Selenium

evidence_access

Primary abstract

experimental_model

Anaerobic C. difficile culture in limiting medium; selenite supplementation and radiolabeled selenium protein analysis.

limitations

This bacterial growth mechanism does not establish that dietary selenium causes or prevents infection.

nutrient_topic

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

plain_language

Selenium also supports some microbial amino-acid fermentation pathways.

primary_references

Analysis of proline reduction in the nosocomial pathogen Clostridium difficile. · 2006 · https://pubmed.ncbi.nlm.nih.gov/17041035/ · DOI 10.1128/JB.01370-06

L-Proline: synthesis, collagen processing, redox metabolism and cross-nutrient mechanisms (2026-09-19) · lines 414–420

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Anaerobic C. difficile culture in limiting medium; selenite supplementation and radiolabeled selenium protein analysis. · source_derived_draft · unverified_draft

## l-proline-microbial-selenium Selenium also supports some microbial amino-acid fermentation pathways. Selenium supplementation was required for the increased bacterial growth yield seen with the tested Stickland amino-acid pairs; proline-related acceptors induced selenoenzyme expression. Model: Anaerobic C. difficile culture in limiting medium; selenite supplementation and radiolabeled selenium protein analysis. Limitations: This bacterial growth mechanism does not establish that dietary selenium causes or prevents infection. Evidence access: Primary abstract Analysis of proline reduction in the nosocomial pathogen Clostridium difficile. · 2006 · https://pubmed.ncbi.nlm.nih.gov/17041035/ · DOI 10.1128/JB.01370-06

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Selenium supply changes processing/defense associated with iodine-containing thyroid hormones; effects differ by tissue and enzyme.

evidence_locator

Primary abstract

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/8505673.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1565}]

experimental_model

Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks

exposure

20 weeks; basal 0.01 mg Se/kg diet versus basal diet plus sodium selenite reported at 0.05, 0.1 or 0.5 mg Se/kg diet.

limitations

Rat feeding study; no universal serum selenium threshold or human repletion dose. Glutathione peroxidase assay does not identify a specific isoform.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Limited selenium supply reduced liver hormone-processing activity.

primary_references

[i-met-8505673] Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. (1993). https://pubmed.ncbi.nlm.nih.gov/8505673/ DOI: 10.1093/jn/123.6.1124

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1054–1067

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks · source_derived_draft · unverified_draft

### i-met-se-liver-dio1 Selenium-restricted rats had lower hepatic type I deiodinase activity than selenium-supplemented groups after 20 weeks. Condition category: nutrient_deficiency nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Limited selenium supply reduced liver hormone-processing activity. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks limitations: Rat feeding study; no universal serum selenium threshold or human repletion dose. Glutathione peroxidase assay does not identify a specific isoform. exposure: 20 weeks; basal 0.01 mg Se/kg diet versus basal diet plus sodium selenite reported at 0.05, 0.1 or 0.5 mg Se/kg diet. cross_nutrient: Selenium supply changes processing/defense associated with iodine-containing thyroid hormones; effects differ by tissue and enzyme. evidence_locator: Primary abstract evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/8505673.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1565}] [i-met-8505673] Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. (1993). https://pubmed.ncbi.nlm.nih.gov/8505673/ DOI: 10.1093/jn/123.6.1124

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Selenium supply changes processing/defense associated with iodine-containing thyroid hormones; effects differ by tissue and enzyme.

evidence_locator

Primary abstract

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/8505673.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1565}]

experimental_model

Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks

exposure

20 weeks; basal 0.01 mg Se/kg diet versus basal diet plus sodium selenite reported at 0.05, 0.1 or 0.5 mg Se/kg diet.

limitations

Rat feeding study; no universal serum selenium threshold or human repletion dose. Glutathione peroxidase assay does not identify a specific isoform.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The thyroid preserved this enzyme under conditions that impaired the liver.

primary_references

[i-met-8505673] Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. (1993). https://pubmed.ncbi.nlm.nih.gov/8505673/ DOI: 10.1093/jn/123.6.1124

tissue_or_cell_type

Thyroid

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1069–1082

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks · source_derived_draft · unverified_draft

### i-met-se-thyroid-dio1 The same 20-week selenium-restricted diet did not suppress thyroid type I deiodinase activity, despite depressed liver activity. Condition category: nutrient_deficiency nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The thyroid preserved this enzyme under conditions that impaired the liver. organism: Rattus norvegicus tissue_or_cell_type: Thyroid experimental_model: Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks limitations: Rat feeding study; no universal serum selenium threshold or human repletion dose. Glutathione peroxidase assay does not identify a specific isoform. exposure: 20 weeks; basal 0.01 mg Se/kg diet versus basal diet plus sodium selenite reported at 0.05, 0.1 or 0.5 mg Se/kg diet. cross_nutrient: Selenium supply changes processing/defense associated with iodine-containing thyroid hormones; effects differ by tissue and enzyme. evidence_locator: Primary abstract evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/8505673.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1565}] [i-met-8505673] Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. (1993). https://pubmed.ncbi.nlm.nih.gov/8505673/ DOI: 10.1093/jn/123.6.1124

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Selenium supply changes processing/defense associated with iodine-containing thyroid hormones; effects differ by tissue and enzyme.

evidence_locator

Primary abstract

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/8505673.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1565}]

experimental_model

Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks

exposure

20 weeks; basal 0.01 mg Se/kg diet versus basal diet plus sodium selenite reported at 0.05, 0.1 or 0.5 mg Se/kg diet.

limitations

Rat feeding study; no universal serum selenium threshold or human repletion dose. Glutathione peroxidase assay does not identify a specific isoform.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Selenium restriction affected thyroid antioxidant activity differently from thyroid deiodination.

primary_references

[i-met-8505673] Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. (1993). https://pubmed.ncbi.nlm.nih.gov/8505673/ DOI: 10.1093/jn/123.6.1124

tissue_or_cell_type

Thyroid

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1084–1097

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks · source_derived_draft · unverified_draft

### i-met-se-thyroid-gpx Thyroid glutathione peroxidase activity in selenium-restricted rats was approximately 40% of that in supplemented groups although thyroid type I deiodinase was maintained. Condition category: nutrient_deficiency nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium restriction affected thyroid antioxidant activity differently from thyroid deiodination. organism: Rattus norvegicus tissue_or_cell_type: Thyroid experimental_model: Male weanling Sprague-Dawley rats fed torula-yeast diets for 20 weeks limitations: Rat feeding study; no universal serum selenium threshold or human repletion dose. Glutathione peroxidase assay does not identify a specific isoform. exposure: 20 weeks; basal 0.01 mg Se/kg diet versus basal diet plus sodium selenite reported at 0.05, 0.1 or 0.5 mg Se/kg diet. cross_nutrient: Selenium supply changes processing/defense associated with iodine-containing thyroid hormones; effects differ by tissue and enzyme. evidence_locator: Primary abstract evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/8505673.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1565}] [i-met-8505673] Selenium requirements of rats for normal hepatic and thyroidal 5'-deiodinase (type I) activities. (1993). https://pubmed.ncbi.nlm.nih.gov/8505673/ DOI: 10.1093/jn/123.6.1124

availability_state

Experimental Coxsackievirus passage through selenium-deficient mice.

experimental_scope

Animal passage experiments; related influenza findings are reported, and vitamin E deficiency produced a similar Coxsackievirus effect.

limitations

The molecular route to individual mutations is unresolved. Selenium is not unique in this respect, and generalization to human infections remains uncertain.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 398–412

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

The best-established finding is narrower than the original “selenium uniquely mutates viruses” claim. selenium deficiency or vitamin E deficiency in experimental mice ↓ changed host oxidative / immune environment ↓ selection or emergence of viral genomic variants ↓ increased virulence can persist after transfer to nutritionally adequate mice Demonstrated in animal models: [10] Coxsackievirus B3: a normally avirulent strain acquired reproducible genomic changes and increased virulence after passage through selenium-deficient mice. Vitamin E deficiency produced a similar phenomenon in the same Coxsackievirus model. Selenium is therefore not unique among micronutrients in this respect.

availability_state

Selenium restriction reduces recoding efficiency in an NMD-compatible GPX1 transcript context.

experimental_scope

Transcript-specific mechanism supported by animal and cell experiments, including rat hepatocytes and cultured-cell GPX1 studies.

limitations

NMD requires susceptible transcript architecture. It is not the fate of every selenoprotein transcript and has no established human plasma onset threshold.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 87–97

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

Layer 4 — nonsense-mediated decay (NMD). If a UGA is interpreted as termination in an NMD-compatible transcript architecture, the mRNA can be destabilized. inefficient UGA recoding ↓ premature termination in a susceptible transcript ↓ NMD machinery engaged ↓ selenoprotein mRNA abundance falls For transcripts such as GPX1, selenium deficiency can therefore reduce expression at more than one level: translation efficiency and mRNA abundance. That is stronger than simple proportional substrate limitation, but it is still transcript-specific.

availability_state

Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses.

experimental_scope

Much of the detailed mechanism comes from cell and animal models; human immune findings are heterogeneous.

limitations

A GPX4 knockout does not specify the response to dietary restriction. No single immune cascade explains every supplementation result, and no clinical immunity cutoff is inferred.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 348–350

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

4.3 Immune system Much of the detailed cell-by-cell mechanism comes from animal and cell models. These findings are biologically important but should not be converted directly into plasma cutoffs or guaranteed clinical outcomes.

Selenium deficiency: a mechanism-first reference · lines 394–394

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

A useful summary is: selenium status can alter immune redox tone and cell survival, but no single immune-cell cascade explains all reported supplementation effects.

availability_state

Selenium intake or availability becomes inadequate for the cellular context.

experimental_scope

Biochemical pathway and experimental shortage model; effects depend on transcript and tissue.

limitations

This is a conditional supply constraint, not a prediction that all selenoproteins fall equally. No validated plasma cutoff is assigned.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 783–790

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

selenium intake / availability ↓ │ ▼ central selenium metabolism and Sec-tRNA supply become constrained │ ├─ tRNA^[Ser]Sec modification can shift (including Um34 / FTSJ1 biology) ├─ SECIS-dependent UGA recoding changes ├─ selected transcripts can undergo stronger repression / NMD

availability_state

Selenium restriction affects sperm biology; genetic disruption of delivery or GPX4 provides related but distinct evidence.

experimental_scope

Animal dietary-restriction and genetic models; the experiments address related mechanisms with different perturbations.

limitations

Genetic loss is not an ordinary dietary-deficiency phenotype. No human plasma threshold or guaranteed fertility outcome is established.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 420–430

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

4.5 Male fertility GPX4 has a distinctive role in sperm: during maturation, a structural form contributes to the mitochondrial sheath. Selenium restriction and disruption of the SELENOP–ApoER2/LRP8 pathway can impair male fertility in animal models. SELENOP delivery / GPX4 biology disrupted ↓ mitochondrial-sheath and membrane defects ↓ reduced sperm motility and fertility in experimental models Evidence: strong genetic and animal-model evidence; translation to a specific human plasma selenium threshold is not established.

availability_state

Dietary selenium availability declines.

experimental_scope

Tissue-selective distribution, largely from experimental models; relative retention differs from absolute protection.

limitations

There is no fixed human organ sacrifice sequence. Low circulating SELENOP can also reflect inflammation, and receptor disruption is a distinct machinery state.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 783–791

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

selenium intake / availability ↓ │ ▼ central selenium metabolism and Sec-tRNA supply become constrained │ ├─ tRNA^[Ser]Sec modification can shift (including Um34 / FTSJ1 biology) ├─ SECIS-dependent UGA recoding changes ├─ selected transcripts can undergo stronger repression / NMD └─ circulating SELENOP and tissue delivery can fall

availability_state

A selenium-responsive circulating biomarker approaches a plateau in a particular study or individual context.

experimental_scope

Human intervention dose-response observations and biomarker interpretation.

limitations

Study-specific plateaus cannot be mapped to GPX1 NMD, thyroid or immune failure, GPX4 loss, or an absolute antioxidant-to-pro-oxidant switch. Plasma and whole-blood values are not interchangeable.

trigger_kind

biomarker_context

Selenium deficiency: a mechanism-first reference · lines 157–161

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

SELENOP plateau near ~125 µg/L in the Hurst trial Human randomized dose-response trial Study-specific plateau, not a universal treatment target [2]

Selenium deficiency: a mechanism-first reference · lines 569–575

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

SELENOP Rises with selenium supply and can plateau Functional selenium transport / selenoprotein-related status Acute-phase sensitive; assay availability limited

availability_state

A selenium-responsive circulating biomarker approaches a plateau in a particular study or individual context.

experimental_scope

Human intervention dose-response observations and biomarker interpretation.

limitations

Study-specific plateaus cannot be mapped to GPX1 NMD, thyroid or immune failure, GPX4 loss, or an absolute antioxidant-to-pro-oxidant switch. Plasma and whole-blood values are not interchangeable.

trigger_kind

biomarker_context

Selenium deficiency: a mechanism-first reference · lines 577–583

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

GPX3 activity Selenium-responsive and can plateau Functional extracellular GPX activity Becomes less informative once activity is near plateau

availability_state

Selenium restriction affects deiodinase expression or activity in a particular tissue.

experimental_scope

Mechanistic synthesis; deiodinase responses and clinical consequences are tissue- and context-dependent.

limitations

Normal serum TSH neither directly measures local T3 generation nor establishes hidden clinical tissue hypothyroidism. Combined iodine deficiency is a distinct context.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 319–325

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

DIO1, DIO2, and DIO3 are selenoproteins. Selenium restriction can therefore affect deiodinase biology and local thyroid-hormone metabolism. selenium restriction ↓ changes in deiodinase expression/activity ↓ changes in local T4 ↔ T3 / rT3 metabolism

availability_state

Severe selenium deficiency reduces selenium-dependent thyroid redox capacity.

experimental_scope

Biochemical redox mechanism in severe deficiency; autoimmune disease is a separate, multifactorial outcome.

limitations

This does not make deficiency a sufficient cause of Hashimoto thyroiditis or thyroid antibodies. No antibody or treatment benefit is inferred.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 329–338

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

B. Oxidative defense in the thyroid Thyroid-hormone synthesis requires locally generated H₂O₂: TSH signaling → DUOX2/DUOXA2 generates H₂O₂ near the apical membrane → TPO uses H₂O₂ to oxidize iodide and iodinate thyroglobulin → antioxidant systems limit peroxide spillover and lipid/protein damage Selenoproteins such as GPXs and thioredoxin reductases contribute to thyroid redox control. Severe selenium deficiency can reduce this defensive capacity, but Hashimoto thyroiditis is multifactorial; selenium deficiency is not a sufficient one-step cause of anti-TPO or anti-thyroglobulin autoimmunity.

availability_state

Selenium supply is restricted for a defined tissue, species, and duration.

experimental_scope

Predominantly animal and cell models; ranking varies with tissue, species, development, duration, and measurement.

limitations

Relative preservation does not mean immunity to severe loss. Um34 alone does not implement a universal ranking, and no plasma-to-protein cutoff is assigned.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 101–117

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

2.1 Protein hierarchy: useful, but schematic Different selenoproteins respond differently to selenium restriction. A useful conceptual grouping is: More selenium-responsive in many models Intermediate / context-dependent Relatively preserved in severe restriction GPX1, SELENOW GPX3, SELENOP, DIO1, SELENOK, SELENOM GPX4, TXNRD1, DIO2, SEPHS2 This is a schematic hierarchy, not a literal universal sequence of death. Ordering varies with tissue, species, developmental stage, duration of deficiency, and how the endpoint is measured.

Selenium deficiency: a mechanism-first reference · lines 287–293

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

GPX1 activity ↓ Often strongly selenium-responsive GPX1 mRNA ↓ in susceptible models NMD can contribute

availability_state

Selenium supply is restricted for a defined tissue, species, and duration.

experimental_scope

Predominantly animal and cell models; ranking varies with tissue, species, development, duration, and measurement.

limitations

Relative preservation does not mean immunity to severe loss. Um34 alone does not implement a universal ranking, and no plasma-to-protein cutoff is assigned.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 295–297

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

SELENOW expression ↓ Sensitive to selenium and tRNA/translation regulation in experimental systems

availability_state

Selenium supply is restricted for a defined tissue, species, and duration.

experimental_scope

Predominantly animal and cell models; ranking varies with tissue, species, development, duration, and measurement.

limitations

Relative preservation does not mean immunity to severe loss. Um34 alone does not implement a universal ranking, and no plasma-to-protein cutoff is assigned.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 101–117

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

2.1 Protein hierarchy: useful, but schematic Different selenoproteins respond differently to selenium restriction. A useful conceptual grouping is: More selenium-responsive in many models Intermediate / context-dependent Relatively preserved in severe restriction GPX1, SELENOW GPX3, SELENOP, DIO1, SELENOK, SELENOM GPX4, TXNRD1, DIO2, SEPHS2 This is a schematic hierarchy, not a literal universal sequence of death. Ordering varies with tissue, species, developmental stage, duration of deficiency, and how the endpoint is measured.

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats

exposure

Dietary selenium depletion; isolated dialyzed cytosol

limitations

Activity assignment also used inhibitor sensitivity; this is a fraction assay, not a direct human outcome.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction.

primary_references

[may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039

tissue_or_cell_type

Liver cytosol

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 429–440

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats · source_derived_draft · unverified_draft

### vc-transport-selenium-cytosolic-radical Dialyzed liver cytosol from selenium-deficient rats lost NADPH-dependent ascorbyl-radical reducing activity attributed to thioredoxin reductase. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium deficiency impaired radical recycling in the rat liver’s soluble fraction. organism: Rattus norvegicus tissue_or_cell_type: Liver cytosol experimental_model: Purified rat liver enzyme, dialyzed cytosol and microsomes from control/selenium-deficient rats limitations: Activity assignment also used inhibitor sensitivity; this is a fraction assay, not a direct human outcome. exposure: Dietary selenium depletion; isolated dialyzed cytosol cross_nutrient: true [may1998] Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. (1998). https://pubmed.ncbi.nlm.nih.gov/9722529/ DOI: 10.1074/jbc.273.36.23039

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver

exposure

Dietary selenium deficiency

limitations

Several selenoenzymes were affected, including glutathione peroxidase; cannot attribute the entire ascorbate decrease solely to thioredoxin reductase.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Selenium shortage reduced a vitamin C recycling pathway and liver vitamin C in rats.

primary_references

[may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 403–414

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver · source_derived_draft · unverified_draft

### vc-transport-selenium-liver-ascorbate Selenium-deficient rats had 33% less liver ascorbate together with an 88% fall in thioredoxin-reductase activity; liver GSH content was unchanged. Condition category: nutrient_deficiency nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium shortage reduced a vitamin C recycling pathway and liver vitamin C in rats. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Purified rat liver thioredoxin reductase/thioredoxin and selenium-deficient rat liver limitations: Several selenoenzymes were affected, including glutathione peroxidase; cannot attribute the entire ascorbate decrease solely to thioredoxin reductase. exposure: Dietary selenium deficiency cross_nutrient: true [may1997] Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase. (1997). https://pubmed.ncbi.nlm.nih.gov/9278416/ DOI: 10.1074/jbc.272.36.22607

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays

exposure

Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants

limitations

Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure.

nutrient_topic

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

organism

Mouse immune cells and mammalian cell models

plain_language

The cell may still make the message but lose a properly maintained receptor.

primary_references

[ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

tissue_or_cell_type

ER-associated IP3 receptor machinery

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Inositol: synthesis, signaling, mineral interactions and conditional deficiency (2026-09-17) · lines 1068–1079

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays · source_derived_draft · unverified_draft

### ino-selenium-receptor Low-selenium culture conditions were associated with defective IP3R palmitoylation and reduced receptor expression in the SELENOK study. Condition category: nutrient_deficiency nutrient_topic: Inositol research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cell may still make the message but lose a properly maintained receptor. organism: Mouse immune cells and mammalian cell models tissue_or_cell_type: ER-associated IP3 receptor machinery experimental_model: Immune-cell perturbation, co-immunoprecipitation and palmitoylation assays limitations: Selenium limitation and genetic deletion are distinct. This does not establish that inositol supplements repair selenium-dependent receptor failure. exposure: Selk deletion, low-selenium media, DHHC6 knockdown and IP3R cysteine mutants evidence_span: {"source_cache": "artifacts/inositol-research/25368151.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9", "start_char": 0, "end_char": 1873, "text_sha256": "84452ee9a1f04bf54aba8030e5384d46a1dafdbb460281fd99c244e57d6644d9"} [ino-p25368151] Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. (2014). https://pubmed.ncbi.nlm.nih.gov/25368151/ DOI: 10.1073/pnas.1417176111

cell_type

· T cell

evidence_scope

Source-derived draft; primary-source verification required

organism

· Human

Selenium in immune cells · lines 11–20

Selenium immune-cell mechanism draft · supports · Source draft; model details require primary-source verification · source_derived_draft · unverified_draft

# I. THE CLEANEST CHAIN — SELENOK → Ca²⁺ → NFAT → IL-2 This is the one to memorize. It's a direct, non-redox, molecule-by-molecule path from a selenium atom to a cytokine. ``` 1. Se → Sec-tRNA → SELENOK (ER membrane, single C-terminal Sec, tail in cytosol) 2. SELENOK binds ZDHHC6 (ER palmitoyl-S-acyltransferase, DHHC motif) → SELENOK is required as a COFACTOR to stabilize the palmitoyl-ZDHHC6 acyl-enzyme intermediate

curation_topic

selenium · Selenium

experimental_condition

Wild-type mice GPX1 overexpression · Mouse Gpx1 overexpression genotype Condition belongs to the full experimental contrast; do not separate a joint intervention.

experimental_contrast

{"intervention": "GPX1 overexpression", "comparator": "Wild-type mice", "endpoint": "Glucose fall after insulin", "effect_direction": "decrease", "combination": "single", "conditions": [{"entity_slug": "mouse-gpx1-overexpression", "state": "GPX1 overexpression"}]} Explicit extracted experimental comparison; source-derived draft.

experimental_model

Male transgenic mice on selenium-adequate diet, evaluated at 24 weeks

limitations

Does not establish that suppressing GPX1 is beneficial in other settings.

primary_references

McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/

Diabetes cascade: targeted primary-source supplement · lines 33–33

See claim-local references; curated paraphrases reviewed 2026-09-20. · supports · Male transgenic mice on selenium-adequate diet, evaluated at 24 weeks · source_derived_draft · unverified_draft

GPX1-overexpressing mice had a smaller blood-glucose fall after insulin challenge and developed hyperglycemia, hyperinsulinemia and greater adiposity. Model: Male transgenic mice on selenium-adequate diet, evaluated at 24 weeks. Limits: Does not establish that suppressing GPX1 is beneficial in other settings. Primary reference: McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/

curation_topic

selenium · Selenium

experimental_condition

Wild-type mice on the same diet GPX1 overexpression · Mouse Gpx1 overexpression genotype Condition belongs to the full experimental contrast; do not separate a joint intervention.

experimental_contrast

{"intervention": "GPX1 overexpression", "comparator": "Wild-type mice on the same diet", "endpoint": "Insulin-stimulated phosphorylation", "effect_direction": "decrease", "combination": "single", "conditions": [{"entity_slug": "mouse-gpx1-overexpression", "state": "GPX1 overexpression"}]} Explicit extracted experimental comparison; source-derived draft.

experimental_model

Male transgenic mice; selenium-adequate 0.4 mg/kg diet, ages 8 to 24 weeks

limitations

Overexpression experiment, not dietary selenium excess. Excess ROS quenching is a proposed explanation rather than a measured universal mechanism.

primary_references

McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/

Diabetes cascade: targeted primary-source supplement · lines 30–30

See claim-local references; curated paraphrases reviewed 2026-09-20. · supports · Male transgenic mice; selenium-adequate 0.4 mg/kg diet, ages 8 to 24 weeks · source_derived_draft · unverified_draft

GPX1-overexpressing mice showed reduced insulin-stimulated receptor phosphorylation in liver and Akt phosphorylation in liver and soleus. Model: Male transgenic mice; selenium-adequate 0.4 mg/kg diet, ages 8 to 24 weeks. Limits: Overexpression experiment, not dietary selenium excess. Excess ROS quenching is a proposed explanation rather than a measured universal mechanism. Primary reference: McClung et al. 2004; DOI:10.1073/pnas.0308096101; PMID:15184668; https://pmc.ncbi.nlm.nih.gov/articles/PMC428436/

evidence_span

{"source_cache": "artifacts/coq10-research/22626835.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587", "start_char": 0, "end_char": 1797, "text_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587"}

experimental_model

Randomized double-blind combined-supplement trial

exposure

Selenium plus CoQ10 versus placebo; 5.2-year follow-up

limitations

Combined intervention without selenium-only and CoQ-only arms; no independent CoQ effect or statistical nutrient synergy can be identified.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

443 Swedish adults aged 70-88

plain_language

A heart-stress marker also differed; this was the same trial, not an independent replication.

primary_references

[coq10-p22626835] Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. (2013). https://pubmed.ncbi.nlm.nih.gov/22626835/ DOI: 10.1016/j.ijcard.2012.04.156

tissue_or_cell_type

Cardiovascular mortality and cardiac measurements

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 1139–1150

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

### coq10-selenium-combination-marker Mean NT-proBNP at 48 months was 214 ng/L in the combined-treatment group versus 302 ng/L with placebo. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A heart-stress marker also differed; this was the same trial, not an independent replication. organism: 443 Swedish adults aged 70-88 tissue_or_cell_type: Cardiovascular mortality and cardiac measurements experimental_model: Randomized double-blind combined-supplement trial limitations: Combined intervention without selenium-only and CoQ-only arms; no independent CoQ effect or statistical nutrient synergy can be identified. exposure: Selenium plus CoQ10 versus placebo; 5.2-year follow-up evidence_span: {"source_cache": "artifacts/coq10-research/22626835.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587", "start_char": 0, "end_char": 1797, "text_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587"} [coq10-p22626835] Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. (2013). https://pubmed.ncbi.nlm.nih.gov/22626835/ DOI: 10.1016/j.ijcard.2012.04.156

evidence_span

{"source_cache": "artifacts/coq10-research/22626835.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587", "start_char": 0, "end_char": 1797, "text_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587"}

experimental_model

Randomized double-blind combined-supplement trial

exposure

Selenium plus CoQ10 versus placebo; 5.2-year follow-up

limitations

Combined intervention without selenium-only and CoQ-only arms; no independent CoQ effect or statistical nutrient synergy can be identified.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

443 Swedish adults aged 70-88

plain_language

The combination had a favorable result, but the design cannot tell how much came from each component.

primary_references

[coq10-p22626835] Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. (2013). https://pubmed.ncbi.nlm.nih.gov/22626835/ DOI: 10.1016/j.ijcard.2012.04.156

tissue_or_cell_type

Cardiovascular mortality and cardiac measurements

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 1126–1137

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

### coq10-selenium-combination-mortality Cardiovascular mortality was 5.9% with combined selenium/CoQ versus 12.6% with placebo in the Swedish trial. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The combination had a favorable result, but the design cannot tell how much came from each component. organism: 443 Swedish adults aged 70-88 tissue_or_cell_type: Cardiovascular mortality and cardiac measurements experimental_model: Randomized double-blind combined-supplement trial limitations: Combined intervention without selenium-only and CoQ-only arms; no independent CoQ effect or statistical nutrient synergy can be identified. exposure: Selenium plus CoQ10 versus placebo; 5.2-year follow-up evidence_span: {"source_cache": "artifacts/coq10-research/22626835.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587", "start_char": 0, "end_char": 1797, "text_sha256": "68f71b162945240d48d14b42d132856ad242c2cc57640eae3a60a3aaa2706587"} [coq10-p22626835] Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. (2013). https://pubmed.ncbi.nlm.nih.gov/22626835/ DOI: 10.1016/j.ijcard.2012.04.156

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/coq10-research/12435734.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55", "start_char": 0, "end_char": 1340, "text_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55"}

experimental_model

Enzyme kinetics, mutants and overexpressing-cell homogenates

exposure

NADPH or NADH; selenite and selenium-deprived enzyme variants

limitations

Biochemical selenium dependence; not proof that all CoQ recycling stops with low selenium or that combined supplements are synergistic clinically.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Mammalian TrxR1 and human HEK293 cells

plain_language

The chemistry depends on the enzyme being assembled correctly.

primary_references

[coq10-p12435734] The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. (2003). https://pubmed.ncbi.nlm.nih.gov/12435734/ DOI: 10.1074/jbc.m210456200

tissue_or_cell_type

Ubiquinone reduction

trigger_kind

machinery_impairment Imported condition classification; unverified.

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 775–786

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme kinetics, mutants and overexpressing-cell homogenates · source_derived_draft · unverified_draft

### coq10-txnrd-selenium Comparison with selenium-deprived and truncated mammalian TrxR forms showed selenium-dependent ubiquinone reduction. Condition category: machinery_impairment nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The chemistry depends on the enzyme being assembled correctly. organism: Mammalian TrxR1 and human HEK293 cells tissue_or_cell_type: Ubiquinone reduction experimental_model: Enzyme kinetics, mutants and overexpressing-cell homogenates limitations: Biochemical selenium dependence; not proof that all CoQ recycling stops with low selenium or that combined supplements are synergistic clinically. exposure: NADPH or NADH; selenite and selenium-deprived enzyme variants evidence_span: {"source_cache": "artifacts/coq10-research/12435734.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55", "start_char": 0, "end_char": 1340, "text_sha256": "929e8de2bc15ea62eb4a3814995fd289de759d721f16b848174ad65f95847c55"} [coq10-p12435734] The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. (2003). https://pubmed.ncbi.nlm.nih.gov/12435734/ DOI: 10.1074/jbc.m210456200

evidence_span

{"source_cache": "artifacts/hbot-research/15642322.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995", "start_char": 0, "end_char": 2646, "text_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995"}

experimental_model

Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR

exposure

99% oxygen at 50 atmospheres for 3 hours, then normal culture for up to 11 days

limitations

Fifty atmospheres is an extreme experimental exposure far above therapy, chosen to probe which defences matter. The selenoenzyme result is the informative part; the pressure is not clinically relevant.

nutrient_topic

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

organism

Human cells

plain_language

The cell rebuilt exactly three proteins: the heme enzyme, the manganese enzyme and the selenium enzyme.

primary_references

[hbot-p15642322] Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15642322/ DOI: 10.1016/j.exer.2004.07.001

tissue_or_cell_type

Lens epithelium

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 426–437

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR · source_derived_draft · unverified_draft

### hbot-trxr-mrna-response Messenger RNA for heme oxygenase-1, manganese superoxide dismutase and cytoplasmic thioredoxin reductase 1 rose three- to six-fold nine hours after exposure, with heme oxygenase-1 rising a few hours before manganese superoxide dismutase, while catalase, copper-zinc superoxide dismutase, glutathione reductase, glutathione peroxidase and thioredoxin did not change. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: The cell rebuilt exactly three proteins: the heme enzyme, the manganese enzyme and the selenium enzyme. organism: Human cells tissue_or_cell_type: Lens epithelium experimental_model: Cultured human lens epithelial cells exposed to extreme hyperbaric oxygen with enzyme assays and real-time PCR limitations: Fifty atmospheres is an extreme experimental exposure far above therapy, chosen to probe which defences matter. The selenoenzyme result is the informative part; the pressure is not clinically relevant. exposure: 99% oxygen at 50 atmospheres for 3 hours, then normal culture for up to 11 days evidence_span: {"source_cache": "artifacts/hbot-research/15642322.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995", "start_char": 0, "end_char": 2646, "text_sha256": "e3bc035a17e4e19dd92d4fadb1a79f8e3801619dac24fb91dcf985728afaf995"} [hbot-p15642322] Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells. (2004). https://pubmed.ncbi.nlm.nih.gov/15642322/ DOI: 10.1016/j.exer.2004.07.001

evidence_span

{"source_cache": "artifacts/hbot-research/10801974.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1627b8b48962b6d2b9bead351b64b71fb60b9681378b44f77a3fc288d35119e3", "start_char": 0, "end_char": 1719, "text_sha256": "1627b8b48962b6d2b9bead351b64b71fb60b9681378b44f77a3fc288d35119e3"}

experimental_model

Chemical modification, peptide sequencing, mass spectrometry and redox titration of mammalian thioredoxin reductase

exposure

Oxidised and NADPH-reduced enzyme states

limitations

Enzyme chemistry on purified protein. It establishes the selenium-containing active site; it is not a statement about selenium intake.

nutrient_topic

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

organism

Rat and human enzyme

plain_language

The enzyme’s working end is built from a selenium amino acid paired with a cysteine.

primary_references

[hbot-p10801974] Structure and mechanism of mammalian thioredoxin reductase: the active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence. (2000). https://pubmed.ncbi.nlm.nih.gov/10801974/ DOI: 10.1073/pnas.100114897

tissue_or_cell_type

Purified enzyme

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 452–463

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Chemical modification, peptide sequencing, mass spectrometry and redox titration of mammalian thioredoxin reductase · source_derived_draft · unverified_draft

### hbot-trxr-selenocysteine-site Mammalian thioredoxin reductase carries an essential selenocysteine in the conserved C-terminal sequence Gly-Cys-SeCys-Gly, forming a selenenylsulfide between Cys497 and SeCys498 that becomes a selenolthiol on reduction, alongside a separate Cys59-Cys64 disulfide identical to the glutathione reductase active site. Condition category: normal nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: The enzyme’s working end is built from a selenium amino acid paired with a cysteine. organism: Rat and human enzyme tissue_or_cell_type: Purified enzyme experimental_model: Chemical modification, peptide sequencing, mass spectrometry and redox titration of mammalian thioredoxin reductase limitations: Enzyme chemistry on purified protein. It establishes the selenium-containing active site; it is not a statement about selenium intake. exposure: Oxidised and NADPH-reduced enzyme states evidence_span: {"source_cache": "artifacts/hbot-research/10801974.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1627b8b48962b6d2b9bead351b64b71fb60b9681378b44f77a3fc288d35119e3", "start_char": 0, "end_char": 1719, "text_sha256": "1627b8b48962b6d2b9bead351b64b71fb60b9681378b44f77a3fc288d35119e3"} [hbot-p10801974] Structure and mechanism of mammalian thioredoxin reductase: the active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence. (2000). https://pubmed.ncbi.nlm.nih.gov/10801974/ DOI: 10.1073/pnas.100114897

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/hbot-research/10849437.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "13fe79ebefbddac9a76f4cae2e0f1aede8d648b6568adca72f0b0a550e66bc90", "start_char": 0, "end_char": 1374, "text_sha256": "13fe79ebefbddac9a76f4cae2e0f1aede8d648b6568adca72f0b0a550e66bc90"}

experimental_model

Recombinant rat thioredoxin reductase with selenocysteine mutations expressed in E. coli

exposure

SeCys498 replaced by cysteine or serine, and a truncated protein lacking the C-terminal SeCys-Gly dipeptide

limitations

The truncated construct is described by the authors as the form expected in selenium deficiency, which is what links this enzyme chemistry to nutrient supply. It remains a recombinant model, not a measurement in a selenium-deficient animal.

nutrient_topic

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

organism

Rat enzyme in a bacterial expression host

plain_language

Without selenium the enzyme can no longer destroy peroxide at all.

primary_references

[hbot-p10849437] Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. (2000). https://pubmed.ncbi.nlm.nih.gov/10849437/ DOI: 10.1074/jbc.m000690200

tissue_or_cell_type

Purified enzyme

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Hyperbaric oxygen: the exposure, its reactive species, the signals they carry, and the nutrient-dependent enzymes that handle them (2026-09-19) · lines 478–489

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant rat thioredoxin reductase with selenocysteine mutations expressed in E. coli · source_derived_draft · unverified_draft

### hbot-trxr-truncated-no-activity Whereas hydrogen peroxide was a substrate for the wild-type enzyme, all mutant enzymes, including the truncated form expected in selenium deficiency, lacked hydroperoxidase activity, so selenium is required for the catalytic activities of thioredoxin reductase. Condition category: nutrient_deficiency nutrient_topic: Hyperbaric oxygen research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Without selenium the enzyme can no longer destroy peroxide at all. organism: Rat enzyme in a bacterial expression host tissue_or_cell_type: Purified enzyme experimental_model: Recombinant rat thioredoxin reductase with selenocysteine mutations expressed in E. coli limitations: The truncated construct is described by the authors as the form expected in selenium deficiency, which is what links this enzyme chemistry to nutrient supply. It remains a recombinant model, not a measurement in a selenium-deficient animal. exposure: SeCys498 replaced by cysteine or serine, and a truncated protein lacking the C-terminal SeCys-Gly dipeptide evidence_span: {"source_cache": "artifacts/hbot-research/10849437.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "13fe79ebefbddac9a76f4cae2e0f1aede8d648b6568adca72f0b0a550e66bc90", "start_char": 0, "end_char": 1374, "text_sha256": "13fe79ebefbddac9a76f4cae2e0f1aede8d648b6568adca72f0b0a550e66bc90"} [hbot-p10849437] Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. (2000). https://pubmed.ncbi.nlm.nih.gov/10849437/ DOI: 10.1074/jbc.m000690200

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Explains why B2-dependent GSH recycling and selenium-dependent GSH use are distinct requirements.

evidence_location

Abstract

experimental_model

Erythrocyte hemolyzates from selenium-deficient rats; glutathione addition during peroxide/ascorbate challenge and 75Se enzyme purification.

exposure

Selenium-deficient diet, then ex-vivo oxidant and glutathione exposure

limitations

Separate from FAD-dependent GSR recycling; neither riboflavin nor combined nutrient repletion was tested.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

Supplying glutathione did not replace the missing selenium-dependent enzyme activity.

primary_references

[rotruck1973] Selenium: biochemical role as a component of glutathione peroxidase. (1973). https://pubmed.ncbi.nlm.nih.gov/4686466/ DOI: 10.1126/science.179.4073.588

tissue_or_cell_type

Erythrocyte hemolyzates

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1472–1484

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Erythrocyte hemolyzates from selenium-deficient rats; glutathione addition during peroxide/ascorbate challenge and 75Se enzyme purification. · source_derived_draft · unverified_draft

### b2-redox-gsh-needs-selenium-peroxidase Added glutathione failed to protect hemoglobin during oxidant challenge of selenium-deficient rat hemolyzates with very low glutathione-peroxidase activity. Condition category: nutrient_deficiency nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supplying glutathione did not replace the missing selenium-dependent enzyme activity. organism: Rattus norvegicus tissue_or_cell_type: Erythrocyte hemolyzates experimental_model: Erythrocyte hemolyzates from selenium-deficient rats; glutathione addition during peroxide/ascorbate challenge and 75Se enzyme purification. limitations: Separate from FAD-dependent GSR recycling; neither riboflavin nor combined nutrient repletion was tested. exposure: Selenium-deficient diet, then ex-vivo oxidant and glutathione exposure cross_nutrient: Explains why B2-dependent GSH recycling and selenium-dependent GSH use are distinct requirements. evidence_location: Abstract [rotruck1973] Selenium: biochemical role as a component of glutathione peroxidase. (1973). https://pubmed.ncbi.nlm.nih.gov/4686466/ DOI: 10.1126/science.179.4073.588

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B2-derived FAD cannot replace the selenium-containing catalytic residue.

evidence_location

Abstract

experimental_model

Rat TXNRD1 Sec498Cys, Sec498Ser and C-terminal truncation expressed in E. coli; FAD analysis, NADPH titration and thioredoxin assays.

exposure

Purified-enzyme assay

limitations

Assay-substrate species is unresolved in accessible source details; engineered proteins do not establish dietary B2-by-selenium synergy.

nutrient_topic

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

organism

Rattus norvegicus protein expressed in Escherichia coli

plain_language

Flavin retention did not preserve efficient thioredoxin reduction.

primary_references

[zhong2000] Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. (2000). https://pubmed.ncbi.nlm.nih.gov/10849437/ DOI: 10.1074/jbc.m000690200

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1388–1400

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat TXNRD1 Sec498Cys, Sec498Ser and C-terminal truncation expressed in E. coli; FAD analysis, NADPH titration and thioredoxin assays. · source_derived_draft · unverified_draft

### b2-txnrd-sec498cys-turnover Replacing rat TXNRD1 Sec498 with cysteine lowered thioredoxin-reduction kcat about 100-fold; serine substitution and terminal truncation lacked detectable activity. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Flavin retention did not preserve efficient thioredoxin reduction. organism: Rattus norvegicus protein expressed in Escherichia coli tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Rat TXNRD1 Sec498Cys, Sec498Ser and C-terminal truncation expressed in E. coli; FAD analysis, NADPH titration and thioredoxin assays. limitations: Assay-substrate species is unresolved in accessible source details; engineered proteins do not establish dietary B2-by-selenium synergy. exposure: Purified-enzyme assay cross_nutrient: B2-derived FAD cannot replace the selenium-containing catalytic residue. evidence_location: Abstract [zhong2000] Essential role of selenium in the catalytic activities of mammalian thioredoxin reductase revealed by characterization of recombinant enzymes with selenocysteine mutations. (2000). https://pubmed.ncbi.nlm.nih.gov/10849437/ DOI: 10.1074/jbc.m000690200

cross_nutrient

B2-dependent electron input and selenium-containing terminal chemistry are separate serial steps.

evidence_location

Abstract

experimental_model

Rat TXNRD1 Sec498Cys recombinant mutant with NADP+, 3.0-A crystallography and substrate-docking interpretation.

exposure

Purified-enzyme assay

limitations

Human thioredoxin was docked onto the rat Sec498Cys structure (Fig 6); the complex and cross-species turnover were not measured.

nutrient_topic

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

organism

Rattus norvegicus reductase and Homo sapiens thioredoxin docking partner

plain_language

A second redox center carries electrons onward to thioredoxin.

primary_references

[sandalova2001] Three-dimensional structure of a mammalian thioredoxin reductase: implications for mechanism and evolution of a selenocysteine-dependent enzyme. (2001). https://pubmed.ncbi.nlm.nih.gov/11481439/ DOI: 10.1073/pnas.171178698

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1360–1372

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat TXNRD1 Sec498Cys recombinant mutant with NADP+, 3.0-A crystallography and substrate-docking interpretation. · source_derived_draft · unverified_draft

### b2-txnrd1-terminal-relay A rat TXNRD1 structure and docking model with human thioredoxin support a relay through the opposite subunit and C-terminal tail toward the substrate. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second redox center carries electrons onward to thioredoxin. organism: Rattus norvegicus reductase and Homo sapiens thioredoxin docking partner tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Rat TXNRD1 Sec498Cys recombinant mutant with NADP+, 3.0-A crystallography and substrate-docking interpretation. limitations: Human thioredoxin was docked onto the rat Sec498Cys structure (Fig 6); the complex and cross-species turnover were not measured. exposure: Purified-enzyme assay cross_nutrient: B2-dependent electron input and selenium-containing terminal chemistry are separate serial steps. evidence_location: Abstract [sandalova2001] Three-dimensional structure of a mammalian thioredoxin reductase: implications for mechanism and evolution of a selenocysteine-dependent enzyme. (2001). https://pubmed.ncbi.nlm.nih.gov/11481439/ DOI: 10.1073/pnas.171178698

cross_nutrient

Selenium incorporation supports an enzyme that inactivates iodine-containing hormones.

evidence_locator

Primary abstract

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/7593630.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1405}]

experimental_model

Human placental DIO3 cDNA and heterologous expression, selenium labeling and SECIS manipulation

exposure

Cloned 2.1-kb DIO3 cDNA; 75Se labeling and SECIS-dependent expression.

limitations

Expression machinery experiment; not evidence for selenium dosing in pregnancy.

nutrient_topic

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

organism

Human placental protein in transfected cells

plain_language

The hormone-inactivating enzyme also needs the cellular system that incorporates selenium into proteins.

primary_references

[i-met-7593630] Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. (1995). https://pubmed.ncbi.nlm.nih.gov/7593630/ DOI: 10.1172/jci118299

tissue_or_cell_type

DIO3 expression system

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1129–1142

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human placental DIO3 cDNA and heterologous expression, selenium labeling and SECIS manipulation · source_derived_draft · unverified_draft

### i-met-dio3-secis-expression The 3-prime-untranslated-region SECIS element was required for expression of cloned human placental DIO3, which incorporated 75Se in transfected cells. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The hormone-inactivating enzyme also needs the cellular system that incorporates selenium into proteins. organism: Human placental protein in transfected cells tissue_or_cell_type: DIO3 expression system experimental_model: Human placental DIO3 cDNA and heterologous expression, selenium labeling and SECIS manipulation limitations: Expression machinery experiment; not evidence for selenium dosing in pregnancy. exposure: Cloned 2.1-kb DIO3 cDNA; 75Se labeling and SECIS-dependent expression. cross_nutrient: Selenium incorporation supports an enzyme that inactivates iodine-containing hormones. evidence_locator: Primary abstract evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/7593630.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1405}] [i-met-7593630] Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. (1995). https://pubmed.ncbi.nlm.nih.gov/7593630/ DOI: 10.1172/jci118299

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_locator

Figure 3B and Results: Analysis of TH content and metabolism in the brain

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3B and Results: Analysis of TH content and metabolism in the brain", "start_char": 26251, "end_char": 27951}]

experimental_model

Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays

exposure

P21, n=8 per genotype; hormone content measurements.

limitations

The content result is local to mouse forebrain and this developmental time.

nutrient_topic

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

organism

Mus musculus

plain_language

Losing both transport routes overwhelms the compensation seen after one loss.

primary_references

[i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

tissue_or_cell_type

Perfused forebrain

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 996–1008

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays · source_derived_draft · unverified_draft

### i-met-double-ko-brain-t3 At postnatal day 21, double-knockout forebrain T3 content was approximately 10% of wild type, whereas Oatp1c1 single-knockout forebrain T3 was preserved. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Losing both transport routes overwhelms the compensation seen after one loss. organism: Mus musculus tissue_or_cell_type: Perfused forebrain experimental_model: Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays limitations: The content result is local to mouse forebrain and this developmental time. exposure: P21, n=8 per genotype; hormone content measurements. evidence_locator: Figure 3B and Results: Analysis of TH content and metabolism in the brain evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3B and Results: Analysis of TH content and metabolism in the brain", "start_char": 26251, "end_char": 27951}] [i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Selenium-containing D2 processes iodine-containing T4; genetic transport failure persists despite increased enzyme activity.

evidence_locator

Figure 4A and Results: Analysis of TH content and metabolism in the brain

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 4A and Results: Analysis of TH content and metabolism in the brain", "start_char": 26902, "end_char": 28402}]

experimental_model

Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays

exposure

P21 double knockout versus wild type; D2 activity assay.

limitations

This is compensatory enzyme activity, not demonstration that selenium supplementation repairs transporter loss.

nutrient_topic

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

organism

Mus musculus

plain_language

The brain increases local hormone activation machinery, but this cannot replace missing substrate delivery.

primary_references

[i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

tissue_or_cell_type

Forebrain and cerebellum homogenates

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1010–1023

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays · source_derived_draft · unverified_draft

### i-met-double-ko-dio2-response D2 activity in P21 forebrain and cerebellum rose almost tenfold in Mct8/Oatp1c1 double-knockout mice despite persistent severe brain hormone depletion. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The brain increases local hormone activation machinery, but this cannot replace missing substrate delivery. organism: Mus musculus tissue_or_cell_type: Forebrain and cerebellum homogenates experimental_model: Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays limitations: This is compensatory enzyme activity, not demonstration that selenium supplementation repairs transporter loss. exposure: P21 double knockout versus wild type; D2 activity assay. cross_nutrient: Selenium-containing D2 processes iodine-containing T4; genetic transport failure persists despite increased enzyme activity. evidence_locator: Figure 4A and Results: Analysis of TH content and metabolism in the brain evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 4A and Results: Analysis of TH content and metabolism in the brain", "start_char": 26902, "end_char": 28402}] [i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_locator

Figure 3A and Results: In vivo T4 transport studies

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3A and Results: In vivo T4 transport studies", "start_char": 23660, "end_char": 25360}]

experimental_model

Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays

exposure

Adults received 1.2 microcuries 125I-T4 intraperitoneally; n=3 per genotype and time point.

limitations

Tracer accumulation is a transport measurement; murine redundancy is not proof of equivalent human compensation.

nutrient_topic

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

organism

Mus musculus

plain_language

The two mouse transporters provide partly overlapping routes into the brain.

primary_references

[i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

tissue_or_cell_type

Brain after systemic tracer injection

trigger_kind

machinery_impairment Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 982–994

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays · source_derived_draft · unverified_draft

### i-met-double-ko-t4-entry Brain uptake of injected radiolabeled T4 was strongly reduced in Mct8/Oatp1c1 double-knockout mice; either single knockout retained roughly half the wild-type uptake. Condition category: machinery_impairment nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two mouse transporters provide partly overlapping routes into the brain. organism: Mus musculus tissue_or_cell_type: Brain after systemic tracer injection experimental_model: Global Mct8 and Oatp1c1 single/double knockout mice, adult tracer experiments and P21 tissue assays limitations: Tracer accumulation is a transport measurement; murine redundancy is not proof of equivalent human compensation. exposure: Adults received 1.2 microcuries 125I-T4 intraperitoneally; n=3 per genotype and time point. evidence_locator: Figure 3A and Results: In vivo T4 transport studies evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/24691440.txt", "locator": "Figure 3A and Results: In vivo T4 transport studies", "start_char": 23660, "end_char": 25360}] [i-met-24691440] Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. (2014). https://pubmed.ncbi.nlm.nih.gov/24691440/ DOI: 10.1172/jci70324

cross_nutrient

Selenium-containing DIO2 metabolizes iodine-containing T4.

evidence_locator

Primary abstract

evidence_spans

[{"source_document": "artifacts/iodine-metabolism-sources/8755651.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1406}]

experimental_model

Rat and human DIO2 cDNA cloning and characterization

exposure

DIO2 sequence and functional characterization; no nutritional intervention.

limitations

Protein composition does not establish a dietary threshold, benefit from extra selenium, or species-independent regulation.

nutrient_topic

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

organism

Human DIO2; study also characterized rat orthologue

plain_language

The T4-activating enzyme contains selenium as part of its protein structure.

primary_references

[i-met-8755651] Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues. (1996). https://pubmed.ncbi.nlm.nih.gov/8755651/ DOI: 10.1172/jci118806

tissue_or_cell_type

Human cDNA and expression characterization

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1114–1127

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat and human DIO2 cDNA cloning and characterization · source_derived_draft · unverified_draft

### i-met-human-dio2-selenoprotein Cloning and characterization of human DIO2 cDNA identified DIO2 as a selenoprotein. Condition category: normal nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The T4-activating enzyme contains selenium as part of its protein structure. organism: Human DIO2; study also characterized rat orthologue tissue_or_cell_type: Human cDNA and expression characterization experimental_model: Rat and human DIO2 cDNA cloning and characterization limitations: Protein composition does not establish a dietary threshold, benefit from extra selenium, or species-independent regulation. exposure: DIO2 sequence and functional characterization; no nutritional intervention. cross_nutrient: Selenium-containing DIO2 metabolizes iodine-containing T4. evidence_locator: Primary abstract evidence_spans: [{"source_document": "artifacts/iodine-metabolism-sources/8755651.json", "source_field": "resultList.result[0].abstractText", "start_char": 0, "end_char": 1406}] [i-met-8755651] Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues. (1996). https://pubmed.ncbi.nlm.nih.gov/8755651/ DOI: 10.1172/jci118806

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary indexed abstract.

experimental_model

Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire

exposure

Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract.

limitations

The abstract reports before/after changes in the selenium group; do not mistake these for adjusted between-group estimates. DIO1 restoration was a proposed explanation, not directly measured. Hormone changes do not themselves establish symptomatic deterioration or a universal order for supplement treatment.

nutrient_topic

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

organism

Homo sapiens

plain_language

The free T4 measurement also fell after selenium was added.

primary_references

[iod-clin-contempre1992] Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. (1992). https://pubmed.ncbi.nlm.nih.gov/1424183/ DOI: 10.1111/j.1365-2265.1992.tb02268.x

tissue_or_cell_type

Serum thyroid-hormone concentrations

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1272–1284

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire · source_derived_draft · unverified_draft

### iod-clin-selenium-free-t4 Mean serum free T4 fell from 11.8 ± 6.7 to 8.4 ± 4.1 pmol/L after selenium treatment (P<0.01). Condition category: nutrient_deficiency nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The free T4 measurement also fell after selenium was added. organism: Homo sapiens tissue_or_cell_type: Serum thyroid-hormone concentrations experimental_model: Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire limitations: The abstract reports before/after changes in the selenium group; do not mistake these for adjusted between-group estimates. DIO1 restoration was a proposed explanation, not directly measured. Hormone changes do not themselves establish symptomatic deterioration or a universal order for supplement treatment. exposure: Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract. cross_nutrient: true evidence_location: Primary indexed abstract. [iod-clin-contempre1992] Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. (1992). https://pubmed.ncbi.nlm.nih.gov/1424183/ DOI: 10.1111/j.1365-2265.1992.tb02268.x

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary indexed abstract.

experimental_model

Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire

exposure

Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract.

limitations

The abstract reports before/after changes in the selenium group; do not mistake these for adjusted between-group estimates. DIO1 restoration was a proposed explanation, not directly measured. Hormone changes do not themselves establish symptomatic deterioration or a universal order for supplement treatment.

nutrient_topic

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

organism

Homo sapiens

plain_language

The hormone pattern changed unevenly; T3 and TSH did not simply rise with selenium.

primary_references

[iod-clin-contempre1992] Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. (1992). https://pubmed.ncbi.nlm.nih.gov/1424183/ DOI: 10.1111/j.1365-2265.1992.tb02268.x

tissue_or_cell_type

Serum thyroid-hormone concentrations

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1286–1298

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire · source_derived_draft · unverified_draft

### iod-clin-selenium-rt3 Mean reverse T3 fell from 124 ± 115 to 90 ± 72 pmol/L after selenium treatment (P<0.05), while serum T3 and TSH did not change significantly. Condition category: nutrient_deficiency nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The hormone pattern changed unevenly; T3 and TSH did not simply rise with selenium. organism: Homo sapiens tissue_or_cell_type: Serum thyroid-hormone concentrations experimental_model: Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire limitations: The abstract reports before/after changes in the selenium group; do not mistake these for adjusted between-group estimates. DIO1 restoration was a proposed explanation, not directly measured. Hormone changes do not themselves establish symptomatic deterioration or a universal order for supplement treatment. exposure: Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract. cross_nutrient: true evidence_location: Primary indexed abstract. [iod-clin-contempre1992] Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. (1992). https://pubmed.ncbi.nlm.nih.gov/1424183/ DOI: 10.1111/j.1365-2265.1992.tb02268.x

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary indexed abstract.

experimental_model

Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire

exposure

Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract.

limitations

The abstract reports before/after changes in the selenium group; do not mistake these for adjusted between-group estimates. DIO1 restoration was a proposed explanation, not directly measured. Hormone changes do not themselves establish symptomatic deterioration or a universal order for supplement treatment.

nutrient_topic

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

organism

Homo sapiens

plain_language

Selenium alone lowered circulating T4 in this co-deficient population.

primary_references

[iod-clin-contempre1992] Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. (1992). https://pubmed.ncbi.nlm.nih.gov/1424183/ DOI: 10.1111/j.1365-2265.1992.tb02268.x

tissue_or_cell_type

Serum thyroid-hormone concentrations

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Iodine: thyroid hormone production, deficiency, excess and nutrient interactions (2026-09-17) · lines 1258–1270

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire · source_derived_draft · unverified_draft

### iod-clin-selenium-total-t4 Mean serum total T4 fell from 73.1 ± 45.4 to 48.3 ± 23.7 nmol/L after two months of selenium treatment (P<0.001) in the iodine/selenium-deficient setting. Condition category: nutrient_deficiency nutrient_topic: Iodine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Selenium alone lowered circulating T4 in this co-deficient population. organism: Homo sapiens tissue_or_cell_type: Serum thyroid-hormone concentrations experimental_model: Placebo-controlled selenium intervention in 52 schoolchildren from a region of severe iodine and selenium deficiency in northern Zaire limitations: The abstract reports before/after changes in the selenium group; do not mistake these for adjusted between-group estimates. DIO1 restoration was a proposed explanation, not directly measured. Hormone changes do not themselves establish symptomatic deterioration or a universal order for supplement treatment. exposure: Selenium 50 micrograms/day as selenomethionine or placebo for two months; no concurrent iodine-repletion regimen reported in the abstract. cross_nutrient: true evidence_location: Primary indexed abstract. [iod-clin-contempre1992] Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. (1992). https://pubmed.ncbi.nlm.nih.gov/1424183/ DOI: 10.1111/j.1365-2265.1992.tb02268.x

evidence_span

{"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"}

experimental_model

Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue

exposure

Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection

limitations

The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone.

nutrient_topic

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

organism

Mouse

plain_language

Cold makes brown fat build a selenium enzyme that manufactures active thyroid hormone on the spot.

primary_references

[cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

tissue_or_cell_type

Brown adipose tissue

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 377–388

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue · source_derived_draft · unverified_draft

### cold-dio2-selenoenzyme Type 2 iodothyronine deiodinase is a selenoenzyme, the product of the cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Cold makes brown fat build a selenium enzyme that manufactures active thyroid hormone on the spot. organism: Mouse tissue_or_cell_type: Brown adipose tissue experimental_model: Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue limitations: The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone. exposure: Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection evidence_span: {"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"} [cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

true

experimental_model

Secondary case-cohort analysis nested within SELECT; 1739 total cases and 3117 sampled cohort members

exposure

Trial supplementation analyzed by baseline toenail selenium; E-alone comparison used below versus at/above the 40th percentile.

limitations

Exploratory subgroup thresholds are cohort percentiles, not deficiency thresholds; baseline selenium was not randomized. Does not justify adding selenium to make high-dose vitamin E safe.

nutrient_topic

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

organism

Homo sapiens

plain_language

Baseline selenium measurements helped identify different trial outcomes, but did not establish a safe supplement combination.

primary_references

[e-clin-select2014] Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. (2014). https://pubmed.ncbi.nlm.nih.gov/24563519/ DOI: 10.1093/jnci/djt456

tissue_or_cell_type

Prostate and toenail selenium biomarker

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1310–1321

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Secondary case-cohort analysis nested within SELECT; 1739 total cases and 3117 sampled cohort members · source_derived_draft · unverified_draft

### e-clin-select-baseline-selenium In the SELECT secondary analysis, vitamin E alone increased total prostate-cancer risk by 63% among men below the 40th percentile of baseline toenail selenium; a significant effect was not found above that split. Condition category: biomarker_context nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Baseline selenium measurements helped identify different trial outcomes, but did not establish a safe supplement combination. organism: Homo sapiens tissue_or_cell_type: Prostate and toenail selenium biomarker experimental_model: Secondary case-cohort analysis nested within SELECT; 1739 total cases and 3117 sampled cohort members limitations: Exploratory subgroup thresholds are cohort percentiles, not deficiency thresholds; baseline selenium was not randomized. Does not justify adding selenium to make high-dose vitamin E safe. exposure: Trial supplementation analyzed by baseline toenail selenium; E-alone comparison used below versus at/above the 40th percentile. cross_nutrient: true [e-clin-select2014] Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. (2014). https://pubmed.ncbi.nlm.nih.gov/24563519/ DOI: 10.1093/jnci/djt456

cross_nutrient

true

experimental_model

SELECT randomized factorial prevention trial; 34887 men in primary analysis, 35533 originally randomized

exposure

All-rac-alpha-tocopheryl acetate 400 IU/day; selenium arm 200 micrograms/day selenium as L-selenomethionine; supplements stopped in 2008, follow-up continued to July 2011.

limitations

Trial-specific formulation, dose and population; does not establish the effect of food intake or of every vitamin E form. Group results cannot identify an intracellular mechanism. The nonsignificant combination estimate is not proof that selenium mechanistically neutralizes vitamin E-associated harm.

nutrient_topic

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

organism

Homo sapiens

plain_language

Adding selenium did not demonstrate a prostate-cancer prevention benefit.

primary_references

[e-clin-select2011] Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). (2011). https://pubmed.ncbi.nlm.nih.gov/21990298/ DOI: 10.1001/jama.2011.1437

tissue_or_cell_type

Prostate and whole-person outcomes

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1297–1308

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · SELECT randomized factorial prevention trial; 34887 men in primary analysis, 35533 originally randomized · source_derived_draft · unverified_draft

### e-clin-select-combination-boundary SELECT did not demonstrate prostate-cancer prevention with vitamin E plus selenium (HR 1.05, 99% CI 0.89–1.22 versus placebo). Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding selenium did not demonstrate a prostate-cancer prevention benefit. organism: Homo sapiens tissue_or_cell_type: Prostate and whole-person outcomes experimental_model: SELECT randomized factorial prevention trial; 34887 men in primary analysis, 35533 originally randomized limitations: Trial-specific formulation, dose and population; does not establish the effect of food intake or of every vitamin E form. Group results cannot identify an intracellular mechanism. The nonsignificant combination estimate is not proof that selenium mechanistically neutralizes vitamin E-associated harm. exposure: All-rac-alpha-tocopheryl acetate 400 IU/day; selenium arm 200 micrograms/day selenium as L-selenomethionine; supplements stopped in 2008, follow-up continued to July 2011. cross_nutrient: true [e-clin-select2011] Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). (2011). https://pubmed.ncbi.nlm.nih.gov/21990298/ DOI: 10.1001/jama.2011.1437

cell_type

cancer cell lines

experimental_model

Genetic disruption and ribosome analyses

limitations

Tumor-cell result; GPX4 priority is context dependent.

organism

human

Selenium: literature corrections and mechanism additions · lines 594–604

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Genetic disruption and ribosome analyses · secondary_verified · secondary_verified

## lrp8-loss-promotes-gpx4-stalling Disrupted selenium uptake hindered GPX4 production in these cancer cells. LRP8 loss caused GPX4 UGA-associated ribosome stalling in the tested cancer cells. Organism: human Cell type: cancer cell lines Experimental model: Genetic disruption and ribosome analyses Limitations: Tumor-cell result; GPX4 priority is context dependent. Primary reference: [Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability](https://pubmed.ncbi.nlm.nih.gov/35637349/)

cell_type

liver-derived enzyme

experimental_model

Purified and recombinant enzyme

limitations

The original assay described elemental selenium; intracellular speciation remains separate.

organism

mouse

Selenium: literature corrections and mechanism additions · lines 510–520

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Purified and recombinant enzyme · secondary_verified · secondary_verified

## scly-decomposes-selenocysteine SCLY recovers selenium from free selenocysteine. SCLY decomposes free L-selenocysteine, yielding L-alanine and released selenium. Organism: mouse Cell type: liver-derived enzyme Experimental model: Purified and recombinant enzyme Limitations: The original assay described elemental selenium; intracellular speciation remains separate. Primary reference: [cDNA cloning, purification, and characterization of mouse liver selenocysteine lyase. Candidate for selenium delivery protein in selenoprotein synthesis](https://pubmed.ncbi.nlm.nih.gov/10692412/)