cirrhosis and portal hypertension with characteristic hepatic storage-cell changes.
Vitamin A → Liver fibrosis source_derived_draftungraded
Experimental context and source evidence
experimental_model
41 selected clinical cases with liver histology.
exposure
Chronic preformed-vitamin-A exposure; excess, not deficiency.
limitations
Case series cannot estimate population incidence or define a safe-dose threshold.
nutrient_topic
Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Prolonged excess can damage the organ that stores vitamin A.
primary_references
[va-geubel1991] Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases (1991). https://pubmed.ncbi.nlm.nih.gov/2019375/ DOI: 10.1016/0016-5085(91)90672-8
tissue_or_cell_type
Liver
Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1834–1844
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 41 selected clinical cases with liver histology. · source_derived_draft · unverified_draft
### va-chronic-excess-liver-injury Chronic vitamin A hepatotoxicity cases included cirrhosis and portal hypertension with characteristic hepatic storage-cell changes. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Prolonged excess can damage the organ that stores vitamin A. organism: Homo sapiens tissue_or_cell_type: Liver experimental_model: 41 selected clinical cases with liver histology. limitations: Case series cannot estimate population incidence or define a safe-dose threshold. exposure: Chronic preformed-vitamin-A exposure; excess, not deficiency. [va-geubel1991] Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases (1991). https://pubmed.ncbi.nlm.nih.gov/2019375/ DOI: 10.1016/0016-5085(91)90672-8
Complete structured claim and evidence
All-trans RA induced Stra8 RNA in cultured fetal mouse testes.
All-trans-retinoic acid → Mouse Stra8 expression source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Embryonic gonad culture
exposure
E12.5 testes; 0.7 micromolar RA for 2 days.
limitations
RNA induction alone did not establish completed meiosis.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
RA can turn on Stra8 in fetal testicular germ cells.
primary_references
[koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103
tissue_or_cell_type
fetal testis
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 161–172
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Embryonic gonad culture · source_derived_draft · unverified_draft
### va-repro-ra-mouse-stra8 All-trans RA induced Stra8 RNA in cultured fetal mouse testes. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: RA can turn on Stra8 in fetal testicular germ cells. organism: Mus musculus tissue_or_cell_type: fetal testis experimental_model: Embryonic gonad culture limitations: RNA induction alone did not establish completed meiosis. exposure: E12.5 testes; 0.7 micromolar RA for 2 days. cross_nutrient: false [koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103
Complete structured claim and evidence
CYP26 inhibition with R115866 induced Stra8 in cultured fetal mouse testes.
R115866 / talarozole → Mouse Stra8 expression source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Embryonic gonad culture
exposure
E12.5 testes; 0.7 micromolar R115866 for 2 days.
limitations
The inhibitor experiment did not establish bona fide meiotic prophase.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Local retinoid breakdown restrains the Stra8 response.
primary_references
[koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103
tissue_or_cell_type
fetal testis
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 174–185
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Embryonic gonad culture · source_derived_draft · unverified_draft
### va-repro-cyp26-inhibitor-stra8 CYP26 inhibition with R115866 induced Stra8 in cultured fetal mouse testes. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Local retinoid breakdown restrains the Stra8 response. organism: Mus musculus tissue_or_cell_type: fetal testis experimental_model: Embryonic gonad culture limitations: The inhibitor experiment did not establish bona fide meiotic prophase. exposure: E12.5 testes; 0.7 micromolar R115866 for 2 days. cross_nutrient: false [koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103
Complete structured claim and evidence
The 2006 study inferred that RAR signaling is required for fetal ovarian Stra8 induction after BMS-204493 suppressed its expression.
Retinoic acid receptor family → Mouse Stra8 expression source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Pharmacologic model inference
exposure
E11.5 ovaries; 5 micromolar BMS-204493 for 2 days.
limitations
Disputed necessity inference; receptor repression differs from receptor deletion.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
An early drug experiment supported a requirement later challenged by genetics.
primary_references
[koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103
tissue_or_cell_type
fetal ovary
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 187–198
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pharmacologic model inference · source_derived_draft · unverified_draft
### va-repro-rar-necessity-model The 2006 study inferred that RAR signaling is required for fetal ovarian Stra8 induction after BMS-204493 suppressed its expression. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: An early drug experiment supported a requirement later challenged by genetics. organism: Mus musculus tissue_or_cell_type: fetal ovary experimental_model: Pharmacologic model inference limitations: Disputed necessity inference; receptor repression differs from receptor deletion. exposure: E11.5 ovaries; 5 micromolar BMS-204493 for 2 days. cross_nutrient: false [koubova2006] Retinoic acid regulates sex-specific timing of meiotic initiation in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16461896/ DOI: 10.1073/pnas.0510813103
Complete structured claim and evidence
Cyp26b1-null mouse fetal testes contained germ cells entering meiosis precociously.
Mouse Cyp26b1 gene → Mouse germ-cell meiotic initiation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Embryonic knockout comparison
exposure
Constitutive Cyp26b1 deletion; exact sampling ages unavailable in retrieved abstract.
limitations
This establishes a knockout phenotype, not a human RA dose threshold.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
A missing catabolic enzyme disrupts fetal male germ-cell timing.
primary_references
[bowles2006] Retinoid signaling determines germ cell fate in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16574820/ DOI: 10.1126/science.1125691
tissue_or_cell_type
fetal testis
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 200–211
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Embryonic knockout comparison · source_derived_draft · unverified_draft
### va-repro-cyp26b1-null-meiosis Cyp26b1-null mouse fetal testes contained germ cells entering meiosis precociously. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: A missing catabolic enzyme disrupts fetal male germ-cell timing. organism: Mus musculus tissue_or_cell_type: fetal testis experimental_model: Embryonic knockout comparison limitations: This establishes a knockout phenotype, not a human RA dose threshold. exposure: Constitutive Cyp26b1 deletion; exact sampling ages unavailable in retrieved abstract. cross_nutrient: false [bowles2006] Retinoid signaling determines germ cell fate in mice. (2006). https://pubmed.ncbi.nlm.nih.gov/16574820/ DOI: 10.1126/science.1125691
Complete structured claim and evidence
Stra8-null female embryonic germ cells failed premeiotic DNA replication despite normal earlier mitotic development.
Mouse Stra8 gene → Mouse ovarian premeiotic DNA replication source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Targeted Stra8 disruption
exposure
Stra8-null versus control embryos; no nutrient withdrawal.
limitations
Female replication result; male knockout phenotypes cannot be inferred from it.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
STRA8 acts before the ovarian cell copies its DNA for meiosis.
primary_references
[baltus2006] In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. (2006). https://pubmed.ncbi.nlm.nih.gov/17115059/ DOI: 10.1038/ng1919
tissue_or_cell_type
fetal ovary
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 213–224
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Targeted Stra8 disruption · source_derived_draft · unverified_draft
### va-repro-stra8-premeiotic-replication Stra8-null female embryonic germ cells failed premeiotic DNA replication despite normal earlier mitotic development. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: STRA8 acts before the ovarian cell copies its DNA for meiosis. organism: Mus musculus tissue_or_cell_type: fetal ovary experimental_model: Targeted Stra8 disruption limitations: Female replication result; male knockout phenotypes cannot be inferred from it. exposure: Stra8-null versus control embryos; no nutrient withdrawal. cross_nutrient: false [baltus2006] In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. (2006). https://pubmed.ncbi.nlm.nih.gov/17115059/ DOI: 10.1038/ng1919
Complete structured claim and evidence
MEIOSIN expression responded to RA in the reported mouse germ-cell experiments.
All-trans-retinoic acid → Mouse MEIOSIN expression source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Mouse germ-cell expression analysis
exposure
RA-responsive expression; exact regimen unavailable in primary abstract.
limitations
Does not establish universal responsiveness at every spermatogonial stage.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The vitamin A signal also induces a partner of STRA8.
primary_references
[ishiguro2020] MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. (2020). https://pubmed.ncbi.nlm.nih.gov/32032549/ DOI: 10.1016/j.devcel.2020.01.010
tissue_or_cell_type
developing germ cells
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 226–237
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse germ-cell expression analysis · source_derived_draft · unverified_draft
### va-repro-ra-meiosin-expression MEIOSIN expression responded to RA in the reported mouse germ-cell experiments. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The vitamin A signal also induces a partner of STRA8. organism: Mus musculus tissue_or_cell_type: developing germ cells experimental_model: Mouse germ-cell expression analysis limitations: Does not establish universal responsiveness at every spermatogonial stage. exposure: RA-responsive expression; exact regimen unavailable in primary abstract. cross_nutrient: false [ishiguro2020] MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. (2020). https://pubmed.ncbi.nlm.nih.gov/32032549/ DOI: 10.1016/j.devcel.2020.01.010
Complete structured claim and evidence
MEIOSIN was identified as a germ-cell factor associating with STRA8.
Mouse MEIOSIN → Mouse STRA8 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Protein association and functional analysis
exposure
Association assays; detailed conditions unavailable in abstract.
limitations
No binding stoichiometry or direct purified-protein affinity is asserted.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Two germ-cell regulators work together.
primary_references
[ishiguro2020] MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. (2020). https://pubmed.ncbi.nlm.nih.gov/32032549/ DOI: 10.1016/j.devcel.2020.01.010
tissue_or_cell_type
mouse germ cells
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 239–250
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Protein association and functional analysis · source_derived_draft · unverified_draft
### va-repro-meiosin-stra8-association MEIOSIN was identified as a germ-cell factor associating with STRA8. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two germ-cell regulators work together. organism: Mus musculus tissue_or_cell_type: mouse germ cells experimental_model: Protein association and functional analysis limitations: No binding stoichiometry or direct purified-protein affinity is asserted. exposure: Association assays; detailed conditions unavailable in abstract. cross_nutrient: false [ishiguro2020] MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. (2020). https://pubmed.ncbi.nlm.nih.gov/32032549/ DOI: 10.1016/j.devcel.2020.01.010
Complete structured claim and evidence
Loss of MEIOSIN impaired meiotic gene activation and the transition into meiosis in mouse germ cells.
Mouse Meiosin gene → Mouse meiotic gene activation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Knockout and transcriptional functional analysis
exposure
Meiosin loss-of-function comparison.
limitations
Abstract-level extraction; no unverified individual promoter target is assigned.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The meiotic program needs the MEIOSIN regulator.
primary_references
[ishiguro2020] MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. (2020). https://pubmed.ncbi.nlm.nih.gov/32032549/ DOI: 10.1016/j.devcel.2020.01.010
tissue_or_cell_type
male and female germ cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 252–263
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Knockout and transcriptional functional analysis · source_derived_draft · unverified_draft
### va-repro-meiosin-transcription Loss of MEIOSIN impaired meiotic gene activation and the transition into meiosis in mouse germ cells. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The meiotic program needs the MEIOSIN regulator. organism: Mus musculus tissue_or_cell_type: male and female germ cells experimental_model: Knockout and transcriptional functional analysis limitations: Abstract-level extraction; no unverified individual promoter target is assigned. exposure: Meiosin loss-of-function comparison. cross_nutrient: false [ishiguro2020] MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. (2020). https://pubmed.ncbi.nlm.nih.gov/32032549/ DOI: 10.1016/j.devcel.2020.01.010
Complete structured claim and evidence
Dietary vitamin A depletion caused undifferentiated spermatogonia to accumulate in prepubertal Lrat-null testes.
All-trans-retinol → Mouse spermatogonial differentiation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Genotype-by-diet mouse comparison
exposure
Maternal vitamin A-free diet from E0.5 through lactation; neonatal endpoints through P18.
limitations
Storage-defective background accelerated depletion; this is not a knockout-only effect.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Vitamin A shortage can stop early sperm-cell differentiation.
primary_references
[li2011] Vitamin A deficiency results in meiotic failure and accumulation of undifferentiated spermatogonia in prepubertal mouse testis. (2011). https://pubmed.ncbi.nlm.nih.gov/20881313/ DOI: 10.1095/biolreprod.110.086157
tissue_or_cell_type
prepubertal testis
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 265–276
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-by-diet mouse comparison · source_derived_draft · unverified_draft
### va-repro-vitamin-a-withdrawal Dietary vitamin A depletion caused undifferentiated spermatogonia to accumulate in prepubertal Lrat-null testes. Condition category: nutrient_deficiency nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin A shortage can stop early sperm-cell differentiation. organism: Mus musculus tissue_or_cell_type: prepubertal testis experimental_model: Genotype-by-diet mouse comparison limitations: Storage-defective background accelerated depletion; this is not a knockout-only effect. exposure: Maternal vitamin A-free diet from E0.5 through lactation; neonatal endpoints through P18. cross_nutrient: false [li2011] Vitamin A deficiency results in meiotic failure and accumulation of undifferentiated spermatogonia in prepubertal mouse testis. (2011). https://pubmed.ncbi.nlm.nih.gov/20881313/ DOI: 10.1095/biolreprod.110.086157
Complete structured claim and evidence
Maternal retinyl-palmitate supplementation rescued SYCP3-positive meiotic cells in vitamin A-depleted Lrat-null pups.
All-trans-retinyl palmitate → Mouse germ-cell meiotic initiation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Dietary rescue experiment
exposure
100 U/day maternal retinyl palmitate from P5; assessment at P10.
limitations
Rescue of early markers is not proof of adult fertility or a human dose.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Replacing the missing nutrient restored early meiotic development.
primary_references
[li2011] Vitamin A deficiency results in meiotic failure and accumulation of undifferentiated spermatogonia in prepubertal mouse testis. (2011). https://pubmed.ncbi.nlm.nih.gov/20881313/ DOI: 10.1095/biolreprod.110.086157
tissue_or_cell_type
neonatal testis
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 278–289
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary rescue experiment · source_derived_draft · unverified_draft
### va-repro-retinyl-palmitate-rescue Maternal retinyl-palmitate supplementation rescued SYCP3-positive meiotic cells in vitamin A-depleted Lrat-null pups. Condition category: nutrient_deficiency nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Replacing the missing nutrient restored early meiotic development. organism: Mus musculus tissue_or_cell_type: neonatal testis experimental_model: Dietary rescue experiment limitations: Rescue of early markers is not proof of adult fertility or a human dose. exposure: 100 U/day maternal retinyl palmitate from P5; assessment at P10. cross_nutrient: false [li2011] Vitamin A deficiency results in meiotic failure and accumulation of undifferentiated spermatogonia in prepubertal mouse testis. (2011). https://pubmed.ncbi.nlm.nih.gov/20881313/ DOI: 10.1095/biolreprod.110.086157
Complete structured claim and evidence
Conditional deletion of Aldh1a1, Aldh1a2 and Aldh1a3 did not prevent fetal ovarian meiotic progression despite strongly reduced RA.
All-trans-retinoic-acid biosynthesis → Mouse fetal ovarian meiotic progression source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Three conditional deletion strategies
exposure
Somatic or ubiquitous Aldh1a1-3 ablation; ovarian analyses around E13.5-E16.5.
limitations
Minor Stra8 delay occurred; analytically zero RA from every source was not demonstrated.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Removing the main RA-synthesis enzymes did not stop fetal ovarian meiosis.
primary_references
[chassot2020] Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. (2020). https://pubmed.ncbi.nlm.nih.gov/32494737/ DOI: 10.1126/sciadv.aaz1261
tissue_or_cell_type
fetal ovary
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 291–302
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Three conditional deletion strategies · source_derived_draft · unverified_draft
### va-repro-aldh-loss-ovarian-meiosis Conditional deletion of Aldh1a1, Aldh1a2 and Aldh1a3 did not prevent fetal ovarian meiotic progression despite strongly reduced RA. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing the main RA-synthesis enzymes did not stop fetal ovarian meiosis. organism: Mus musculus tissue_or_cell_type: fetal ovary experimental_model: Three conditional deletion strategies limitations: Minor Stra8 delay occurred; analytically zero RA from every source was not demonstrated. exposure: Somatic or ubiquitous Aldh1a1-3 ablation; ovarian analyses around E13.5-E16.5. cross_nutrient: false [chassot2020] Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. (2020). https://pubmed.ncbi.nlm.nih.gov/32494737/ DOI: 10.1126/sciadv.aaz1261
Complete structured claim and evidence
Fetal ovarian germ cells lacking all RARs expressed meiotic markers and reached zygotene, challenging an obligatory RAR trigger.
Retinoic acid receptor family → Mouse fetal ovarian meiotic progression source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Timed receptor deletion with excision reporter
exposure
Tamoxifen induction at E9.5; meiosis assessed at E15.5.
limitations
Does not test dietary vitamin A deprivation or every possible RAR-independent action.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The tested fetal ovarian program progressed without the RA receptors.
primary_references
[vernet2020] Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. (2020). https://pubmed.ncbi.nlm.nih.gov/32917583/ DOI: 10.1126/sciadv.aaz1139
tissue_or_cell_type
fetal ovary
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 304–315
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Timed receptor deletion with excision reporter · source_derived_draft · unverified_draft
### va-repro-rar-null-ovarian-meiosis Fetal ovarian germ cells lacking all RARs expressed meiotic markers and reached zygotene, challenging an obligatory RAR trigger. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tested fetal ovarian program progressed without the RA receptors. organism: Mus musculus tissue_or_cell_type: fetal ovary experimental_model: Timed receptor deletion with excision reporter limitations: Does not test dietary vitamin A deprivation or every possible RAR-independent action. exposure: Tamoxifen induction at E9.5; meiosis assessed at E15.5. cross_nutrient: false [vernet2020] Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. (2020). https://pubmed.ncbi.nlm.nih.gov/32917583/ DOI: 10.1126/sciadv.aaz1139
Complete structured claim and evidence
RAR-null fetal ovaries grafted into adult females produced oocytes that contributed to offspring carrying the deleted alleles.
Retinoic acid receptor family → Production of functional mouse oocytes source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
Ovarian graft and breeding experiment
exposure
E17.5 mutant ovaries grafted into nude females; mating with wild-type males.
limitations
Recipient support bypassed mutant fetal lethality; not intact-knockout fertility.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The receptor-deficient ovarian grafts could produce functional eggs.
primary_references
[vernet2020] Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. (2020). https://pubmed.ncbi.nlm.nih.gov/32917583/ DOI: 10.1126/sciadv.aaz1139
tissue_or_cell_type
fetal ovarian graft in adult recipient
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 317–328
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ovarian graft and breeding experiment · source_derived_draft · unverified_draft
### va-repro-rar-null-functional-oocytes RAR-null fetal ovaries grafted into adult females produced oocytes that contributed to offspring carrying the deleted alleles. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The receptor-deficient ovarian grafts could produce functional eggs. organism: Mus musculus tissue_or_cell_type: fetal ovarian graft in adult recipient experimental_model: Ovarian graft and breeding experiment limitations: Recipient support bypassed mutant fetal lethality; not intact-knockout fertility. exposure: E17.5 mutant ovaries grafted into nude females; mating with wild-type males. cross_nutrient: false [vernet2020] Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. (2020). https://pubmed.ncbi.nlm.nih.gov/32917583/ DOI: 10.1126/sciadv.aaz1139
Complete structured claim and evidence
RA increased STRA8 RNA 2.2-fold in cultured human fetal testis cells.
All-trans-retinoic acid → Human STRA8 expression source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Disaggregated fetal testis culture
exposure
14-15 weeks gestation; 1 micromolar RA for 24 h; n=5 for STRA8.
limitations
This transcript response does not establish entry into meiosis.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
Human fetal testis cells can respond to RA by increasing STRA8.
primary_references
[human2011] Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. (2011). https://pubmed.ncbi.nlm.nih.gov/21674038/ DOI: 10.1371/journal.pone.0020249
tissue_or_cell_type
human fetal testis
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 330–341
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Disaggregated fetal testis culture · source_derived_draft · unverified_draft
### va-repro-human-stra8-induction RA increased STRA8 RNA 2.2-fold in cultured human fetal testis cells. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human fetal testis cells can respond to RA by increasing STRA8. organism: Homo sapiens tissue_or_cell_type: human fetal testis experimental_model: Disaggregated fetal testis culture limitations: This transcript response does not establish entry into meiosis. exposure: 14-15 weeks gestation; 1 micromolar RA for 24 h; n=5 for STRA8. cross_nutrient: false [human2011] Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. (2011). https://pubmed.ncbi.nlm.nih.gov/21674038/ DOI: 10.1371/journal.pone.0020249
Complete structured claim and evidence
The same 24-hour RA exposure did not significantly increase SYCP3 or DMC1 RNA in human fetal testis cultures.
All-trans-retinoic acid → Human meiotic marker expression source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Paired cell-culture transcript assay
exposure
14-15 weeks gestation; 1 micromolar RA for 24 h; n=6.
limitations
A limited time and marker panel cannot prove permanent failure to enter meiosis.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
STRA8 induction did not activate the full tested meiotic marker panel.
primary_references
[human2011] Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. (2011). https://pubmed.ncbi.nlm.nih.gov/21674038/ DOI: 10.1371/journal.pone.0020249
tissue_or_cell_type
human fetal testis
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 343–354
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Paired cell-culture transcript assay · source_derived_draft · unverified_draft
### va-repro-human-meiotic-panel-boundary The same 24-hour RA exposure did not significantly increase SYCP3 or DMC1 RNA in human fetal testis cultures. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: STRA8 induction did not activate the full tested meiotic marker panel. organism: Homo sapiens tissue_or_cell_type: human fetal testis experimental_model: Paired cell-culture transcript assay limitations: A limited time and marker panel cannot prove permanent failure to enter meiosis. exposure: 14-15 weeks gestation; 1 micromolar RA for 24 h; n=6. cross_nutrient: false [human2011] Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. (2011). https://pubmed.ncbi.nlm.nih.gov/21674038/ DOI: 10.1371/journal.pone.0020249
Complete structured claim and evidence
RA increased meiotic cells in developmentally competent human fetal ovarian cultures.
All-trans-retinoic acid → Human fetal ovarian meiotic initiation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
experimental_model
Fetal ovarian organ culture
exposure
Meiotic entry examined in 10-11-week-post-fertilization ovaries; exact RA dose/time unavailable in abstract.
limitations
Ovaries at 8 weeks post fertilization or earlier did not enter meiosis simply with RA and serum.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens
plain_language
The human ovarian response depends on developmental readiness.
primary_references
[human2010] Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. (2010). https://pubmed.ncbi.nlm.nih.gov/20670969/ DOI: 10.1093/humrep/deq195
tissue_or_cell_type
human fetal ovary
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 356–367
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fetal ovarian organ culture · source_derived_draft · unverified_draft
### va-repro-human-ovary-ra-response RA increased meiotic cells in developmentally competent human fetal ovarian cultures. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The human ovarian response depends on developmental readiness. organism: Homo sapiens tissue_or_cell_type: human fetal ovary experimental_model: Fetal ovarian organ culture limitations: Ovaries at 8 weeks post fertilization or earlier did not enter meiosis simply with RA and serum. exposure: Meiotic entry examined in 10-11-week-post-fertilization ovaries; exact RA dose/time unavailable in abstract. cross_nutrient: false [human2010] Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. (2010). https://pubmed.ncbi.nlm.nih.gov/20670969/ DOI: 10.1093/humrep/deq195
Complete structured claim and evidence
Maternal vitamin C withdrawal increased Dazl-promoter methylation in female fetal germ cells, with reduced Dazl expression.
L-Ascorbic acid → Mouse Dazl promoter demethylation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
experimental_model
Same-genotype nutritional comparison and bisulfite sequencing
exposure
Gulo-null dams: water vitamin C withdrawn 3-7 days before mating through E13.5; controls 3.3 g/L.
limitations
Methylation-expression association does not prove the sole causal mediator or impaired RA synthesis.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Vitamin C shortage altered an epigenetic step in germ-cell development.
primary_references
[ditroia2019] Maternal vitamin C regulates reprogramming of DNA methylation and germline development. (2019). https://pubmed.ncbi.nlm.nih.gov/31485074/ DOI: 10.1038/s41586-019-1536-1
tissue_or_cell_type
female fetal germ cells
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 369–380
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same-genotype nutritional comparison and bisulfite sequencing · source_derived_draft · unverified_draft
### va-repro-vitamin-c-demethylation Maternal vitamin C withdrawal increased Dazl-promoter methylation in female fetal germ cells, with reduced Dazl expression. Condition category: nutrient_deficiency nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin C shortage altered an epigenetic step in germ-cell development. organism: Mus musculus tissue_or_cell_type: female fetal germ cells experimental_model: Same-genotype nutritional comparison and bisulfite sequencing limitations: Methylation-expression association does not prove the sole causal mediator or impaired RA synthesis. exposure: Gulo-null dams: water vitamin C withdrawn 3-7 days before mating through E13.5; controls 3.3 g/L. cross_nutrient: true [ditroia2019] Maternal vitamin C regulates reprogramming of DNA methylation and germline development. (2019). https://pubmed.ncbi.nlm.nih.gov/31485074/ DOI: 10.1038/s41586-019-1536-1
Complete structured claim and evidence
Maternal vitamin C deficiency delayed female fetal meiotic progression, with reduced STRA8 expression.
L-Ascorbic acid → Mouse fetal ovarian meiotic progression source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
experimental_model
Nutrient withdrawal with histology and meiotic staging
exposure
Withdrawal before mating through E13.5; same-genotype supplemented controls; staging at E14.5.
limitations
The individual SYCP3-positive protein fraction was not significantly reduced; this is not an A-C supplementation trial.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
A second nutrient shortage affected the germ-cell program also studied in vitamin A biology.
primary_references
[ditroia2019] Maternal vitamin C regulates reprogramming of DNA methylation and germline development. (2019). https://pubmed.ncbi.nlm.nih.gov/31485074/ DOI: 10.1038/s41586-019-1536-1
tissue_or_cell_type
female fetal ovary
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 382–393
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nutrient withdrawal with histology and meiotic staging · source_derived_draft · unverified_draft
### va-repro-vitamin-c-meiotic-delay Maternal vitamin C deficiency delayed female fetal meiotic progression, with reduced STRA8 expression. Condition category: nutrient_deficiency nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second nutrient shortage affected the germ-cell program also studied in vitamin A biology. organism: Mus musculus tissue_or_cell_type: female fetal ovary experimental_model: Nutrient withdrawal with histology and meiotic staging limitations: The individual SYCP3-positive protein fraction was not significantly reduced; this is not an A-C supplementation trial. exposure: Withdrawal before mating through E13.5; same-genotype supplemented controls; staging at E14.5. cross_nutrient: true [ditroia2019] Maternal vitamin C regulates reprogramming of DNA methylation and germline development. (2019). https://pubmed.ncbi.nlm.nih.gov/31485074/ DOI: 10.1038/s41586-019-1536-1
Complete structured claim and evidence
Targeted mutation of Stra8 RA-response elements reduced its expression in fetal mouse ovaries.
Mouse Stra8 gene → Mouse Stra8 expression source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
experimental_model
CRISPR/Cas9 cis-regulatory mutation
exposure
RARE1 and RARE3 mutated singly or together; endogenous Stra8 expression assessed in vivo.
limitations
Reduced optimal expression does not establish complete loss of expression or prove an obligatory RA trigger for all ovarian meiosis.
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Later genetic promoter tests confirmed a contribution from RA-responsive DNA elements.
primary_references
[feng2021] Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. (2021). https://pubmed.ncbi.nlm.nih.gov/33574039/ DOI: 10.1242/dev.194977
tissue_or_cell_type
fetal ovarian germ cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 395–406
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CRISPR/Cas9 cis-regulatory mutation · source_derived_draft · unverified_draft
### va-repro-stra8-rare-mutations Targeted mutation of Stra8 RA-response elements reduced its expression in fetal mouse ovaries. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Later genetic promoter tests confirmed a contribution from RA-responsive DNA elements. organism: Mus musculus tissue_or_cell_type: fetal ovarian germ cells experimental_model: CRISPR/Cas9 cis-regulatory mutation limitations: Reduced optimal expression does not establish complete loss of expression or prove an obligatory RA trigger for all ovarian meiosis. exposure: RARE1 and RARE3 mutated singly or together; endogenous Stra8 expression assessed in vivo. cross_nutrient: false [feng2021] Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. (2021). https://pubmed.ncbi.nlm.nih.gov/33574039/ DOI: 10.1242/dev.194977
Complete structured claim and evidence
RGR purified from bovine RPE contained predominantly all-trans-retinal as its endogenous dark-state chromophore.
Retinal G protein-coupled receptor / RGR opsin → All-trans-retinal source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Abstract: endogenous retinaloxime isomers
experimental_model
Native RGR purification and hydroxylamine derivatization
exposure
Dark-handled purified protein; retinal-oxime isomers identified.
limitations
Abstract-limited; binding composition does not quantify whole-eye recycling.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
RGR carries the spent all-trans retinal isomer before light reaches it.
primary_references
[vav-hao1999] The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. (1999). https://pubmed.ncbi.nlm.nih.gov/10037690/ DOI: 10.1074/jbc.274.10.6085
tissue_or_cell_type
retinal pigment epithelium
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 408–421
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native RGR purification and hydroxylamine derivatization · source_derived_draft · unverified_draft
### vae-rgr-dark-chromophore RGR purified from bovine RPE contained predominantly all-trans-retinal as its endogenous dark-state chromophore. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: RGR carries the spent all-trans retinal isomer before light reaches it. organism: Bos taurus tissue_or_cell_type: retinal pigment epithelium experimental_model: Native RGR purification and hydroxylamine derivatization limitations: Abstract-limited; binding composition does not quantify whole-eye recycling. exposure: Dark-handled purified protein; retinal-oxime isomers identified. cross_nutrient: false evidence_location: Abstract: endogenous retinaloxime isomers nutrient: Vitamin A [vav-hao1999] The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. (1999). https://pubmed.ncbi.nlm.nih.gov/10037690/ DOI: 10.1074/jbc.274.10.6085
Complete structured claim and evidence
Illuminating native bovine RGR converted its bound all-trans-retinal stereospecifically to the 11-cis configuration.
All-trans-retinal → 11-cis-retinal source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Abstract: irradiation and isomer analysis
experimental_model
Purified native RGR photochemistry
exposure
470-nm monochromatic or near-UV irradiation; duration absent from the abstract.
limitations
Abstract-limited; the finding does not establish relative flux in living human eyes.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
Light lets RGR reverse the retinal isomer change used in visual pigments.
primary_references
[vav-hao1999] The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. (1999). https://pubmed.ncbi.nlm.nih.gov/10037690/ DOI: 10.1074/jbc.274.10.6085
tissue_or_cell_type
RPE-derived protein
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 423–436
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified native RGR photochemistry · source_derived_draft · unverified_draft
### vae-rgr-photoisomerization Illuminating native bovine RGR converted its bound all-trans-retinal stereospecifically to the 11-cis configuration. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Light lets RGR reverse the retinal isomer change used in visual pigments. organism: Bos taurus tissue_or_cell_type: RPE-derived protein experimental_model: Purified native RGR photochemistry limitations: Abstract-limited; the finding does not establish relative flux in living human eyes. exposure: 470-nm monochromatic or near-UV irradiation; duration absent from the abstract. cross_nutrient: false evidence_location: Abstract: irradiation and isomer analysis nutrient: Vitamin A [vav-hao1999] The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. (1999). https://pubmed.ncbi.nlm.nih.gov/10037690/ DOI: 10.1074/jbc.274.10.6085
Complete structured claim and evidence
Adding native CRALBP increased the accumulation of light-generated 11-cis-retinal in bovine RPE microsomal assays compared with denatured CRALBP.
Cellular retinaldehyde-binding protein / CRALBP → 11-cis-retinal source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Results: Impact of CRALBP on the RPE photoisomerase activity; Figure 3d
experimental_model
Native versus denatured CRALBP in RPE microsomes
exposure
530-nm illumination; retinal substrate; Figure 3d comparison.
limitations
Product protection was inferred from yield; these assays do not establish supplement effects.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus; recombinant human CRALBP reagent
plain_language
The retinoid-binding protein helps retain RGR pathway product.
primary_references
[vav-zhang2019] Photic generation of 11-cis-retinal in bovine retinal pigment epithelium. (2019). https://pubmed.ncbi.nlm.nih.gov/31694912/ DOI: 10.1074/jbc.ra119.011169
tissue_or_cell_type
RPE microsomes
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 438–451
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native versus denatured CRALBP in RPE microsomes · source_derived_draft · unverified_draft
### vae-cralbp-rgr-product-accumulation Adding native CRALBP increased the accumulation of light-generated 11-cis-retinal in bovine RPE microsomal assays compared with denatured CRALBP. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The retinoid-binding protein helps retain RGR pathway product. organism: Bos taurus; recombinant human CRALBP reagent tissue_or_cell_type: RPE microsomes experimental_model: Native versus denatured CRALBP in RPE microsomes limitations: Product protection was inferred from yield; these assays do not establish supplement effects. exposure: 530-nm illumination; retinal substrate; Figure 3d comparison. cross_nutrient: false evidence_location: Results: Impact of CRALBP on the RPE photoisomerase activity; Figure 3d nutrient: Vitamin A [vav-zhang2019] Photic generation of 11-cis-retinal in bovine retinal pigment epithelium. (2019). https://pubmed.ncbi.nlm.nih.gov/31694912/ DOI: 10.1074/jbc.ra119.011169
Complete structured claim and evidence
Bovine RGR K255A produced little 11-cis-retinal under illumination despite expression comparable to wild-type RGR in HEK293S GnTI-negative cells.
RGR K255A variant → 11-cis-retinal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Results/Figure 7a-c
experimental_model
Recombinant bovine wild-type/K255A RGR comparison
exposure
All-trans-retinal and 530-nm light, with CRALBP; Figure 7.
limitations
Construct-specific assay; K255A numbering is retained from this paper.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus protein in Homo sapiens cells
plain_language
Disrupting the retinal-binding lysine impaired the light-driven reaction.
primary_references
[vav-zhang2019] Photic generation of 11-cis-retinal in bovine retinal pigment epithelium. (2019). https://pubmed.ncbi.nlm.nih.gov/31694912/ DOI: 10.1074/jbc.ra119.011169
tissue_or_cell_type
HEK293S GnTI-negative homogenates
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 453–466
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant bovine wild-type/K255A RGR comparison · source_derived_draft · unverified_draft
### vae-rgr-k255a-photoactivity Bovine RGR K255A produced little 11-cis-retinal under illumination despite expression comparable to wild-type RGR in HEK293S GnTI-negative cells. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Disrupting the retinal-binding lysine impaired the light-driven reaction. organism: Bos taurus protein in Homo sapiens cells tissue_or_cell_type: HEK293S GnTI-negative homogenates experimental_model: Recombinant bovine wild-type/K255A RGR comparison limitations: Construct-specific assay; K255A numbering is retained from this paper. exposure: All-trans-retinal and 530-nm light, with CRALBP; Figure 7. cross_nutrient: false evidence_location: Results/Figure 7a-c nutrient: Vitamin A [vav-zhang2019] Photic generation of 11-cis-retinal in bovine retinal pigment epithelium. (2019). https://pubmed.ncbi.nlm.nih.gov/31694912/ DOI: 10.1074/jbc.ra119.011169
Complete structured claim and evidence
HEK293T cells coexpressing bovine RGR and RDH10 generated more 11-cis-retinol from all-trans-retinol during illumination than cells expressing either protein alone.
Retinal G protein-coupled receptor / RGR opsin → Retinol dehydrogenase 10 / RDH10 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 1A; STAR Methods: Expression of RGR and RDH10
experimental_model
Recombinant bovine RGR/RDH10 coexpression
exposure
30-minute illumination; 5 micromolar all-trans-retinol; assay medium contained 250 micromolar NADPH.
limitations
Coupled output does not prove every proposed intermediate reaction or RDH10 necessity in intact retina. Added NADPH is an assay component, not a demonstrated dietary requirement.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus proteins in Homo sapiens cells
plain_language
The two proteins supported light-dependent retinol recycling together in cultured cells.
primary_references
[vav-morshedian2019] Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31056353/ DOI: 10.1016/j.neuron.2019.04.004
tissue_or_cell_type
HEK293T culture
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 468–481
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant bovine RGR/RDH10 coexpression · source_derived_draft · unverified_draft
### vae-rgr-rdh10-coupled-retinol HEK293T cells coexpressing bovine RGR and RDH10 generated more 11-cis-retinol from all-trans-retinol during illumination than cells expressing either protein alone. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two proteins supported light-dependent retinol recycling together in cultured cells. organism: Bos taurus proteins in Homo sapiens cells tissue_or_cell_type: HEK293T culture experimental_model: Recombinant bovine RGR/RDH10 coexpression limitations: Coupled output does not prove every proposed intermediate reaction or RDH10 necessity in intact retina. Added NADPH is an assay component, not a demonstrated dietary requirement. exposure: 30-minute illumination; 5 micromolar all-trans-retinol; assay medium contained 250 micromolar NADPH. cross_nutrient: false evidence_location: Figure 1A; STAR Methods: Expression of RGR and RDH10 nutrient: Vitamin A [vav-morshedian2019] Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31056353/ DOI: 10.1016/j.neuron.2019.04.004
Complete structured claim and evidence
Isolated Rgr-null/Gnat1-null mouse retinas lost cone flash sensitivity faster during continuous light exposure than Rgr-intact/Gnat1-null controls.
RGR loss → Cone flash sensitivity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figures 4-5; Results: RGR opsin contributes to cone visual function
experimental_model
Ex vivo cone recordings without RPE; rod transduction disabled by Gnat1 deletion
exposure
505-nm background for up to 60 minutes; 10 micromolar all-trans-retinol in perfusate; 565-nm test flashes.
limitations
Whole-retina Rgr deletion alone does not localize the responsible cells; isolated tissue and supplied substrate differ from intact vision.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Cones maintained sensitivity less well when the isolated retina lacked RGR.
primary_references
[vav-morshedian2019] Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31056353/ DOI: 10.1016/j.neuron.2019.04.004
tissue_or_cell_type
isolated neural retina
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 483–496
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ex vivo cone recordings without RPE; rod transduction disabled by Gnat1 deletion · source_derived_draft · unverified_draft
### vae-rgr-isolated-cone-sensitivity Isolated Rgr-null/Gnat1-null mouse retinas lost cone flash sensitivity faster during continuous light exposure than Rgr-intact/Gnat1-null controls. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cones maintained sensitivity less well when the isolated retina lacked RGR. organism: Mus musculus tissue_or_cell_type: isolated neural retina experimental_model: Ex vivo cone recordings without RPE; rod transduction disabled by Gnat1 deletion limitations: Whole-retina Rgr deletion alone does not localize the responsible cells; isolated tissue and supplied substrate differ from intact vision. exposure: 505-nm background for up to 60 minutes; 10 micromolar all-trans-retinol in perfusate; 565-nm test flashes. cross_nutrient: false evidence_location: Figures 4-5; Results: RGR opsin contributes to cone visual function nutrient: Vitamin A [vav-morshedian2019] Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells. (2019). https://pubmed.ncbi.nlm.nih.gov/31056353/ DOI: 10.1016/j.neuron.2019.04.004
Complete structured claim and evidence
After photoisomerization in native bovine RPE microsomes, the RGR 11-cis-retinylidene Schiff base hydrolyzed with an estimated 7.5-second half-life at 20 degrees Celsius.
Retinal G protein-coupled receptor / RGR opsin → 11-cis-retinal source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 1D-F; STAR Methods: hydrolysis kinetics
experimental_model
LC-MS/MS and retinoid analysis of native microsomes
exposure
20 micromolar all-trans-retinal; 10-second 530-nm exposure, followed by dark incubation at 20 degrees Celsius.
limitations
Temperature-specific membrane kinetics do not directly specify a human whole-eye rate.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Bos taurus
plain_language
RGR released regenerated retinal within seconds in the membrane preparation.
primary_references
[vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
tissue_or_cell_type
RPE microsomes
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 498–511
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · LC-MS/MS and retinoid analysis of native microsomes · source_derived_draft · unverified_draft
### vae-rgr-photoproduct-release After photoisomerization in native bovine RPE microsomes, the RGR 11-cis-retinylidene Schiff base hydrolyzed with an estimated 7.5-second half-life at 20 degrees Celsius. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: RGR released regenerated retinal within seconds in the membrane preparation. organism: Bos taurus tissue_or_cell_type: RPE microsomes experimental_model: LC-MS/MS and retinoid analysis of native microsomes limitations: Temperature-specific membrane kinetics do not directly specify a human whole-eye rate. exposure: 20 micromolar all-trans-retinal; 10-second 530-nm exposure, followed by dark incubation at 20 degrees Celsius. cross_nutrient: false evidence_location: Figure 1D-F; STAR Methods: hydrolysis kinetics nutrient: Vitamin A [vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
Complete structured claim and evidence
Tamoxifen-induced Rgr reactivation through Rpe65-CreERT2 improved cone sensitivity during sustained light in RgrStop/Stop/Gnat1-null mice compared with untreated rescue-line controls.
RPE-restored RGR → Cone flash sensitivity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 7A; Table S1
experimental_model
Cell-directed excision of a floxed transcriptional stop cassette
exposure
530-nm background at 300 cd/m2 for 60 minutes; cone b-wave sensitivity.
limitations
Each cellular rescue was partial; native relative contributions need not match other species.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Restoring RGR in retinal pigment epithelium helped cones respond during prolonged light.
primary_references
[vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
tissue_or_cell_type
retinal pigment epithelium; intact-eye ERG
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 513–526
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-directed excision of a floxed transcriptional stop cassette · source_derived_draft · unverified_draft
### vae-rgr-rpe-rescue-cones Tamoxifen-induced Rgr reactivation through Rpe65-CreERT2 improved cone sensitivity during sustained light in RgrStop/Stop/Gnat1-null mice compared with untreated rescue-line controls. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring RGR in retinal pigment epithelium helped cones respond during prolonged light. organism: Mus musculus tissue_or_cell_type: retinal pigment epithelium; intact-eye ERG experimental_model: Cell-directed excision of a floxed transcriptional stop cassette limitations: Each cellular rescue was partial; native relative contributions need not match other species. exposure: 530-nm background at 300 cd/m2 for 60 minutes; cone b-wave sensitivity. cross_nutrient: false evidence_location: Figure 7A; Table S1 nutrient: Vitamin A [vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
Complete structured claim and evidence
Tamoxifen-induced Rgr reactivation through Glast-CreERT2 improved cone sensitivity during sustained light in RgrStop/Stop/Gnat1-null mice compared with untreated rescue-line controls.
Müller-glia-restored RGR → Cone flash sensitivity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 7B; Table S1
experimental_model
Cell-directed excision of a floxed transcriptional stop cassette
exposure
530-nm background at 300 cd/m2 for 60 minutes; cone b-wave sensitivity.
limitations
Each cellular rescue was partial; native relative contributions need not match other species.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Restoring RGR in Müller glia helped cones respond during prolonged light.
primary_references
[vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
tissue_or_cell_type
Müller glia; intact-eye ERG
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 528–541
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-directed excision of a floxed transcriptional stop cassette · source_derived_draft · unverified_draft
### vae-rgr-muller-rescue-cones Tamoxifen-induced Rgr reactivation through Glast-CreERT2 improved cone sensitivity during sustained light in RgrStop/Stop/Gnat1-null mice compared with untreated rescue-line controls. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring RGR in Müller glia helped cones respond during prolonged light. organism: Mus musculus tissue_or_cell_type: Müller glia; intact-eye ERG experimental_model: Cell-directed excision of a floxed transcriptional stop cassette limitations: Each cellular rescue was partial; native relative contributions need not match other species. exposure: 530-nm background at 300 cd/m2 for 60 minutes; cone b-wave sensitivity. cross_nutrient: false evidence_location: Figure 7B; Table S1 nutrient: Vitamin A [vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
Complete structured claim and evidence
RgrStop/Stop mice with intact Gnat1 recovered rod ERG responses more slowly after sustained bright illumination than Rgr-intact controls.
RGR loss → Rod dark adaptation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 8A; Results: RGR supports rod dark adaptation
experimental_model
Transcriptional-stop Rgr knockout; rod-driven ERG
exposure
530-nm background at 300 cd/m2 for 30 minutes; recovery followed in darkness.
limitations
Post-illumination recovery does not imply RGR catalyzes isomerization in darkness.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The light-driven recycling route also helped rods recover after the light was switched off.
primary_references
[vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
tissue_or_cell_type
intact eye; rod photoreceptors
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 543–556
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transcriptional-stop Rgr knockout; rod-driven ERG · source_derived_draft · unverified_draft
### vae-rgr-loss-rod-dark-adaptation RgrStop/Stop mice with intact Gnat1 recovered rod ERG responses more slowly after sustained bright illumination than Rgr-intact controls. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The light-driven recycling route also helped rods recover after the light was switched off. organism: Mus musculus tissue_or_cell_type: intact eye; rod photoreceptors experimental_model: Transcriptional-stop Rgr knockout; rod-driven ERG limitations: Post-illumination recovery does not imply RGR catalyzes isomerization in darkness. exposure: 530-nm background at 300 cd/m2 for 30 minutes; recovery followed in darkness. cross_nutrient: false evidence_location: Figure 8A; Results: RGR supports rod dark adaptation nutrient: Vitamin A [vav-tworak2023] Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia. (2023). https://pubmed.ncbi.nlm.nih.gov/37585292/ DOI: 10.1016/j.celrep.2023.112982
Complete structured claim and evidence
Homogenates of DES1-expressing HEK293T cells formed 11-cis-retinol from all-trans-retinol, alongside more abundant alternative cis isomers.
Dihydroceramide desaturase 1 / DES1 → 11-cis-retinol source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 3a-d; Results: DES1 catalyzes equilibrium isomerization
experimental_model
Recombinant human DES1 expression; HPLC isomer analysis
exposure
Retinol isomerase assays in darkness at 37 degrees Celsius.
limitations
Activity in homogenates does not establish its quantitative contribution or necessity in an intact visual cycle.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens protein/cells
plain_language
DES1-associated activity made some 11-cis-retinol in biochemical assays.
primary_references
[vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
tissue_or_cell_type
HEK293T homogenates
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 558–571
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human DES1 expression; HPLC isomer analysis · source_derived_draft · unverified_draft
### vae-des1-retinol-isomerization Homogenates of DES1-expressing HEK293T cells formed 11-cis-retinol from all-trans-retinol, alongside more abundant alternative cis isomers. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: DES1-associated activity made some 11-cis-retinol in biochemical assays. organism: Homo sapiens protein/cells tissue_or_cell_type: HEK293T homogenates experimental_model: Recombinant human DES1 expression; HPLC isomer analysis limitations: Activity in homogenates does not establish its quantitative contribution or necessity in an intact visual cycle. exposure: Retinol isomerase assays in darkness at 37 degrees Celsius. cross_nutrient: false evidence_location: Figure 3a-d; Results: DES1 catalyzes equilibrium isomerization nutrient: Vitamin A [vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
Complete structured claim and evidence
CRALBP coexpression increased 11-cis-retinol production approximately threefold in homogenates of cells stably expressing chicken DES1.
Cellular retinaldehyde-binding protein / CRALBP → 11-cis-retinol source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 5b
experimental_model
Chicken CRALBP transfection into stable DES1-expressing 293T cells
exposure
All-trans-retinol substrate; CRALBP plasmid versus empty-vector comparison.
limitations
An assay yield effect does not prove physiological transport or human supplementation benefit.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Gallus gallus proteins in Homo sapiens cells
plain_language
The binding protein shifted the measured output toward the visual-cycle alcohol.
primary_references
[vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
tissue_or_cell_type
cell homogenates
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 573–586
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chicken CRALBP transfection into stable DES1-expressing 293T cells · source_derived_draft · unverified_draft
### vae-cralbp-des1-isomer-yield CRALBP coexpression increased 11-cis-retinol production approximately threefold in homogenates of cells stably expressing chicken DES1. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The binding protein shifted the measured output toward the visual-cycle alcohol. organism: Gallus gallus proteins in Homo sapiens cells tissue_or_cell_type: cell homogenates experimental_model: Chicken CRALBP transfection into stable DES1-expressing 293T cells limitations: An assay yield effect does not prove physiological transport or human supplementation benefit. exposure: All-trans-retinol substrate; CRALBP plasmid versus empty-vector comparison. cross_nutrient: false evidence_location: Figure 5b nutrient: Vitamin A [vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
Complete structured claim and evidence
DES1-targeted siRNA reduced 11-cis-retinol formation from all-trans-retinol in homogenates of primary chicken Müller cultures compared with nonsilencing RNA.
DES1 siRNA reduction → 11-cis-retinol source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Supplementary Figure 8; Results: RNAi knockdown
experimental_model
Targeted RNA interference with nonsilencing control
exposure
Approximately 50% DES1 expression reduction; retinol-substrate homogenate assay.
limitations
Neither complete gene deletion nor a physiological necessity test in an intact retina.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Gallus gallus
plain_language
Reducing DES1 lowered the culture preparation’s isomerase output.
primary_references
[vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
tissue_or_cell_type
primary Müller cultures
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 588–601
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Targeted RNA interference with nonsilencing control · source_derived_draft · unverified_draft
### vae-des1-sirna-isomerization DES1-targeted siRNA reduced 11-cis-retinol formation from all-trans-retinol in homogenates of primary chicken Müller cultures compared with nonsilencing RNA. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing DES1 lowered the culture preparation’s isomerase output. organism: Gallus gallus tissue_or_cell_type: primary Müller cultures experimental_model: Targeted RNA interference with nonsilencing control limitations: Neither complete gene deletion nor a physiological necessity test in an intact retina. exposure: Approximately 50% DES1 expression reduction; retinol-substrate homogenate assay. cross_nutrient: false evidence_location: Supplementary Figure 8; Results: RNAi knockdown nutrient: Vitamin A [vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
Complete structured claim and evidence
Intravitreal adenovirus expressing human DES1 increased retinal 9-cis-retinal in Rpe65-null mice relative to the RFP control virus.
Adenoviral DES1 expression → 9-cis-retinal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 4a; Results: Gene therapy of rpe65-null mice
experimental_model
Adenoviral human DES1 versus RFP in Rpe65-null mice
exposure
Retinoids measured one day after injection; Figure 4a without added intravitreal retinol.
limitations
11-cis-retinoids remained undetectable in this comparison; viral cell targeting was not exclusive.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Homo sapiens transgene in Mus musculus
plain_language
Extra DES1 increased an alternative cis-retinal isomer in the mutant eyes.
primary_references
[vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
tissue_or_cell_type
retina
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 603–616
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Adenoviral human DES1 versus RFP in Rpe65-null mice · source_derived_draft · unverified_draft
### vae-des1-gene-transfer-9cis Intravitreal adenovirus expressing human DES1 increased retinal 9-cis-retinal in Rpe65-null mice relative to the RFP control virus. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra DES1 increased an alternative cis-retinal isomer in the mutant eyes. organism: Homo sapiens transgene in Mus musculus tissue_or_cell_type: retina experimental_model: Adenoviral human DES1 versus RFP in Rpe65-null mice limitations: 11-cis-retinoids remained undetectable in this comparison; viral cell targeting was not exclusive. exposure: Retinoids measured one day after injection; Figure 4a without added intravitreal retinol. cross_nutrient: false evidence_location: Figure 4a; Results: Gene therapy of rpe65-null mice nutrient: Vitamin A [vav-kaylor2013] Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. (2013). https://pubmed.ncbi.nlm.nih.gov/23143414/ DOI: 10.1038/nchembio.1114
Complete structured claim and evidence
Müller-directed Degs1 deletion did not slow cone dark adaptation after greater than 90% pigment bleaching in isolated mouse retinas or intact eyes.
Müller-directed DES1 loss → Cone dark adaptation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 7C-D
experimental_model
Degs1-flox/Pdgfra-Cre conditional knockout on Gnat1-null background
exposure
505-nm ex vivo or 520-nm in vivo bleach; mutant versus heterozygous littermate controls.
limitations
Does not exclude other DES1 functions, residual extra-Müller activity, or species-specific contributions.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The tested mice regenerated cone pigment normally despite targeted DES1 loss.
primary_references
[vav-kiser2019] Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones. (2019). https://pubmed.ncbi.nlm.nih.gov/30645148/ DOI: 10.1096/fj.201802493r
tissue_or_cell_type
neural retina and intact-eye recordings
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 618–631
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Degs1-flox/Pdgfra-Cre conditional knockout on Gnat1-null background · source_derived_draft · unverified_draft
### vae-des1-deletion-cone-recovery Müller-directed Degs1 deletion did not slow cone dark adaptation after greater than 90% pigment bleaching in isolated mouse retinas or intact eyes. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tested mice regenerated cone pigment normally despite targeted DES1 loss. organism: Mus musculus tissue_or_cell_type: neural retina and intact-eye recordings experimental_model: Degs1-flox/Pdgfra-Cre conditional knockout on Gnat1-null background limitations: Does not exclude other DES1 functions, residual extra-Müller activity, or species-specific contributions. exposure: 505-nm ex vivo or 520-nm in vivo bleach; mutant versus heterozygous littermate controls. cross_nutrient: false evidence_location: Figure 7C-D nutrient: Vitamin A [vav-kiser2019] Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones. (2019). https://pubmed.ncbi.nlm.nih.gov/30645148/ DOI: 10.1096/fj.201802493r
Complete structured claim and evidence
Müller-directed Degs1 conditional mutants showed slightly faster cone photoresponse termination than controls in ex vivo retinal recordings.
Müller-directed DES1 loss → Cone photoresponse termination source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 7A-B; Discussion
experimental_model
Degs1-flox/Pdgfra-Cre conditional knockout on Gnat1-null background
exposure
Dark-adapted transretinal cone flash responses.
limitations
The responsible cellular or lipid mechanism was unresolved; do not equate termination kinetics with pigment regeneration.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
The response switched off faster even though pigment recovery was preserved.
primary_references
[vav-kiser2019] Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones. (2019). https://pubmed.ncbi.nlm.nih.gov/30645148/ DOI: 10.1096/fj.201802493r
tissue_or_cell_type
isolated retina
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 633–646
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Degs1-flox/Pdgfra-Cre conditional knockout on Gnat1-null background · source_derived_draft · unverified_draft
### vae-des1-deletion-cone-termination Müller-directed Degs1 conditional mutants showed slightly faster cone photoresponse termination than controls in ex vivo retinal recordings. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: The response switched off faster even though pigment recovery was preserved. organism: Mus musculus tissue_or_cell_type: isolated retina experimental_model: Degs1-flox/Pdgfra-Cre conditional knockout on Gnat1-null background limitations: The responsible cellular or lipid mechanism was unresolved; do not equate termination kinetics with pigment regeneration. exposure: Dark-adapted transretinal cone flash responses. cross_nutrient: false evidence_location: Figure 7A-B; Discussion nutrient: Vitamin A [vav-kiser2019] Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones. (2019). https://pubmed.ncbi.nlm.nih.gov/30645148/ DOI: 10.1096/fj.201802493r
Complete structured claim and evidence
Six3-Cre-directed Rdh10 deletion left mouse cone dark adaptation comparable to controls after pigment bleaching in isolated retinas and intact eyes.
Retina-directed RDH10 loss → Cone dark adaptation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Figure 7A-B; Results: retina RDH10 and dark adaptation
experimental_model
Six3-Cre Rdh10-flox homozygotes on Gnat1-null background
exposure
Approximately 90% pigment bleach; Figure 7A-B.
limitations
Müller-specific mutants were not separately tested for dark adaptation; whole-retina results must not be relabeled as that experiment.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Removing neural-retinal RDH10 did not impair the tested cone recovery.
primary_references
[vav-xue2017] The role of retinol dehydrogenase 10 in the cone visual cycle. (2017). https://pubmed.ncbi.nlm.nih.gov/28539612/ DOI: 10.1038/s41598-017-02549-8
tissue_or_cell_type
neural retina; intact-eye and transretinal ERG
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 648–661
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Six3-Cre Rdh10-flox homozygotes on Gnat1-null background · source_derived_draft · unverified_draft
### vae-rdh10-retinal-deletion-recovery Six3-Cre-directed Rdh10 deletion left mouse cone dark adaptation comparable to controls after pigment bleaching in isolated retinas and intact eyes. Condition category: machinery_impairment nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing neural-retinal RDH10 did not impair the tested cone recovery. organism: Mus musculus tissue_or_cell_type: neural retina; intact-eye and transretinal ERG experimental_model: Six3-Cre Rdh10-flox homozygotes on Gnat1-null background limitations: Müller-specific mutants were not separately tested for dark adaptation; whole-retina results must not be relabeled as that experiment. exposure: Approximately 90% pigment bleach; Figure 7A-B. cross_nutrient: false evidence_location: Figure 7A-B; Results: retina RDH10 and dark adaptation nutrient: Vitamin A [vav-xue2017] The role of retinol dehydrogenase 10 in the cone visual cycle. (2017). https://pubmed.ncbi.nlm.nih.gov/28539612/ DOI: 10.1038/s41598-017-02549-8
Complete structured claim and evidence
Ectopic RDH10 expression did not enable bleached mouse rods to recover sensitivity when supplied with 9-cis-retinol.
Rod-expressed transgenic RDH10 → Rod dark adaptation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Figure 9C; Results: ectopic RDH10 expression
experimental_model
Rod RDH10 transgenesis; single-cell suction recordings
exposure
100 micromolar 9-cis-retinol after approximately 50% pigment bleach.
limitations
Expression was mosaic; the substrate was 9-cis-retinol, not 11-cis-retinol. This tests sufficiency in rods, not necessity in cones.
nutrient
Vitamin A · Vitamin A
nutrient_topic
Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A
organism
Mus musculus
plain_language
Adding RDH10 alone did not let rods use the supplied retinol isomer.
primary_references
[vav-xue2017] The role of retinol dehydrogenase 10 in the cone visual cycle. (2017). https://pubmed.ncbi.nlm.nih.gov/28539612/ DOI: 10.1038/s41598-017-02549-8
tissue_or_cell_type
isolated rods
Vitamin A expansion: reproduction, light-driven vision and shared mechanisms (2026-09-17) · lines 663–676
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rod RDH10 transgenesis; single-cell suction recordings · source_derived_draft · unverified_draft
### vae-rdh10-rod-transgene-9cis-retinol Ectopic RDH10 expression did not enable bleached mouse rods to recover sensitivity when supplied with 9-cis-retinol. Condition category: normal nutrient_topic: Vitamin A expansion research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding RDH10 alone did not let rods use the supplied retinol isomer. organism: Mus musculus tissue_or_cell_type: isolated rods experimental_model: Rod RDH10 transgenesis; single-cell suction recordings limitations: Expression was mosaic; the substrate was 9-cis-retinol, not 11-cis-retinol. This tests sufficiency in rods, not necessity in cones. exposure: 100 micromolar 9-cis-retinol after approximately 50% pigment bleach. cross_nutrient: false evidence_location: Figure 9C; Results: ectopic RDH10 expression nutrient: Vitamin A [vav-xue2017] The role of retinol dehydrogenase 10 in the cone visual cycle. (2017). https://pubmed.ncbi.nlm.nih.gov/28539612/ DOI: 10.1038/s41598-017-02549-8
Complete structured claim and evidence

Availability and dependencies

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

Experimental iron sequestration limits provitamin A cleavage

Condition: machinery_impairment · Desferrioxamine exposure in human intestinal preparations.

Normal role: Iron supports carotenoid cleavage.

Recorded consequence: Reduced retinal-generating cleavage.

Scope: Human in vitro preparations.

A missing catabolic enzyme disrupts fetal male germ-cell timing.

Condition: machinery_impairment · Embryonic Cyp26b1 deletion.

Normal role: Fetal CYP26B1 contributes to postponement of testicular meiotic entry.

Recorded consequence: Cyp26b1-null mouse fetal testes contained germ cells entering meiosis precociously.

Scope: Embryonic knockout comparison; Mus musculus

Disrupted BCO1 iron coordination

Condition: machinery_impairment · Engineered mouse BCO1 amino-acid substitutions.

Normal role: BCO1 cleaves provitamin A carotenoids.

Recorded consequence: Reduced bound iron and catalytic loss.

Scope: Recombinant proteins.

STRA8 acts before the ovarian cell copies its DNA for meiosis.

Condition: machinery_impairment · Stra8 gene disruption.

Normal role: STRA8 enables the female germ-cell transition into the meiotic replication program.

Recorded consequence: Stra8-null female embryonic germ cells failed premeiotic DNA replication despite normal earlier mitotic development.

Scope: Targeted Stra8 disruption; Mus musculus

Vitamin A status changes lycopene handling in mice

Condition: nutrient_deficiency · Experimental vitamin-A-deficient diet.

Normal role: Vitamin A status participates in carotenoid-handling feedback.

Recorded consequence: Greater liver lycopene accumulation than with a vitamin-A-sufficient diet.

Scope: Wild-type mice; cannot diagnose human vitamin A or lycopene status.

Impaired eccentric carotenoid cleavage

Condition: machinery_impairment · Bco2 deletion with injected beta-cryptoxanthin.

Normal role: BCO2 clears selected carotenoid substrates.

Recorded consequence: Hepatic beta-cryptoxanthin accumulation.

Scope: Female mice exposed pharmacologically.

The meiotic program needs the MEIOSIN regulator.

Condition: machinery_impairment · Meiosin gene disruption.

Normal role: MEIOSIN cooperates with STRA8 in meiotic transcription.

Recorded consequence: Loss of MEIOSIN impaired meiotic gene activation and the transition into meiosis in mouse germ cells.

Scope: Knockout and transcriptional functional analysis; Mus musculus

Intestinal feedback machinery loss

Condition: machinery_impairment · Isx knockout, including Bco2 compound mutants.

Normal role: ISX represses intestinal uptake/conversion genes.

Recorded consequence: Altered SCARB1 and alpha-tocopherol accumulation.

Scope: Controlled mouse diets.

Vitamin A shortage can stop early sperm-cell differentiation.

Condition: nutrient_deficiency · Vitamin A withdrawal in Lrat-null mothers and offspring.

Normal role: Available retinoid supports spermatogonial differentiation.

Recorded consequence: Dietary vitamin A depletion caused undifferentiated spermatogonia to accumulate in prepubertal Lrat-null testes.

Scope: Genotype-by-diet mouse comparison; Mus musculus

Impaired retinol esterification machinery

Condition: machinery_impairment · Lrat deletion.

Normal role: LRAT supports retinyl ester storage.

Recorded consequence: Large loss of hepatic stores and changed chylomicron retinoid forms.

Scope: Mouse knockout.

Replacing the missing nutrient restored early meiotic development.

Condition: nutrient_deficiency · Dietary replacement after prenatal and neonatal vitamin A withdrawal.

Normal role: Vitamin A supply permits neonatal germ-cell progression.

Recorded consequence: Maternal retinyl-palmitate supplementation rescued SYCP3-positive meiotic cells in vitamin A-depleted Lrat-null pups.

Scope: Dietary rescue experiment; Mus musculus

Storage impairment plus dietary vitamin A withdrawal

Condition: nutrient_deficiency · Lrat knockout followed by one month without dietary retinoids.

Normal role: Retinyl ester stores buffer dietary shortage.

Recorded consequence: Circulating retinol falls sooner than in wild type.

Scope: Three-month-old male and female mice.

Removing the main RA-synthesis enzymes did not stop fetal ovarian meiosis.

Condition: machinery_impairment · Conditional triple Aldh1a deletion.

Normal role: ALDH1A enzymes provide local RA synthesis.

Recorded consequence: Conditional deletion of Aldh1a1, Aldh1a2 and Aldh1a3 did not prevent fetal ovarian meiotic progression despite strongly reduced RA.

Scope: Three conditional deletion strategies; Mus musculus

Defective hepatic retinol mobilization

Condition: machinery_impairment · Rbp4 knockout.

Normal role: RBP4 distributes retinol from stores.

Recorded consequence: Hepatic stores are poorly mobilized.

Scope: Mouse diet comparisons.

The tested fetal ovarian program progressed without the RA receptors.

Condition: machinery_impairment · Rara/Rarg excision on a Rarb-null background.

Normal role: RARs transduce RA-dependent transcription; their necessity here was tested genetically.

Recorded consequence: Fetal ovarian germ cells lacking all RARs expressed meiotic markers and reached zygotene, challenging an obligatory RAR trigger.

Scope: Timed receptor deletion with excision reporter; Mus musculus

Retinol transport loss during dietary deprivation

Condition: nutrient_deficiency · Rbp4 knockout plus vitamin A-deficient diet.

Normal role: RBP4 buffers reduced dietary delivery.

Recorded consequence: Circulating retinol becomes undetectable within one week.

Scope: Adult knockout mice.

The receptor-deficient ovarian grafts could produce functional eggs.

Condition: machinery_impairment · All-RAR mutant ovaries studied by grafting.

Normal role: Functional oocytes complete meiosis and contribute to fertilization.

Recorded consequence: RAR-null fetal ovaries grafted into adult females produced oocytes that contributed to offspring carrying the deleted alleles.

Scope: Ovarian graft and breeding experiment; Mus musculus

Altered circulating retinol transport

Condition: machinery_impairment · Ttr knockout.

Normal role: TTR associates with circulating RBP4.

Recorded consequence: Markedly reduced plasma retinol despite preserved stores in tested tissues.

Scope: Mouse genetic model.

Altered circulating retinol transport

Condition: biomarker_context · Ttr knockout.

Normal role: TTR associates with circulating RBP4.

Recorded consequence: Markedly reduced plasma retinol despite preserved stores in tested tissues.

Scope: Mouse genetic model.

Reduced retinol oxidation capacity

Condition: machinery_impairment · siRNA silencing of endogenous RDH10.

Normal role: RDH10 supplies retinal for retinoic-acid synthesis.

Recorded consequence: Reduced retinoic-acid formation from retinol.

Scope: Human cell culture.

Later genetic promoter tests confirmed a contribution from RA-responsive DNA elements.

Condition: machinery_impairment · Targeted cis-regulatory mutations at the Stra8 locus.

Normal role: RA-responsive promoter elements contribute to the level of Stra8 expression.

Recorded consequence: Targeted mutation of Stra8 RA-response elements reduced its expression in fetal mouse ovaries.

Scope: CRISPR/Cas9 cis-regulatory mutation; Mus musculus

Loss of ocular retinol esterification

Condition: machinery_impairment · Lrat gene deletion

Normal role: LRAT supplies retinyl esters.

Recorded consequence: Ocular ester and chromophore availability fall.

Scope: Knockout mouse eye

RGR chromophore-binding site disruption

Condition: machinery_impairment · Engineered bovine RGR K255A substitution

Normal role: RGR binds and photoisomerizes retinal.

Recorded consequence: Strongly reduced photic 11-cis-retinal production

Scope: Recombinant cell-homogenate assay

RDH5-associated delayed dark adaptation

Condition: machinery_impairment · Inherited RDH5 variants

Normal role: RDH5 supports cis-retinal production.

Recorded consequence: Enzyme activity and pigment regeneration are impaired.

Scope: Two human families and recombinant proteins

RGR loss during sustained retinal illumination

Condition: machinery_impairment · Genetic absence of RGR

Normal role: RGR supplies a light-dependent route for chromophore recycling.

Recorded consequence: Reduced maintenance or subsequent recovery of photoreceptor sensitivity

Scope: Mouse genetic models; exact allele, light regimen and photoreceptor class are specified in each claim.

Impaired retinaldehyde clearance

Condition: machinery_impairment · Targeted clearance-enzyme/transporter deletions

Normal role: ABCA4 and RDHs dispose of photoproduct retinal.

Recorded consequence: Retinoid by-products and retinal vulnerability increase.

Scope: Specified mouse genotypes

Cell-directed RGR reactivation in retinal pigment epithelium

Condition: machinery_impairment · Rgr stop-cassette null background followed by Rpe65-CreERT2 reactivation

Normal role: RGR supports photic chromophore supply.

Recorded consequence: Improved cone sensitivity during illumination

Scope: Tamoxifen-inducible genetic rescue in Gnat1-null mice

Cell-specific CRALBP impairment

Condition: machinery_impairment · Timed cell-selective Rlbp1 knockout

Normal role: CRALBP supports cis-retinoid availability.

Recorded consequence: Chromophore recovery depends on the affected cell pool.

Scope: Mouse RPE versus Müller glia

Cell-directed RGR reactivation in Müller glia

Condition: machinery_impairment · Rgr stop-cassette null background followed by Glast-CreERT2 reactivation

Normal role: RGR supports photic chromophore supply.

Recorded consequence: Improved cone sensitivity during illumination

Scope: Tamoxifen-inducible genetic rescue in Gnat1-null mice

Loss of calcium feedback sensors

Condition: machinery_impairment · Combined Guca1a/Guca1b disruption

Normal role: GCAPs couple calcium to cGMP recovery.

Recorded consequence: Rod responses recover more slowly.

Scope: Mouse rods

DES1 reduction in chicken Müller cultures

Condition: machinery_impairment · DES1-targeted siRNA

Normal role: DES1-associated activity can isomerize retinol in the tested preparation.

Recorded consequence: Reduced retinol isomerization in culture homogenates

Scope: Primary chicken Müller-cell culture

Vitamin A depletion and night vision

Condition: nutrient_deficiency · Clinical vitamin A deficiency with biliary or intestinal disease

Normal role: Retinoid availability supports pigment regeneration.

Recorded consequence: Night sensitivity and dark adaptation deteriorate.

Scope: Three patients

DES1 gain of function on an Rpe65-null background

Condition: machinery_impairment · Rpe65 genetic loss followed by intravitreal DES1 adenovirus

Normal role: RPE65 normally supplies cis-retinoid through the classical cycle.

Recorded consequence: Increased 9-cis-retinal

Scope: Mutant mouse gain-of-function experiment

Vitamin A depletion and intestinal T cells

Condition: nutrient_deficiency · Experimental vitamin A deficiency

Normal role: Retinoid availability supports intestinal trafficking.

Recorded consequence: Fewer intestinal T cells

Scope: Mouse dietary model

Müller-directed DES1 deletion in mice

Condition: machinery_impairment · Pdgfra-Cre excision of floxed Degs1 exon 2 on a Gnat1-null background

Normal role: The tested proposal assigned DES1 a retinol-isomerase role in Müller cells.

Recorded consequence: Preserved cone pigment recovery with altered response termination

Scope: Conditional mutant mouse comparison

Vitamin A depletion and intestinal IgA cells

Condition: nutrient_deficiency · Experimental vitamin A deficiency

Normal role: Retinoids support intestinal B-cell programming.

Recorded consequence: Loss of intestinal IgA-secreting cells

Scope: Mouse dietary model

RDH10 deletion in the neural retina

Condition: machinery_impairment · Six3-Cre-mediated Rdh10 deletion on a Gnat1-null background

Normal role: RDH10 was a candidate enzyme for intraretinal cis-retinol processing.

Recorded consequence: Preserved measured cone dark adaptation

Scope: Mouse neural-retina conditional deletion

RARA machinery impairment in T cells

Condition: machinery_impairment · Rara deletion or receptor antagonism

Normal role: RARA supports activation and expansion.

Recorded consequence: Reduced T-cell proliferation

Scope: Mouse experimental T cells

Intestinal epithelial RARB loss

Condition: machinery_impairment · Villin-Cre-mediated Rarb deletion

Normal role: Epithelial RARB supports immune effector function.

Recorded consequence: Reduced Th17 IL-17A production

Scope: Mouse intestinal epithelium and lamina propria

Retinoid withdrawal in epithelial culture

Condition: nutrient_deficiency · RA omitted from culture medium

Normal role: RA supports secretory differentiation.

Recorded consequence: Reduced mucus-related output

Scope: Human cells in air-liquid interface culture

Correcting more than one shortage improved the measured response in this population.

Condition: nutrient_deficiency · Anemia or poor vitamin A/iron status in the study population.

Normal role: Vitamin A metabolism and erythropoiesis interact with iron availability.

Recorded consequence: Vitamin A intervention altered hematologic measures.

Scope: Selected human trial populations.

Tet2 regulatory DNA deletion

Condition: machinery_impairment · CRISPR deletion of intronic RARE-containing segment

Normal role: Retinoid response element supports Tet2 transcription

Recorded consequence: Retinol no longer induces the normal Tet2 transcript response

Scope: CRISPR Tet2 ΔRARE naïve ESCs compared with wild type; Mus musculus; Naïve embryonic stem cells

An additional shortage may limit the response, but this result was subgroup-specific.

Condition: nutrient_deficiency · Night blindness during pregnancy with low initial serum zinc in a trial subgroup.

Normal role: Retinoids support visual adaptation; other nutritional constraints may matter.

Recorded consequence: Combined vitamin A/zinc was associated with better restoration of night vision.

Scope: Subgroup of randomized zinc trial.

Vitamin A status affected how strongly the thyroid was being stimulated.

Condition: nutrient_deficiency · Concurrent mild-to-moderate vitamin A and iodine deficits.

Normal role: Iodine supplies thyroid hormone; retinoid signaling can affect endocrine regulation.

Recorded consequence: Vitamin A supplementation altered thyroid stimulation and size.

Scope: Six-month childhood factorial trial.

A low blood value did not mean the measured tissue stores had been emptied.

Condition: biomarker_context · Acute inflammation or comparison of serum with isotope-modelled reserves.

Normal role: Retinol transport supports delivery while liver stores buffer supply.

Recorded consequence: Blood concentration can misclassify nutritional reserves.

Scope: Animal mechanistic and human biomarker studies, kept distinct.

Iron could be retained in one tissue while circulating availability fell.

Condition: nutrient_deficiency · Experimental vitamin A-deficient diet.

Normal role: Iron recycling and erythropoietic signals coordinate iron use.

Recorded consequence: Iron distribution and regulatory transcripts changed.

Scope: Male rat dietary experiments.

The sources

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

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

Recorded disagreements

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

Does all-trans-retinoic acid directly trap radicals in ferroptosis assays?A 2023 primary study attributes direct radical-trapping to ATRA; the 2024 study found no ATRA activity in two cell-free assays and instead supported receptor-dependent protection. Both distinguish retinoid chemical forms.Read the recorded disagreement
Does vitamin A enhance nonheme iron absorption from cereal meals?The 1998 human studies reported enhancement; five follow-up experiments explicitly failed to reproduce it. The disagreement concerns direct meal iron absorption, separate from longer-term anemia responses.Read the recorded disagreement
Is RAR signaling obligatory for fetal ovarian meiotic entry?The 2006 pharmacologic study explicitly inferred an obligatory RAR-to-Stra8 trigger. The 2020 all-RAR genetic study explicitly disputed that necessity model after observing meiotic progression and functional oocytes.Read the recorded disagreement
Vitamin C suppresses leukaemia in animals and cells, but the published patient trial found no responsePreclinical work restores TET2 function with vitamin C and slows leukaemia in mice and xenografts. The one registered phase 2 trial in TET2-mutant clonal cytopenia found no haematologic responses at week 20. The studies differ in species, disease stage, endpoint and duration, so this is recorded as a difference in what was tested rather than as a refutation of the mechanism. It is kept visible because the mechanistic records alone would otherwise read as clinical support.Read the recorded disagreement

Open questions in this collection

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

Which ovarian signals initiate meiosis when ALDH1A or RAR functions are removed?The genetic studies constrain the obligatory RA model without fully identifying the alternative inducing mechanism.
How are MEIOSIN responsiveness and germ-cell competence timed across stages?The extracted primary abstract supports RA-responsive temporal regulation but not a complete causal pulse-to-promoter mechanism.
Can the human fetal-testis STRA8 response lead to completed meiosis under other conditions?The retrieved experiment measured a 24-hour transcript response, not long-term gamete development.
Does maternal vitamin C alter a defined vitamin A response independently of its broader germline epigenetic effects?Shared STRA8 and meiotic outcomes do not establish a direct nutritional A-C interaction or supplementation benefit.
What endogenous contribution does DES1 make to retinoid recycling outside the tested mouse Müller-cell model?Recombinant assays, chicken culture knockdown, mutant-mouse overexpression and normal mouse conditional deletion test different causal questions.
Which oxidoreductases supply the intact retinal RGR pathway under different light regimens?RGR/RDH10 coexpression demonstrates coupled capability; neural-retinal Rdh10 deletion preserved tested cone recovery. The precise intermediate steps and cellular cofactors remain incompletely established.
How much chromophore flux does RGR provide in living human eyes?Human expression and recombinant activity do not quantify human functional flux; cell-directed physiological evidence here is from mice.
Which steps mediate vitamin A-associated improvement in human anemia?Absorption, iron redistribution, erythropoietic signaling and inflammation are distinct explanations.
When does zinc status materially limit response to vitamin A?Human biomarker and subgroup findings do not establish one universal enzyme/cofactor bottleneck.
How do local retinoid gradients, bone-cell stage and vitamin D status combine in vivo?Organ cultures, precursor cultures and acute serum-calcium experiments measure different steps.
Can retinoid modulation of GPX4/FSP1 translate to a nutritional interaction in humans?Pharmacological cell experiments do not establish dietary synergy, selenium substitution or disease prevention.
How should blood retinol be interpreted during an individual inflammatory illness?Tissue stores, carrier regulation and inflammation affect the value; the selected studies do not provide a universal diagnostic algorithm.
Whether RXRA sharing creates clinically important vitamin A-vitamin D or iodine interactions at ordinary intakes.Reconstituted receptor partnerships do not establish nutrient competition, deficiency thresholds or repletion failure.
The quantitatively dominant endogenous RXR ligand in each human tissue and nutritional state.High-affinity 9-cis RA binding is established biochemistry; ligand occurrence and abundance cannot be assumed from these assays.
Whether epithelial SAA delivers retinol directly to Th17 cells or to RA-producing antigen-presenting cells.Gattu et al. propose these transport routes; their promoter and rescue experiments do not test the full transfer chain.
Whether the airway mucin-culture effects improve barrier integrity or clinical infection outcomes.Mucin transcript/secretion assays are not permeability, pathogen-clearance or treatment trials.
Human dietary intake thresholds for the immune and embryonic effects described here.Added RA, culture depletion and genetic receptor perturbations cannot be converted into human intake recommendations.
How much does dietary iron deficiency reduce human carotenoid-to-retinol conversion, independently of inflammation and intake?Chelation rescue and enzyme mutagenesis establish molecular dependence, not a clinical conversion effect size.
How strongly does the retinoid-ISX-SCARB1 loop change vitamin E absorption in humans?The direct perturbation evidence here is mouse genetic/dietary work.
Does nutritional choline or niacin limitation impair these particular retinoid reactions in humans?Phosphatidylcholine and NAD(P) cofactor requirements do not prove a dietary-deficiency chain.
What is the quantitative human contribution of BCO2-dependent beta-cryptoxanthin processing?Purified human BCO1 accepts this substrate; the BCO2 pathway tested here uses murine enzyme and injected mice.
Which intracellular retinoid concentrations establish tissue-specific functional sufficiency?Blood retinol and tissue pools diverge in transport knockouts; no universal cellular threshold is established.
A/D/E/K competitive absorption, dietary retinyl-ester hydrolases, chylomicron remnant hepatic uptake and CYP26C1 require a separate primary-source expansion.Not claimed from indirect transporter sharing; module scope prioritizes verified atomic steps.
The clinical iron or zinc threshold at which human RPE65 flux becomes limiting is not established by these assays.Direct iron-cofactor rescue cannot be converted into a serum threshold or a supplement recommendation.
Relative RPE and Müller-cell contributions to human cone chromophore supply remain incompletely defined.Global knockout/rescue and selective knockout interrogate different contexts; these records do not label ordinary model differences as a contradiction.
How mouse bisretinoid changes translate into human genotype-specific vision outcomes remains unresolved here.Radu measured excess exposure in mice; pigmentation and genotype changed retinal degeneration independently of the biochemical endpoint.
The module does not claim dietary calcium or magnesium deficiency causes the reported GCAP knockout phenotype.Intracellular cofactor/sensor experiments do not test systemic deficiency.
Complete alternative cone-cycle enzyme chemistry, including proposed DES1 or RGR routes, is outside this verified claim set.Only the CRALBP functional contribution was verified here, so no complete alternative pathway is asserted.

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

Evidence, AI assistance and curation standards

Vitamin A

The mechanisms

Recombinant human CYP26B1 formed 4-hydroxy-retinoic acid from all-trans-retinoic acid.

Lrat-null mice retained only trace hepatic retinyl esters.

Recombinant RPE65 catalyzed conversion of all-trans-retinyl esters to 11-cis-retinol in visual-cycle reconstitution.

FeSO4 restored chelator-inhibited RPE65 isomerohydrolase activity in bovine microsomes and recombinant assays; ferric salts did not.

Bovine RDH5 expressed in COS cells oxidized 11-cis-retinol using NAD+; NADP did not support the tested activity.

Recombinant human RDH10 oxidized all-trans-retinol with NAD+ in microsomal assays.

Müller-cell-directed CRALBP restoration in Rlbp1-null/Gnat1-null mice improved cone recovery in the isolated-retina paradigm.

RPE-selective CRALBP deletion slowed bulk visual chromophore regeneration approximately 15-fold in mice.

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

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

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

Sequencing the TET2 coding region in 320 patients found somatic deletions or mutations in 19% of myelodysplastic syndromes (15 of 81), 12% of myeloproliferative disorders (24 of 198), 24% of secondary acute myeloid leukaemia (5 of 21) and 22% of chronic myelomonocytic leukaemia (2 of 9).

TET2 defects were present in haematopoietic stem cells and preceded the JAK2 V617F mutation in the five analysed samples from patients with myeloproliferative disorders.

Bone marrow from patients carrying TET2 mutations showed uniformly low 5-hydroxymethylcytosine in genomic DNA compared with bone marrow from healthy controls, and the mutations compromised catalytic activity in the same study.

Short-hairpin-RNA depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte and macrophage lineages in culture.

Conditional deletion of Tet2 in the mouse haematopoietic compartment increased stem-cell self-renewal in competitive transplant assays, and Tet2 heterozygous mice also showed increased self-renewal and extramedullary haematopoiesis.

Conditional Tet2 loss produced progressive enlargement of the haematopoietic stem-cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis and extramedullary haematopoiesis.

Inactivating Tet2 in mouse perturbed both early and late haematopoiesis in a cell-autonomous manner, gave the cells a competitive advantage, and eventually led to the development of haematological malignancies.

TET2 mutations were observed in human lymphoid disorders and could be detected in immature progenitors that retained myeloid colony-forming potential.

Restoring endogenous Tet2 expression in a reversible transgenic RNAi mouse reversed aberrant haematopoietic stem and progenitor cell self-renewal both in vitro and in vivo.

Vitamin C treatment enhanced 5-hydroxymethylcytosine formation in Tet2-deficient mouse haematopoietic stem and progenitor cells, mimicking genetic Tet2 restoration.

Vitamin C treatment suppressed leukaemic colony formation by human leukaemia cells and slowed leukaemia progression in primary human acute-myeloid-leukaemia patient-derived xenografts.

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.

Systemic ascorbate depletion cooperated with Flt3 internal tandem duplication to accelerate leukaemogenesis in mice, and restoring dietary ascorbate reversed that acceleration.

All-trans retinoic acid induced retinoic-acid-receptor-alpha-mediated TET2 transcription in myeloid leukaemia cells.

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.

In patient-derived primary acute-myeloid-leukaemia cells, vitamin C restored TET2 activity only when SLC2A3 was expressed, and SLC2A3 knockdown in the KG-1 cell line decreased the response to vitamin C.

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.

TET2 knockout in human HAP1 cells lowered 5-hydroxymethylcytosine and 5-formylcytosine measured by 2D-UPLC-MS/MS, and vitamin C treatment did not restore them to the levels seen in treated wild-type cells, so loss of one TET paralog was not compensated by the remaining ones.

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.

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.

SCARB1 supported intestinal beta-carotene absorption in mice on a high-fat diet.

Purified human BCO1 cleaved all-trans-beta-carotene centrally to all-trans-retinal.

Human BCO1 generated retinal from alpha-carotene in substrate assays.

Human BCO1 generated retinal from beta-cryptoxanthin in substrate assays.

Isotope tracing showed that oxygen incorporated into both BCO1-generated retinal products originated from molecular oxygen.

Desferrioxamine reduced beta-carotene-cleaving activity in human intestinal mucosa and TC7 cells.

Adding iron reversed desferrioxamine inhibition of carotenoid cleavage in TC7 cells.

Substitution of conserved histidines or Glu405 in mouse BCO1 abolished cleavage and reduced protein-bound iron.

Recombinant murine BCO2 cleaved beta-cryptoxanthin mainly to beta-apo-10-prime-carotenal.

Bco2-null mice accumulated more hepatic beta-cryptoxanthin than wild-type and Bco1-null mice after repeated injections.

Retinoic-acid receptor signaling increased intestinal ISX expression.

ISX bound upstream SCARB1 regulatory motifs and repressed intestinal SCARB1 expression.

ISX recognized upstream BCO1 regulatory motifs and repressed its expression.

Isx-deficient mice had higher hepatic alpha-tocopherol; the Isx/Bco2 double mutant showed about twice wild-type levels.

Human and rat liver LRAT activity transferred the sn-1 acyl group of phosphatidylcholine to CRBP-bound retinol.

Lrat-null mice still secreted chylomicron retinyl esters whose acyl composition reflected the gavage oil.

One month of dietary retinoid withdrawal lowered serum retinol in Lrat-null mice, with no comparable fall in wild type.

Rbp4-null mice acquired hepatic vitamin A stores but could not mobilize them normally.

Circulating retinol became undetectable after one week of vitamin A-deficient feeding in adult Rbp4-null mice.

Ttr-null mice had plasma retinol averaging about 6% of wild type.

Ttr-null mice maintained normal retinol/retinyl-ester levels in the tested liver and extrahepatic tissues despite low plasma retinol.

STRA6 was identified as a high-affinity membrane receptor for retinol-binding protein.

STRA6 accelerated retinol release from extracellular RBP in real-time assays.

Coexpression of LRAT enhanced STRA6-mediated retinol uptake by coupling transport to ester storage.

Cellular RBP1 enhanced STRA6-mediated uptake of RBP-bound retinol.

Silencing endogenous RDH10 reduced retinoic-acid production from retinol in human cells.

RDH10-activated DHRS3 reduced all-trans-retinal to retinol preferentially using NADPH.

RDH10 coexpression increased DHRS3 retinaldehyde reductase activity even when RDH10 itself was catalytically inactive.

DHRS3 coexpression enhanced RDH10 retinol dehydrogenase activity independently of DHRS3 catalytic activity.

Human ALDH1A1 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.

Human ALDH1A2 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.

Human ALDH1A3 oxidized all-trans-retinaldehyde to retinoic acid in comparative enzyme assays.

Recombinant human CYP26A1 hydroxylated all-trans-retinoic acid to 4-hydroxy-retinoic acid.

CYP26A1 further metabolized 4-hydroxy-all-trans-retinoic acid.

Bovine rhodopsin crystallography identifies 11-cis-retinal within the inactive seven-helix receptor.

Light activation changes rhodopsin-bound 11-cis-retinal into its all-trans geometry, coupled to receptor activation.

ZnCl2 did not restore isomerohydrolase activity after metal chelation in the bovine RPE assay, whereas FeSO4 did.

Lrat deletion severely depleted the ocular all-trans-retinyl ester pool in mice.

Lrat-null mice had severely attenuated rod and cone visual function by electroretinography and pupil-response testing.

RDH5 variants segregating with fundus albipunctatus showed lower recombinant enzyme activity than wild type.

The RDH5-associated fundus albipunctatus phenotype included delayed visual-pigment regeneration and night blindness.

Single-cell knockout comparisons showed RDH8 supplies most reduction of bleach-generated all-trans-retinal in mouse rod outer segments.

Mouse rod imaging identified RDH12-dependent reduction of retinaldehyde entering inner segments from the outer segment or extracellular medium.

Purified human RDH12 used NADPH for retinal reduction and had much lower apparent cofactor Km for NADP(H) than NAD(H).

IRBP at at least 10 micromolar increased all-trans-retinol release from bleached isolated toad retina during dark incubation.

ABCA4 drove ATP-dependent transport of retinal-PE adduct from the disc lumen-facing leaflet toward the cytoplasmic leaflet.

Reconstituted ABCA4 also transported phosphatidylethanolamine in the import orientation.