AA

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ceylon-research/24516781.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5605569464035286614b12021fc60adbaf6c8a003a6b634d03fc5b544ce59d27", "start_char": 0, "end_char": 1685, "text_sha256": "5605569464035286614b12021fc60adbaf6c8a003a6b634d03fc5b544ce59d27"}

experimental_model

Human TRPA1 expression, calcium fluorescence and patch clamp

exposure

Cinnamaldehyde concentration response; 300 micromolar challenge; triple cysteine-to-serine construct

limitations

Channel expression and high cell-assay concentrations do not establish dietary exposure or a human calcium-deficiency effect.

nutrient_topic

Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. · Ceylon cinnamon / Cinnamomum verum bark preparations

organism

Human TRPA1 in HEK293 cells

plain_language

This fatty acid could still partly activate the altered channel, showing that channel triggers need not use the same mechanism.

primary_references

[ceylon-p24516781] Ligand determinants of fatty acid activation of the pronociceptive ion channel TRPA1. (2014). https://pubmed.ncbi.nlm.nih.gov/24516781/ DOI: 10.7717/peerj.248

tissue_or_cell_type

Engineered cultured cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Ceylon cinnamon: metabolism, signaling and nutrient connections (2026-09-17) · lines 363–374

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human TRPA1 expression, calcium fluorescence and patch clamp · source_derived_draft · unverified_draft

### ceylon-trpa1-aa-mutant Arachidonic acid at 100 micromolar retained about 40% of the wild-type response in the triple-cysteine TRPA1 mutant. Condition category: machinery_impairment nutrient_topic: Ceylon cinnamon research collection; topical membership is not evidence of a direct dietary effect. plain_language: This fatty acid could still partly activate the altered channel, showing that channel triggers need not use the same mechanism. organism: Human TRPA1 in HEK293 cells tissue_or_cell_type: Engineered cultured cells experimental_model: Human TRPA1 expression, calcium fluorescence and patch clamp limitations: Channel expression and high cell-assay concentrations do not establish dietary exposure or a human calcium-deficiency effect. exposure: Cinnamaldehyde concentration response; 300 micromolar challenge; triple cysteine-to-serine construct evidence_span: {"source_cache": "artifacts/ceylon-research/24516781.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5605569464035286614b12021fc60adbaf6c8a003a6b634d03fc5b544ce59d27", "start_char": 0, "end_char": 1685, "text_sha256": "5605569464035286614b12021fc60adbaf6c8a003a6b634d03fc5b544ce59d27"} [ceylon-p24516781] Ligand determinants of fatty acid activation of the pronociceptive ion channel TRPA1. (2014). https://pubmed.ncbi.nlm.nih.gov/24516781/ DOI: 10.7717/peerj.248

evidence_span

{"source_cache": "artifacts/thc-research/1470919.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2", "start_char": 0, "end_char": 757, "text_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2"}

experimental_model

Isolation from porcine brain with mass spectrometry, NMR and synthetic confirmation

exposure

Screen for endogenous ligands of the cannabinoid receptor

limitations

The isolation of the first endogenous ligand. The bioassay is a peripheral tissue twitch, not a central behavioural effect.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Pig brain, with mouse bioassay

plain_language

The brain makes its own version of the drug, and it is built from a fatty acid.

primary_references

[thc-p1470919] Isolation and structure of a brain constituent that binds to the cannabinoid receptor. (1992). https://pubmed.ncbi.nlm.nih.gov/1470919/ DOI: 10.1126/science.1470919

tissue_or_cell_type

Brain and vas deferens

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 244–255

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolation from porcine brain with mass spectrometry, NMR and synthetic confirmation · source_derived_draft · unverified_draft

### thc-anandamide-isolated Arachidonylethanolamide, an arachidonic acid derivative isolated from porcine brain, competitively inhibited binding of a radiolabelled cannabinoid probe to synaptosomal membranes and produced concentration-dependent inhibition of the electrically evoked twitch of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: The brain makes its own version of the drug, and it is built from a fatty acid. organism: Pig brain, with mouse bioassay tissue_or_cell_type: Brain and vas deferens experimental_model: Isolation from porcine brain with mass spectrometry, NMR and synthetic confirmation limitations: The isolation of the first endogenous ligand. The bioassay is a peripheral tissue twitch, not a central behavioural effect. exposure: Screen for endogenous ligands of the cannabinoid receptor evidence_span: {"source_cache": "artifacts/thc-research/1470919.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2", "start_char": 0, "end_char": 757, "text_sha256": "45d534b5ac88c3edf040431942aea2f8421399c88e3931e8bc28b4b5e438f2f2"} [thc-p1470919] Isolation and structure of a brain constituent that binds to the cannabinoid receptor. (1992). https://pubmed.ncbi.nlm.nih.gov/1470919/ DOI: 10.1126/science.1470919

evidence_span

{"source_cache": "artifacts/thc-research/18316044.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa2ad40ef984af77cc4c50a6126ce53354a2fd56fe6fada84871e2382cef07b3", "start_char": 0, "end_char": 1668, "text_sha256": "fa2ad40ef984af77cc4c50a6126ce53354a2fd56fe6fada84871e2382cef07b3"}

experimental_model

Rats fed five different dietary fats with tissue endocannabinoid and fatty acid measurement

exposure

Short-term feeding of palm, olive, safflower, fish or arachidonic acid enriched diets

limitations

A five-arm dietary comparison measuring the mediators directly. Short-term feeding, and some changes occurred without any change in tissue fatty acid composition.

nutrient_topic

THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. · Delta-9-tetrahydrocannabinol / THC

organism

Rat

plain_language

Feeding the precursor raises the messengers, and feeding fish oil lowers them.

primary_references

[thc-p18316044] Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. (2008). https://pubmed.ncbi.nlm.nih.gov/18316044/ DOI: 10.1016/j.bbalip.2008.01.006

tissue_or_cell_type

Brain, liver and small intestine

THC: the cannabinoid receptors, the endocannabinoid system it occupies, what the drug does, and the dietary fat it is built from (2026-09-21) · lines 673–684

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rats fed five different dietary fats with tissue endocannabinoid and fatty acid measurement · source_derived_draft · unverified_draft

### thc-arachidonic-diet-raises-both The arachidonic acid diet increased anandamide and 2-arachidonoylglycerol in jejunum without effect on liver, and the fish oil diet decreased liver levels of most N-acylethanolamines with similar changes in their precursors. Condition category: normal nutrient_topic: THC research collection; topical membership is not evidence of a direct clinical effect, and THC is recorded separately from the endocannabinoids it imitates. plain_language: Feeding the precursor raises the messengers, and feeding fish oil lowers them. organism: Rat tissue_or_cell_type: Brain, liver and small intestine experimental_model: Rats fed five different dietary fats with tissue endocannabinoid and fatty acid measurement limitations: A five-arm dietary comparison measuring the mediators directly. Short-term feeding, and some changes occurred without any change in tissue fatty acid composition. exposure: Short-term feeding of palm, olive, safflower, fish or arachidonic acid enriched diets evidence_span: {"source_cache": "artifacts/thc-research/18316044.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fa2ad40ef984af77cc4c50a6126ce53354a2fd56fe6fada84871e2382cef07b3", "start_char": 0, "end_char": 1668, "text_sha256": "fa2ad40ef984af77cc4c50a6126ce53354a2fd56fe6fada84871e2382cef07b3"} [thc-p18316044] Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. (2008). https://pubmed.ncbi.nlm.nih.gov/18316044/ DOI: 10.1016/j.bbalip.2008.01.006

dose

Eugenol 2 micromolar

duration

Acute

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Washed human platelets; ADP-treated mouse pulmonary-thrombosis arm

limitations

Ex-vivo platelet inhibition and mouse thrombosis do not establish oral antithrombotic efficacy or bleeding safety in humans.

nutrient_topic

Eugenol chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Eugenol

organism

Washed human platelets; ADP-treated mouse pulmonary-thrombosis arm

plain_language

At 2 micromolar, eugenol inhibited collagen- and arachidonic-acid-induced aggregation in human platelets but did not inhibit thrombin- or U46619-induced aggregation.

primary_references

Eugenol Suppresses Platelet Activation and Mitigates Pulmonary Thromboembolism in Humans and Murine Models. (2024). https://pubmed.ncbi.nlm.nih.gov/38396774/ DOI: 10.3390/ijms25042098

route

In vitro; mouse intervention

tissue

Agonist-specific platelet aggregation

Eugenol: mechanism of action and interactions (2026-09-20) · lines 11–20

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Washed human platelets; ADP-treated mouse pulmonary-thrombosis arm · source_derived_draft · unverified_draft

## eugenol-platelet-agonist-selectivity At 2 micromolar, eugenol inhibited collagen- and arachidonic-acid-induced aggregation in human platelets but did not inhibit thrombin- or U46619-induced aggregation. Model/species: Washed human platelets; ADP-treated mouse pulmonary-thrombosis arm Tissue/system: Agonist-specific platelet aggregation Exposure: Eugenol 2 micromolar Route: In vitro; mouse intervention Duration: Acute Limits: Ex-vivo platelet inhibition and mouse thrombosis do not establish oral antithrombotic efficacy or bleeding safety in humans. Primary reference: Eugenol Suppresses Platelet Activation and Mitigates Pulmonary Thromboembolism in Humans and Murine Models. (2024). https://pubmed.ncbi.nlm.nih.gov/38396774/ DOI: 10.3390/ijms25042098 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_span

{"source_cache": "artifacts/ibuprofen-research/8567676.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda", "start_char": 0, "end_char": 2200, "text_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda"}

experimental_model

Site-directed mutants of ovine cyclooxygenase-1 at Arg120, Glu524 and Tyr355 expressed in COS-1 cells

exposure

D- and L-ibuprofen and flurbiprofen tested against the mutant panel

limitations

Identifies which residue does the stereochemical discrimination by changing it and watching the discrimination collapse. Ovine recombinant enzyme.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Sheep enzyme

plain_language

A single arginine grips the acid group of both the substrate and the drug, and without it the slow kind of inhibition cannot happen.

primary_references

[ibu-p8567676] Involvement of arginine 120, glutamate 524, and tyrosine 355 in the binding of arachidonate and 2-phenylpropionic acid inhibitors to the cyclooxygenase active site of ovine prostaglandin endoperoxide H synthase-1. (1996). https://pubmed.ncbi.nlm.nih.gov/8567676/ DOI: 10.1074/jbc.271.4.2179

tissue_or_cell_type

Recombinant cyclooxygenase-1

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 253–264

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutants of ovine cyclooxygenase-1 at Arg120, Glu524 and Tyr355 expressed in COS-1 cells · source_derived_draft · unverified_draft

### ibu-arg120-anchors-the-carboxylate All mutants retained at least part of their activity except R120E which had none, Km values for arachidonic acid were 87 and 3300 micromolar for R120K and R120Q against 4 micromolar for native enzyme, and the R120Q mutant failed to undergo suicide inactivation during catalysis or time-dependent inhibition by flurbiprofen, results consistent with Arg120 binding the carboxylate group of arachidonate and indicating that interaction of the carboxylate of substrates and inhibitors with Arg120 is necessary for suicide inactivation and time-dependent inhibition respectively; Glu524 substitutions did not significantly change Km. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: A single arginine grips the acid group of both the substrate and the drug, and without it the slow kind of inhibition cannot happen. organism: Sheep enzyme tissue_or_cell_type: Recombinant cyclooxygenase-1 experimental_model: Site-directed mutants of ovine cyclooxygenase-1 at Arg120, Glu524 and Tyr355 expressed in COS-1 cells limitations: Identifies which residue does the stereochemical discrimination by changing it and watching the discrimination collapse. Ovine recombinant enzyme. exposure: D- and L-ibuprofen and flurbiprofen tested against the mutant panel evidence_span: {"source_cache": "artifacts/ibuprofen-research/8567676.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda", "start_char": 0, "end_char": 2200, "text_sha256": "773dc61cda18ae93ea7dfaf128870c2c5926fb828d7a1563f413e97e29893eda"} [ibu-p8567676] Involvement of arginine 120, glutamate 524, and tyrosine 355 in the binding of arachidonate and 2-phenylpropionic acid inhibitors to the cyclooxygenase active site of ovine prostaglandin endoperoxide H synthase-1. (1996). https://pubmed.ncbi.nlm.nih.gov/8567676/ DOI: 10.1074/jbc.271.4.2179

evidence_span

{"source_cache": "artifacts/ibuprofen-research/10722687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8e9ebedd8a4d791246c951376fa2f6f07a5ca8af828bafd15836bec26c090348", "start_char": 0, "end_char": 2063, "text_sha256": "8e9ebedd8a4d791246c951376fa2f6f07a5ca8af828bafd15836bec26c090348"}

experimental_model

Product analysis and kinetics for solubilised, membrane-associated and active-site-mutant ovine cyclooxygenase-1

exposure

Arachidonate product profiling with ibuprofen as a competitive inhibitor

limitations

The identical inhibitory concentration across three different products is the informative result. The concentrations are high and the enzyme is ovine.

nutrient_topic

Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. · Ibuprofen

organism

Sheep enzyme

plain_language

The drug blocks the door rather than any one position inside, which is why it stops every product equally.

primary_references

[ibu-p10722687] Different catalytically competent arrangements of arachidonic acid within the cyclooxygenase active site of prostaglandin endoperoxide H synthase-1 lead to the formation of different oxygenated products. (2000). https://pubmed.ncbi.nlm.nih.gov/10722687/ DOI: 10.1074/jbc.275.12.8501

tissue_or_cell_type

Cyclooxygenase-1

Ibuprofen: the enantiomer that works, the one that was called inactive, the one-way chemistry that turns one into the other, and the targets that are not cyclooxygenase (2026-09-22) · lines 305–316

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Product analysis and kinetics for solubilised, membrane-associated and active-site-mutant ovine cyclooxygenase-1 · source_derived_draft · unverified_draft

### ibu-blocks-entry-not-orientation Native ovine cyclooxygenase-1 produced primarily prostaglandin G2 along with 11R-, 15S- and 15R-hydroxyeicosatetraenoic acids with different Km values for each product, establishing that arachidonate can assume at least three catalytically productive arrangements within the site, and half-maximal inhibitory concentrations for the competitive inhibitor ibuprofen were the same for every product of a given enzyme form, 175 micromolar for the native enzyme and 15 micromolar for the V349L mutant, most simply rationalised by a model in which arachidonate forms its various arrangements only after entering the cyclooxygenase active site. Condition category: normal nutrient_topic: Ibuprofen research collection; topical membership is not evidence of a direct clinical effect, and the racemate is recorded separately from each of its two enantiomers. plain_language: The drug blocks the door rather than any one position inside, which is why it stops every product equally. organism: Sheep enzyme tissue_or_cell_type: Cyclooxygenase-1 experimental_model: Product analysis and kinetics for solubilised, membrane-associated and active-site-mutant ovine cyclooxygenase-1 limitations: The identical inhibitory concentration across three different products is the informative result. The concentrations are high and the enzyme is ovine. exposure: Arachidonate product profiling with ibuprofen as a competitive inhibitor evidence_span: {"source_cache": "artifacts/ibuprofen-research/10722687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8e9ebedd8a4d791246c951376fa2f6f07a5ca8af828bafd15836bec26c090348", "start_char": 0, "end_char": 2063, "text_sha256": "8e9ebedd8a4d791246c951376fa2f6f07a5ca8af828bafd15836bec26c090348"} [ibu-p10722687] Different catalytically competent arrangements of arachidonic acid within the cyclooxygenase active site of prostaglandin endoperoxide H synthase-1 lead to the formation of different oxygenated products. (2000). https://pubmed.ncbi.nlm.nih.gov/10722687/ DOI: 10.1074/jbc.275.12.8501

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/paracetamol-research/15987694.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8da7599ee6674ced34346ae03fae0e421bcc5c1f53b0cb879145d7a511502001", "start_char": 0, "end_char": 1093, "text_sha256": "8da7599ee6674ced34346ae03fae0e421bcc5c1f53b0cb879145d7a511502001"}

experimental_model

Brain and spinal cord metabolite identification in wild-type and fatty acid amide hydrolase knockout mice

exposure

Acetaminophen, with the conjugation step tested by genetic deletion of the conjugating enzyme

limitations

Identifies a previously unknown route of drug metabolism and proves the enzyme by knockout. The downstream activities are measured on purified enzyme and cell lines rather than in the treated animal.

nutrient_topic

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

organism

Mouse

plain_language

The brain takes the drug apart and builds the pieces into something new, and that something is what acts.

primary_references

[apap-p15987694] Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. (2005). https://pubmed.ncbi.nlm.nih.gov/15987694/ DOI: 10.1074/jbc.m501489200

tissue_or_cell_type

Brain and spinal cord

trigger_kind

machinery_impairment Imported condition classification; unverified.

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 298–309

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Brain and spinal cord metabolite identification in wild-type and fatty acid amide hydrolase knockout mice · source_derived_draft · unverified_draft

### apap-faah-builds-am404 Acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine, and this conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase; AM404 also inhibits purified cyclooxygenase-1 and -2 and prostaglandin synthesis in lipopolysaccharide-stimulated macrophages and acts on the endogenous cannabinoid system, identifying fatty acid conjugation as a novel pathway for drug metabolism. Condition category: machinery_impairment nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The brain takes the drug apart and builds the pieces into something new, and that something is what acts. organism: Mouse tissue_or_cell_type: Brain and spinal cord experimental_model: Brain and spinal cord metabolite identification in wild-type and fatty acid amide hydrolase knockout mice limitations: Identifies a previously unknown route of drug metabolism and proves the enzyme by knockout. The downstream activities are measured on purified enzyme and cell lines rather than in the treated animal. exposure: Acetaminophen, with the conjugation step tested by genetic deletion of the conjugating enzyme evidence_span: {"source_cache": "artifacts/paracetamol-research/15987694.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8da7599ee6674ced34346ae03fae0e421bcc5c1f53b0cb879145d7a511502001", "start_char": 0, "end_char": 1093, "text_sha256": "8da7599ee6674ced34346ae03fae0e421bcc5c1f53b0cb879145d7a511502001"} [apap-p15987694] Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. (2005). https://pubmed.ncbi.nlm.nih.gov/15987694/ DOI: 10.1074/jbc.m501489200

evidence_span

{"source_cache": "artifacts/paracetamol-research/2511429.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8dbe8c6f23fc857be6bba07e2a518c59f8dc76c9f8625c25ba84030c43f6e636", "start_char": 0, "end_char": 1593, "text_sha256": "8dbe8c6f23fc857be6bba07e2a518c59f8dc76c9f8625c25ba84030c43f6e636"}

experimental_model

Prostaglandin H synthase apoenzyme reconstituted with manganese or iron protoporphyrin

exposure

Eugenol, guaiacol, butylated hydroxyanisole and acetaminophen against both reconstituted forms, with prostaglandin G2 added

limitations

The manganese-reconstituted enzyme retains cyclooxygenase but little peroxidase activity, which is what lets this study separate the two proposed sites. Its conclusion is the opposite of the peroxide-tone account.

nutrient_topic

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

organism

Enzyme

plain_language

In an enzyme stripped of its peroxidase the drug still works, which argues it also competes at the other site.

primary_references

[apap-p2511429] Mechanism of inhibition of prostaglandin H synthase by eugenol and other phenolic peroxidase substrates. (1989). https://pubmed.ncbi.nlm.nih.gov/2511429/ DOI: 10.1016/s0026-895x(25)09658-0

tissue_or_cell_type

Reconstituted prostaglandin H synthase

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 155–166

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prostaglandin H synthase apoenzyme reconstituted with manganese or iron protoporphyrin · source_derived_draft · unverified_draft

### apap-maybe-the-cox-site-instead Higher concentrations of eugenol were required to inhibit iron-reconstituted prostaglandin H synthase than the manganese-reconstituted enzyme which retains cyclooxygenase but not peroxidase activity, inhibition was highly dependent on arachidonic acid concentration, adding 10 micromolar prostaglandin G2 did not prevent the inhibitory effects, and other phenolic compounds including guaiacol, butylated hydroxyanisole and acetaminophen inhibited the manganese enzyme similarly, demonstrating that these compounds specifically inhibit the cyclooxygenase component in addition to or independent of their effect on peroxide tone, which the authors suggest is due to competition with arachidonic acid for the active site. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: In an enzyme stripped of its peroxidase the drug still works, which argues it also competes at the other site. organism: Enzyme tissue_or_cell_type: Reconstituted prostaglandin H synthase experimental_model: Prostaglandin H synthase apoenzyme reconstituted with manganese or iron protoporphyrin limitations: The manganese-reconstituted enzyme retains cyclooxygenase but little peroxidase activity, which is what lets this study separate the two proposed sites. Its conclusion is the opposite of the peroxide-tone account. exposure: Eugenol, guaiacol, butylated hydroxyanisole and acetaminophen against both reconstituted forms, with prostaglandin G2 added evidence_span: {"source_cache": "artifacts/paracetamol-research/2511429.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8dbe8c6f23fc857be6bba07e2a518c59f8dc76c9f8625c25ba84030c43f6e636", "start_char": 0, "end_char": 1593, "text_sha256": "8dbe8c6f23fc857be6bba07e2a518c59f8dc76c9f8625c25ba84030c43f6e636"} [apap-p2511429] Mechanism of inhibition of prostaglandin H synthase by eugenol and other phenolic peroxidase substrates. (1989). https://pubmed.ncbi.nlm.nih.gov/2511429/ DOI: 10.1016/s0026-895x(25)09658-0

evidence_span

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

experimental_model

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

exposure

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

limitations

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

nutrient_topic

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

organism

Sheep

plain_language

At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons.

primary_references

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

tissue_or_cell_type

Seminal vesicle microsomes

Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 116–127

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

### apap-stimulates-then-inhibits Relatively low concentrations of acetaminophen from 20 to 200 micromolar stimulate prostaglandin H synthase activity in ram seminal vesicle microsomes whereas concentrations above 10 millimolar inhibit the conversion of arachidonic acid to prostaglandin G2, both activities apparently involving reduction of oxidized complexes of the enzyme and roughly correlating with the electrochemical half-wave oxidation potentials of a series of hydroxyacetanilides, consistent with common intermediate enzyme forms for both cyclooxygenase and hydroperoxidase catalysed reactions of which one is reduced at low drug concentrations to stimulate and another at higher concentrations to inhibit. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: At low concentrations the drug feeds the enzyme and at high concentrations it stalls it, both by handing over electrons. organism: Sheep tissue_or_cell_type: Seminal vesicle microsomes experimental_model: Ram seminal vesicle microsomal prostaglandin H synthase with product identification by cooxidation limitations: Shows that the drug both stimulates and inhibits the same enzyme depending on concentration, and that the enzyme makes NAPQI from it. A microsomal preparation at concentrations far above therapeutic. exposure: Acetaminophen from 20 micromolar to above 10 millimolar, with glutathione, ascorbate and indomethacin evidence_span: {"source_cache": "artifacts/paracetamol-research/3124965.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502", "start_char": 0, "end_char": 2236, "text_sha256": "dcc85a1ab66984973092042b5553f43fbbe5eb10b674614c9b1fa991b3969502"} [apap-p3124965] Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase. (1988). https://pubmed.ncbi.nlm.nih.gov/3124965/ DOI: 10.1016/0009-2797(88)90101-9

cross_nutrient

Human hydroxycarboxylic acid receptor 2 / HCAR2 (upstream_receptor); Nicotinic acid (agonist); arachidonic acid (released_substrate)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/walters2009.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "2eb822534ed0c8ea9f71ec67288c302e4e375ed9e86cfe70b28f21ae65ffbd4b", "start_char": 0, "end_char": 1537, "text_sha256": "2eb822534ed0c8ea9f71ec67288c302e4e375ed9e86cfe70b28f21ae65ffbd4b"}

experimental_model

Human cell-line nicotinic-acid receptor signaling assay

exposure

Nicotinic-acid stimulation and beta-arrestin perturbation

limitations

Pharmacological receptor signaling, not an essential effect of every B3 precursor. Cell signaling and mouse physiology are distinct arms. Reduced fatty acids or flushing does not establish cardiovascular benefit.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

A separate receptor branch recruits beta-arrestin and releases the fatty-acid material used to make flushing signals.

primary_references

[nia-clin-walters2009] beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice. (2009). https://pubmed.ncbi.nlm.nih.gov/19349687/ DOI: 10.1172/jci36806

tissue_or_cell_type

Cultured human cells

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1305–1317

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cell-line nicotinic-acid receptor signaling assay · source_derived_draft · unverified_draft

### nia-clin-arrb1-pla2 Nicotinic acid promoted beta-arrestin1 association with activated cytosolic phospholipase A2 and beta-arrestin1-dependent phospholipase activation with arachidonate release in the cell assay. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separate receptor branch recruits beta-arrestin and releases the fatty-acid material used to make flushing signals. organism: Homo sapiens tissue_or_cell_type: Cultured human cells experimental_model: Human cell-line nicotinic-acid receptor signaling assay limitations: Pharmacological receptor signaling, not an essential effect of every B3 precursor. Cell signaling and mouse physiology are distinct arms. Reduced fatty acids or flushing does not establish cardiovascular benefit. exposure: Nicotinic-acid stimulation and beta-arrestin perturbation cross_nutrient: Human hydroxycarboxylic acid receptor 2 / HCAR2 (upstream_receptor); Nicotinic acid (agonist); arachidonic acid (released_substrate) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/walters2009.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "2eb822534ed0c8ea9f71ec67288c302e4e375ed9e86cfe70b28f21ae65ffbd4b", "start_char": 0, "end_char": 1537, "text_sha256": "2eb822534ed0c8ea9f71ec67288c302e4e375ed9e86cfe70b28f21ae65ffbd4b"} [nia-clin-walters2009] beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice. (2009). https://pubmed.ncbi.nlm.nih.gov/19349687/ DOI: 10.1172/jci36806

dose

Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL

duration

Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h

evidence_access

Primary open full text, relevant results/methods and PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Mouse RAW 264.7 macrophages

limitations

High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation. Opposite to the COX-2 response in IL-1beta-exposed human intestinal cells; different species, stimulus and concentration are retained rather than declared a contradiction.

nutrient_topic

Dedicated indicaxanthin chapter; original betalain family identity and shared claims preserved. · Indicaxanthin

organism

Mouse RAW 264.7 macrophages

plain_language

Indicaxanthin pretreatment increased COX-2 expression in LPS-stimulated RAW 264.7 cells.

primary_references

Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004

route

In vitro pretreatment then challenge

tissue

Cellular membranes and prostaglandin pathway

Indicaxanthin: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 129–138

Original AI-assisted curation of thirteen additional primary studies, with twenty-six existing claims from eight studies linked unchanged. Study-specific citations and limitations retained. Not publisher full text. · supports · Mouse RAW 264.7 macrophages · source_derived_draft · unverified_draft

## indicaxanthin-macrophage-cox2 Indicaxanthin pretreatment increased COX-2 expression in LPS-stimulated RAW 264.7 cells. Model/species: Mouse RAW 264.7 macrophages Tissue: Cellular membranes and prostaglandin pathway Exposure: Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL Route: In vitro pretreatment then challenge Duration: Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h Limits: High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation. Opposite to the COX-2 response in IL-1beta-exposed human intestinal cells; different species, stimulus and concentration are retained rather than declared a contradiction. Primary reference: Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004 Access: Primary open full text, relevant results/methods and PubMed metadata.

dose

Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL

duration

Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h

evidence_access

Primary open full text, relevant results/methods and PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Mouse RAW 264.7 macrophages

limitations

High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation.

nutrient_topic

Dedicated indicaxanthin chapter; original betalain family identity and shared claims preserved. · Indicaxanthin

organism

Mouse RAW 264.7 macrophages

plain_language

Indicaxanthin pretreatment increased hematopoietic PGD synthase expression in LPS-stimulated RAW 264.7 cells.

primary_references

Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004

route

In vitro pretreatment then challenge

tissue

Cellular membranes and prostaglandin pathway

Indicaxanthin: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 140–149

Original AI-assisted curation of thirteen additional primary studies, with twenty-six existing claims from eight studies linked unchanged. Study-specific citations and limitations retained. Not publisher full text. · supports · Mouse RAW 264.7 macrophages · source_derived_draft · unverified_draft

## indicaxanthin-macrophage-hpgds Indicaxanthin pretreatment increased hematopoietic PGD synthase expression in LPS-stimulated RAW 264.7 cells. Model/species: Mouse RAW 264.7 macrophages Tissue: Cellular membranes and prostaglandin pathway Exposure: Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL Route: In vitro pretreatment then challenge Duration: Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h Limits: High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation. Primary reference: Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004 Access: Primary open full text, relevant results/methods and PubMed metadata.

dose

Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL

duration

Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h

evidence_access

Primary open full text, relevant results/methods and PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Mouse RAW 264.7 macrophages

limitations

High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation.

nutrient_topic

Dedicated indicaxanthin chapter; original betalain family identity and shared claims preserved. · Indicaxanthin

organism

Mouse RAW 264.7 macrophages

plain_language

Indicaxanthin pretreatment reduced LPS-induced microsomal PGE synthase-1 overexpression in RAW 264.7 cells.

primary_references

Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004

route

In vitro pretreatment then challenge

tissue

Cellular membranes and prostaglandin pathway

Indicaxanthin: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 118–127

Original AI-assisted curation of thirteen additional primary studies, with twenty-six existing claims from eight studies linked unchanged. Study-specific citations and limitations retained. Not publisher full text. · supports · Mouse RAW 264.7 macrophages · source_derived_draft · unverified_draft

## indicaxanthin-macrophage-mpges Indicaxanthin pretreatment reduced LPS-induced microsomal PGE synthase-1 overexpression in RAW 264.7 cells. Model/species: Mouse RAW 264.7 macrophages Tissue: Cellular membranes and prostaglandin pathway Exposure: Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL Route: In vitro pretreatment then challenge Duration: Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h Limits: High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation. Primary reference: Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004 Access: Primary open full text, relevant results/methods and PubMed metadata.

dose

Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL

duration

Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h

evidence_access

Primary open full text, relevant results/methods and PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Mouse RAW 264.7 macrophages

limitations

High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation.

nutrient_topic

Dedicated indicaxanthin chapter; original betalain family identity and shared claims preserved. · Indicaxanthin

organism

Mouse RAW 264.7 macrophages

plain_language

Indicaxanthin pretreatment increased production of 15-deoxy-PGJ2 in LPS-stimulated RAW 264.7 cells.

primary_references

Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004

route

In vitro pretreatment then challenge

tissue

Cellular membranes and prostaglandin pathway

Indicaxanthin: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 151–160

Original AI-assisted curation of thirteen additional primary studies, with twenty-six existing claims from eight studies linked unchanged. Study-specific citations and limitations retained. Not publisher full text. · supports · Mouse RAW 264.7 macrophages · source_derived_draft · unverified_draft

## indicaxanthin-macrophage-pgj2 Indicaxanthin pretreatment increased production of 15-deoxy-PGJ2 in LPS-stimulated RAW 264.7 cells. Model/species: Mouse RAW 264.7 macrophages Tissue: Cellular membranes and prostaglandin pathway Exposure: Indicaxanthin 50-100 micromolar; LPS 1 microgram/mL Route: In vitro pretreatment then challenge Duration: Indicaxanthin 1 h before LPS; signaling time courses 0.5-16 h Limits: High cell-culture exposure; expression changes are not direct enzyme binding. Pro-oxidant signaling in this setting differs from red-cell antioxidant preservation. Primary reference: Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages. (2014). https://pubmed.ncbi.nlm.nih.gov/25180166/ DOI: 10.1016/j.redox.2014.07.004 Access: Primary open full text, relevant results/methods and PubMed metadata.

evidence_span

{"source_cache": "artifacts/dihydrocapsaicin-research/24953906.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717", "start_char": 0, "end_char": 1870, "text_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717"}

experimental_model

In-vitro human platelet aggregation with agonist-specified stimulation and an LDH viability control

exposure

Capsaicin and dihydrocapsaicin against the endogenous vanilloids N-oleoyldopamine and N-arachidonoyl-dopamine, with ADP, collagen and arachidonic acid as agonists

limitations

The agonist-by-agonist design is what makes this useful: it separates the two plant compounds where a single-agonist study would have merged them. A TRPV1 antagonist control was included.

nutrient_topic

Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

organism

Human

plain_language

Capsaicin blocks clumping triggered two ways; dihydrocapsaicin blocks only one of them.

primary_references

[dhc-p24953906] Vanilloid-like agents inhibit aggregation of human platelets. (2014). https://pubmed.ncbi.nlm.nih.gov/24953906/ DOI: 10.1016/j.thromres.2014.05.038

tissue_or_cell_type

Platelets

Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21) · lines 153–164

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In-vitro human platelet aggregation with agonist-specified stimulation and an LDH viability control · source_derived_draft · unverified_draft

### dhc-platelet-divergence Capsaicin, N-oleoyldopamine and N-arachidonoyl-dopamine inhibited ADP-induced platelet aggregation in a concentration-dependent manner, while arachidonic-acid-induced aggregation was inhibited by capsaicin, dihydrocapsaicin and N-arachidonoyl-dopamine but not by N-oleoyldopamine, and collagen-induced aggregation was inhibited only by the endogenous vanilloids and not by capsaicin or dihydrocapsaicin. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: Capsaicin blocks clumping triggered two ways; dihydrocapsaicin blocks only one of them. organism: Human tissue_or_cell_type: Platelets experimental_model: In-vitro human platelet aggregation with agonist-specified stimulation and an LDH viability control limitations: The agonist-by-agonist design is what makes this useful: it separates the two plant compounds where a single-agonist study would have merged them. A TRPV1 antagonist control was included. exposure: Capsaicin and dihydrocapsaicin against the endogenous vanilloids N-oleoyldopamine and N-arachidonoyl-dopamine, with ADP, collagen and arachidonic acid as agonists evidence_span: {"source_cache": "artifacts/dihydrocapsaicin-research/24953906.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717", "start_char": 0, "end_char": 1870, "text_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717"} [dhc-p24953906] Vanilloid-like agents inhibit aggregation of human platelets. (2014). https://pubmed.ncbi.nlm.nih.gov/24953906/ DOI: 10.1016/j.thromres.2014.05.038

evidence_span

{"source_cache": "artifacts/dihydrocapsaicin-research/24953906.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717", "start_char": 0, "end_char": 1870, "text_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717"}

experimental_model

In-vitro human platelet aggregation with agonist-specified stimulation and an LDH viability control

exposure

Capsaicin and dihydrocapsaicin against the endogenous vanilloids N-oleoyldopamine and N-arachidonoyl-dopamine, with ADP, collagen and arachidonic acid as agonists

limitations

The agonist-by-agonist design is what makes this useful: it separates the two plant compounds where a single-agonist study would have merged them. A TRPV1 antagonist control was included.

nutrient_topic

Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. · Dihydrocapsaicin

organism

Human

plain_language

The platelets were not simply being killed, and again the receptor is not the route.

primary_references

[dhc-p24953906] Vanilloid-like agents inhibit aggregation of human platelets. (2014). https://pubmed.ncbi.nlm.nih.gov/24953906/ DOI: 10.1016/j.thromres.2014.05.038

tissue_or_cell_type

Platelets

Dihydrocapsaicin: the second capsaicinoid, the hypothermia it is used to induce, what the gut and liver do to it, and what it does without TRPV1 (2026-09-21) · lines 166–177

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In-vitro human platelet aggregation with agonist-specified stimulation and an LDH viability control · source_derived_draft · unverified_draft

### dhc-platelet-effect-not-trpv1 Inhibition of aggregation was not due to direct toxicity of these agents towards platelets as judged by LDH release, and the TRPV1 antagonist SB-452533 did not affect inhibition of ADP-induced platelet aggregation by capsaicin and N-oleoyldopamine. Condition category: normal nutrient_topic: Dihydrocapsaicin research collection; topical membership is not evidence of a direct clinical effect, and dihydrocapsaicin is recorded separately from capsaicin. plain_language: The platelets were not simply being killed, and again the receptor is not the route. organism: Human tissue_or_cell_type: Platelets experimental_model: In-vitro human platelet aggregation with agonist-specified stimulation and an LDH viability control limitations: The agonist-by-agonist design is what makes this useful: it separates the two plant compounds where a single-agonist study would have merged them. A TRPV1 antagonist control was included. exposure: Capsaicin and dihydrocapsaicin against the endogenous vanilloids N-oleoyldopamine and N-arachidonoyl-dopamine, with ADP, collagen and arachidonic acid as agonists evidence_span: {"source_cache": "artifacts/dihydrocapsaicin-research/24953906.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717", "start_char": 0, "end_char": 1870, "text_sha256": "8d11f6733abf59c36bf8e2b6ed6f44f759cab3fdd209ff3c84c21b20e178a717"} [dhc-p24953906] Vanilloid-like agents inhibit aggregation of human platelets. (2014). https://pubmed.ncbi.nlm.nih.gov/24953906/ DOI: 10.1016/j.thromres.2014.05.038

cross_nutrient

false

experimental_model

Primary human PMNL and recombinant enzyme, Table 1

exposure

10 min compound pretreatment at 37°C; PMNL in PBS pH 7.4, 1 mg/mL glucose and 1 mM CaCl2, stimulated with 2.5 µM A23187 and/or 20 µM arachidonic acid for 10 min; IC50 80 nM.

limitations

Potency cannot be equated with oral vitamin E dosing. The activated leukocyte IC50 differs greatly from parent alpha-tocopherol and from other laboratories’ assay results.

nutrient_topic

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

organism

Homo sapiens

plain_language

The alpha-tocopherol metabolite reduced leukotriene-pathway enzyme output in isolated human immune cells.

primary_references

[pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5

tissue_or_cell_type

Isolated blood polymorphonuclear leukocytes and cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1011–1022

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Primary human PMNL and recombinant enzyme, Table 1 · source_derived_draft · unverified_draft

### e-sig-alpha-acid-leukocyte-lox Alpha-tocopherol-13′-carboxychromanol inhibited 5-LO product formation in activated human polymorphonuclear leukocytes with an IC50 of approximately 0.08 µM, compared with 0.27 µM for isolated recombinant human 5-LO. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The alpha-tocopherol metabolite reduced leukotriene-pathway enzyme output in isolated human immune cells. organism: Homo sapiens tissue_or_cell_type: Isolated blood polymorphonuclear leukocytes and cell-free enzyme experimental_model: Primary human PMNL and recombinant enzyme, Table 1 limitations: Potency cannot be equated with oral vitamin E dosing. The activated leukocyte IC50 differs greatly from parent alpha-tocopherol and from other laboratories’ assay results. exposure: 10 min compound pretreatment at 37°C; PMNL in PBS pH 7.4, 1 mg/mL glucose and 1 mM CaCl2, stimulated with 2.5 µM A23187 and/or 20 µM arachidonic acid for 10 min; IC50 80 nM. cross_nutrient: false [pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5

cross_nutrient

false

experimental_model

A549 culture and preinduced cellular COX assay

exposure

IL-1β 10 ng/mL for 24 h; postinduction gamma-CEHC 1 h, then 5 or 15 µM arachidonic acid for 10 min at 37°C.

limitations

Cancer-derived culture, not treatment evidence. Intact-cell IC50 and purified COX inhibition are distinct measurements; increasing substrate weakened inhibition.

nutrient_topic

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

organism

Homo sapiens

plain_language

A breakdown product of gamma-tocopherol reduced prostaglandin production in a human lung cell model, including after brief exposure.

primary_references

[jiang2000] gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. (2000). https://pubmed.ncbi.nlm.nih.gov/11005841/ DOI: 10.1073/pnas.200357097

tissue_or_cell_type

Lung epithelial carcinoma cell line

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 842–853

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · A549 culture and preinduced cellular COX assay · source_derived_draft · unverified_draft

### e-sig-cehc-a549-pge2 Gamma-CEHC suppressed cytokine-stimulated PGE2 in A549 cells, with an apparent IC50 near 30 µM. It also inhibited PGE2 after only 1 h exposure of COX-2-preinduced cells before arachidonic acid addition. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: A breakdown product of gamma-tocopherol reduced prostaglandin production in a human lung cell model, including after brief exposure. organism: Homo sapiens tissue_or_cell_type: Lung epithelial carcinoma cell line experimental_model: A549 culture and preinduced cellular COX assay limitations: Cancer-derived culture, not treatment evidence. Intact-cell IC50 and purified COX inhibition are distinct measurements; increasing substrate weakened inhibition. exposure: IL-1β 10 ng/mL for 24 h; postinduction gamma-CEHC 1 h, then 5 or 15 µM arachidonic acid for 10 min at 37°C. cross_nutrient: false [jiang2000] gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. (2000). https://pubmed.ncbi.nlm.nih.gov/11005841/ DOI: 10.1073/pnas.200357097

cross_nutrient

false

experimental_model

Human recombinant 5-LOX oxygen-electrode initial-rate kinetics

exposure

10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM.

limitations

Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts.

nutrient_topic

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

organism

Homo sapiens

plain_language

Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase.

primary_references

[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1050–1061

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant 5-LOX oxygen-electrode initial-rate kinetics · source_derived_draft · unverified_draft

### e-sig-delta-acid-competitive Park and colleagues classified Delta-tocopherol-13′-carboxychromanol as a competitive inhibitor of human recombinant 5-LOX, with Ki 1.6 µM; oxygen-consumption kinetics showed increased apparent substrate requirement without an apparent decrease in Vmax. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Human recombinant 5-LOX oxygen-electrode initial-rate kinetics limitations: Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts. exposure: 10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM. cross_nutrient: false [park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

cross_nutrient

false

experimental_model

Purified-enzyme oxygen-electrode kinetics

exposure

13′-COOH 0, 7.5, 15 or 25 µM; arachidonic acid 6–200 µM in Tris pH 8 with 1 µM hematin, phenol and EDTA.

limitations

Purified enzyme kinetics do not establish human anti-inflammatory benefit. Cyclooxygenase and peroxidase activities must not be conflated.

nutrient_topic

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

organism

Ovis aries

plain_language

The long-chain delta-tocopherol metabolite interfered with this purified enzyme’s use of arachidonic acid.

primary_references

[jiang2008] Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. (2008). https://pubmed.ncbi.nlm.nih.gov/19074288/ DOI: 10.1073/pnas.0810962106

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 855–866

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

### e-sig-delta-acid-cox1 Delta-tocopherol-13′-carboxychromanol competitively inhibited purified ovine COX-1 cyclooxygenase activity with a reported Ki of 3.9 µM, measured by initial oxygen consumption while varying arachidonic acid. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The long-chain delta-tocopherol metabolite interfered with this purified enzyme’s use of arachidonic acid. organism: Ovis aries tissue_or_cell_type: Cell-free enzyme experimental_model: Purified-enzyme oxygen-electrode kinetics limitations: Purified enzyme kinetics do not establish human anti-inflammatory benefit. Cyclooxygenase and peroxidase activities must not be conflated. exposure: 13′-COOH 0, 7.5, 15 or 25 µM; arachidonic acid 6–200 µM in Tris pH 8 with 1 µM hematin, phenol and EDTA. cross_nutrient: false [jiang2008] Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. (2008). https://pubmed.ncbi.nlm.nih.gov/19074288/ DOI: 10.1073/pnas.0810962106

cross_nutrient

false

experimental_model

Purified-enzyme oxygen-electrode kinetics

exposure

13′-COOH 0, 7.5, 15 or 25 µM; arachidonic acid 6–200 µM in Tris pH 8 with 1 µM hematin, phenol and EDTA.

limitations

Purified enzyme kinetics do not establish human anti-inflammatory benefit. Cyclooxygenase and peroxidase activities must not be conflated.

nutrient_topic

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

organism

Homo sapiens

plain_language

The long-chain delta-tocopherol metabolite interfered with this purified enzyme’s use of arachidonic acid.

primary_references

[jiang2008] Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. (2008). https://pubmed.ncbi.nlm.nih.gov/19074288/ DOI: 10.1073/pnas.0810962106

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 868–879

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

### e-sig-delta-acid-cox2 Delta-tocopherol-13′-carboxychromanol competitively inhibited purified human COX-2 cyclooxygenase activity with a reported Ki of 10.7 µM, measured by initial oxygen consumption while varying arachidonic acid. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The long-chain delta-tocopherol metabolite interfered with this purified enzyme’s use of arachidonic acid. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Purified-enzyme oxygen-electrode kinetics limitations: Purified enzyme kinetics do not establish human anti-inflammatory benefit. Cyclooxygenase and peroxidase activities must not be conflated. exposure: 13′-COOH 0, 7.5, 15 or 25 µM; arachidonic acid 6–200 µM in Tris pH 8 with 1 µM hematin, phenol and EDTA. cross_nutrient: false [jiang2008] Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. (2008). https://pubmed.ncbi.nlm.nih.gov/19074288/ DOI: 10.1073/pnas.0810962106

cross_nutrient

false

experimental_model

Human recombinant 5-LOX and FOX endpoint

exposure

4 min preincubation; arachidonic acid 75 µM; FOX absorbance at 560 and 575 nm.

limitations

FOX reports oxidation products, not binding-site structure. Potency depends on assay conditions; later papers use other assays.

nutrient_topic

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

organism

Homo sapiens

plain_language

The long-chain metabolite inhibited the isolated leukotriene-producing enzyme much more strongly than the parent tocopherols in this assay.

primary_references

[jiang2011] Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. (2011). https://pubmed.ncbi.nlm.nih.gov/21169551/ DOI: 10.4049/jimmunol.1002342

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 920–931

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant 5-LOX and FOX endpoint · source_derived_draft · unverified_draft

### e-sig-delta-acid-lox Delta-tocopherol-13′-carboxychromanol inhibited human recombinant 5-LOX with IC50 0.5–1 µM in a hydroperoxide-sensitive FOX assay; parent alpha-, gamma- and delta-tocopherols did not inhibit at 50 µM. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The long-chain metabolite inhibited the isolated leukotriene-producing enzyme much more strongly than the parent tocopherols in this assay. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Human recombinant 5-LOX and FOX endpoint limitations: FOX reports oxidation products, not binding-site structure. Potency depends on assay conditions; later papers use other assays. exposure: 4 min preincubation; arachidonic acid 75 µM; FOX absorbance at 560 and 575 nm. cross_nutrient: false [jiang2011] Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. (2011). https://pubmed.ncbi.nlm.nih.gov/21169551/ DOI: 10.4049/jimmunol.1002342

cross_nutrient

false

experimental_model

Washed rat platelet stimulation and TXB2 enzyme immunoassay

exposure

25 min compound preincubation at 37°C; 1–2 µM A23187 with 1–2 mM CaCl2 for 10 min.

limitations

TXB2 is a stable surrogate for TXA2 production; neither clinical bleeding nor platelet aggregation was measured in this endpoint. Isolated rat platelets do not establish human antithrombotic benefit.

nutrient_topic

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

organism

Rattus norvegicus

plain_language

The metabolite reduced a measured marker of thromboxane production in isolated rat platelets.

primary_references

[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

tissue_or_cell_type

Isolated blood platelets

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1076–1087

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Washed rat platelet stimulation and TXB2 enzyme immunoassay · source_derived_draft · unverified_draft

### e-sig-delta-acid-platelet-txb2 Delta-tocopherol-13′-carboxychromanol reduced A23187-stimulated TXB2 output from washed rat platelets, with the metabolite experiments reporting IC50 values in the 1.5–2.5 µM range. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The metabolite reduced a measured marker of thromboxane production in isolated rat platelets. organism: Rattus norvegicus tissue_or_cell_type: Isolated blood platelets experimental_model: Washed rat platelet stimulation and TXB2 enzyme immunoassay limitations: TXB2 is a stable surrogate for TXA2 production; neither clinical bleeding nor platelet aggregation was measured in this endpoint. Isolated rat platelets do not establish human antithrombotic benefit. exposure: 25 min compound preincubation at 37°C; 1–2 µM A23187 with 1–2 mM CaCl2 for 10 min. cross_nutrient: false [park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

cross_nutrient

false

experimental_model

DMSO-differentiated human HL-60 neutrophil-like cells

exposure

10 min pretreatment; S1P 50 µM, LPA 100 µM or fMLP 1 µM for 10 min.

limitations

Stimulus specificity precludes a universal anti-inflammatory claim. High-dose lipid stimuli and transformed cells limit extrapolation.

nutrient_topic

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

organism

Homo sapiens

plain_language

Delta-tocopherol reduced leukotriene output only for some ways of activating these cells.

primary_references

[jiang2011] Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. (2011). https://pubmed.ncbi.nlm.nih.gov/21169551/ DOI: 10.4049/jimmunol.1002342

tissue_or_cell_type

Neutrophil-like leukemia-derived cell culture

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 881–892

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · DMSO-differentiated human HL-60 neutrophil-like cells · source_derived_draft · unverified_draft

### e-sig-delta-ltb4-stimulus Delta-tocopherol at 50 µM inhibited LTB4 production stimulated by S1P or LPA in differentiated HL-60 cells, but did not inhibit the response to fMLP under the tested conditions. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Delta-tocopherol reduced leukotriene output only for some ways of activating these cells. organism: Homo sapiens tissue_or_cell_type: Neutrophil-like leukemia-derived cell culture experimental_model: DMSO-differentiated human HL-60 neutrophil-like cells limitations: Stimulus specificity precludes a universal anti-inflammatory claim. High-dose lipid stimuli and transformed cells limit extrapolation. exposure: 10 min pretreatment; S1P 50 µM, LPA 100 µM or fMLP 1 µM for 10 min. cross_nutrient: false [jiang2011] Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. (2011). https://pubmed.ncbi.nlm.nih.gov/21169551/ DOI: 10.4049/jimmunol.1002342

cross_nutrient

false

experimental_model

Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down

exposure

Purified 5-LO 0.5 µg in PBS pH 7.4, EDTA 1 mM and ATP 1 mM; 10 min compound preincubation at 4°C, then 5–80 µM arachidonic acid and 2 mM CaCl2 at 37°C. Reported IC50 35–40 nM; pull-down competitor arachidonic acid 100 µM.

limitations

Binding-site assignment combines biochemical evidence with docking and mutagenesis, not a solved inhibitor-bound structure. Park 2022 explicitly disputes the noncompetitive interpretation.

nutrient_topic

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

organism

Homo sapiens

plain_language

One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site.

primary_references

[pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1024–1035

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down · source_derived_draft · unverified_draft

### e-sig-delta-te-acid-allosteric Pein and colleagues interpreted delta-tocotrienol-13′-carboxychromanol inhibition of human 5-LO as reversible and allosteric: activity inhibition persisted when arachidonic acid was varied, and immobilized metabolite captured the enzyme despite excess arachidonic acid. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: One study concluded that this tocotrienol metabolite inhibits 5-lipoxygenase at a site distinct from the usual fatty-acid binding site. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Purified human 5-LO; substrate variation, dilution and immobilized-ligand pull-down limitations: Binding-site assignment combines biochemical evidence with docking and mutagenesis, not a solved inhibitor-bound structure. Park 2022 explicitly disputes the noncompetitive interpretation. exposure: Purified 5-LO 0.5 µg in PBS pH 7.4, EDTA 1 mM and ATP 1 mM; 10 min compound preincubation at 4°C, then 5–80 µM arachidonic acid and 2 mM CaCl2 at 37°C. Reported IC50 35–40 nM; pull-down competitor arachidonic acid 100 µM. cross_nutrient: false [pein2018] Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. (2018). https://pubmed.ncbi.nlm.nih.gov/30237488/ DOI: 10.1038/s41467-018-06158-5

cross_nutrient

false

experimental_model

Human recombinant 5-LOX oxygen-electrode initial-rate kinetics

exposure

10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM.

limitations

Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts.

nutrient_topic

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

organism

Homo sapiens

plain_language

Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase.

primary_references

[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1037–1048

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant 5-LOX oxygen-electrode initial-rate kinetics · source_derived_draft · unverified_draft

### e-sig-delta-te-acid-competitive Park and colleagues classified Delta-tocotrienol-13′-carboxychromanol as a competitive inhibitor of human recombinant 5-LOX, with Ki 0.8 µM; oxygen-consumption kinetics showed increased apparent substrate requirement without an apparent decrease in Vmax. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Human recombinant 5-LOX oxygen-electrode initial-rate kinetics limitations: Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts. exposure: 10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM. cross_nutrient: false [park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

cross_nutrient

false

experimental_model

Human recombinant 5-LOX oxygen-electrode initial-rate kinetics

exposure

10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM.

limitations

Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts.

nutrient_topic

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

organism

Homo sapiens

plain_language

Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase.

primary_references

[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1063–1074

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant 5-LOX oxygen-electrode initial-rate kinetics · source_derived_draft · unverified_draft

### e-sig-delta-te-competitive Park and colleagues classified Delta-tocotrienol as a competitive inhibitor of human recombinant 5-LOX, with Ki 2.2 µM; oxygen-consumption kinetics showed increased apparent substrate requirement without an apparent decrease in Vmax. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Kinetic measurements in this study indicated competition between this compound and arachidonic acid at 5-lipoxygenase. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Human recombinant 5-LOX oxygen-electrode initial-rate kinetics limitations: Kinetic classification is not a solved binding structure. The delta-tocotrienol metabolite result conflicts with Pein’s allosteric interpretation; differing IC50 values alone are not treated as conflicts. exposure: 10 min inhibitor preincubation; arachidonic acid 5–50 µM in 50 mM Tris pH 7.4 and 0.4 mM CaCl2; reported substrate Km 2.1 µM. cross_nutrient: false [park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

cross_nutrient

false

experimental_model

Recombinant human COX enzyme assay; PGF2alpha readout after chemical reduction

exposure

10 min compound preincubation; arachidonic acid 5 µM for 2 min; stannous chloride converted PG intermediates to PGF2alpha for ELISA.

limitations

This assay differs from older ovine COX-1/oxygen-electrode work; species and substrate differences preclude labeling every potency discrepancy as a contradiction.

nutrient_topic

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

organism

Homo sapiens

plain_language

Gamma-tocopherol reduced activity of purified human COX-1 under these assay conditions.

primary_references

[park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

tissue_or_cell_type

Cell-free enzyme

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 1089–1100

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human COX enzyme assay; PGF2alpha readout after chemical reduction · source_derived_draft · unverified_draft

### e-sig-gamma-human-cox1 Gamma-tocopherol inhibited human recombinant COX-1 in a prostaglandin-product assay, with the tested non-alpha vitamin E forms showing IC50 values of 1–2.5 µM. Parent vitamin E forms did not significantly inhibit COX-2 in the same system. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gamma-tocopherol reduced activity of purified human COX-1 under these assay conditions. organism: Homo sapiens tissue_or_cell_type: Cell-free enzyme experimental_model: Recombinant human COX enzyme assay; PGF2alpha readout after chemical reduction limitations: This assay differs from older ovine COX-1/oxygen-electrode work; species and substrate differences preclude labeling every potency discrepancy as a contradiction. exposure: 10 min compound preincubation; arachidonic acid 5 µM for 2 min; stannous chloride converted PG intermediates to PGF2alpha for ELISA. cross_nutrient: false [park2022] Different forms of vitamin E and metabolite 13'-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase. (2022). https://pubmed.ncbi.nlm.nih.gov/34710615/ DOI: 10.1016/j.jnutbio.2021.108884

cross_nutrient

false

experimental_model

Stimulated RAW264.7 culture; PGE2 assay and immunoblot

exposure

8–14 h tocopherol pretreatment in 0.5% FBS-DMEM, then 0.1 µg/mL LPS for 14 h.

limitations

A cellular product endpoint does not establish direct parent-vitamin binding to COX-2, exclude metabolism, or predict human supplement benefit.

nutrient_topic

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

organism

Mus musculus

plain_language

Gamma-tocopherol lowered this inflammatory lipid signal in cultured mouse immune cells without reducing the measured amount of COX-2 protein.

primary_references

[jiang2000] gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. (2000). https://pubmed.ncbi.nlm.nih.gov/11005841/ DOI: 10.1073/pnas.200357097

tissue_or_cell_type

Macrophage cell line

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 829–840

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stimulated RAW264.7 culture; PGE2 assay and immunoblot · source_derived_draft · unverified_draft

### e-sig-gamma-macrophage-pge2 Gamma-tocopherol reduced LPS-stimulated PGE2 in mouse RAW264.7 macrophages with an apparent IC50 of 7.5 µM. COX-2 protein expression was not reduced in the tested 10 and 40 µM groups. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gamma-tocopherol lowered this inflammatory lipid signal in cultured mouse immune cells without reducing the measured amount of COX-2 protein. organism: Mus musculus tissue_or_cell_type: Macrophage cell line experimental_model: Stimulated RAW264.7 culture; PGE2 assay and immunoblot limitations: A cellular product endpoint does not establish direct parent-vitamin binding to COX-2, exclude metabolism, or predict human supplement benefit. exposure: 8–14 h tocopherol pretreatment in 0.5% FBS-DMEM, then 0.1 µg/mL LPS for 14 h. cross_nutrient: false [jiang2000] gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. (2000). https://pubmed.ncbi.nlm.nih.gov/11005841/ DOI: 10.1073/pnas.200357097

evidence_access

Primary abstract

experimental_model

Human endothelial radiotracer experiment.

limitations

Does not show that extra choline reproduces the effect.

nutrient_topic

CLA collection; isomer, preparation, species, exposure and manipulation remain explicit. · Conjugated linoleic acid / CLA isomer family

plain_language

A fatty acid was redistributed between membrane lipid pools.

primary_references

The effect of conjugated linoleic acid on arachidonic acid metabolism and eicosanoid production in human saphenous vein endothelial cells. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11880240/ · DOI 10.1016/s1388-1981(01)00198-6

Conjugated linoleic acid: isomers, signaling, nutrient interactions and discovery (2026-09-19) · lines 302–308

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human endothelial radiotracer experiment. · source_derived_draft · unverified_draft

## cla-aa-pc A fatty acid was redistributed between membrane lipid pools. c9,t11 increased arachidonate incorporation into phosphatidylcholine despite lower overall incorporation into membrane phospholipids. Model: Human endothelial radiotracer experiment. Limitations: Does not show that extra choline reproduces the effect. Evidence access: Primary abstract The effect of conjugated linoleic acid on arachidonic acid metabolism and eicosanoid production in human saphenous vein endothelial cells. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11880240/ · DOI 10.1016/s1388-1981(01)00198-6

evidence_access

Primary abstract

experimental_model

Human saphenous-vein endothelial cells with calcium-ionophore stimulation.

limitations

Lower-concentration results differed; no universal anti-inflammatory label.

nutrient_topic

CLA collection; isomer, preparation, species, exposure and manipulation remain explicit. · Conjugated linoleic acid / CLA isomer family

plain_language

Isomer and concentration changed the direction of the response.

primary_references

The effect of conjugated linoleic acid on arachidonic acid metabolism and eicosanoid production in human saphenous vein endothelial cells. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11880240/ · DOI 10.1016/s1388-1981(01)00198-6

Conjugated linoleic acid: isomers, signaling, nutrient interactions and discovery (2026-09-19) · lines 294–300

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human saphenous-vein endothelial cells with calcium-ionophore stimulation. · source_derived_draft · unverified_draft

## cla-endothelium-c9 Isomer and concentration changed the direction of the response. At 100 micromolar, c9,t11 inhibited endothelial eicosanoid production, whereas t10,c12 stimulated it. Model: Human saphenous-vein endothelial cells with calcium-ionophore stimulation. Limitations: Lower-concentration results differed; no universal anti-inflammatory label. Evidence access: Primary abstract The effect of conjugated linoleic acid on arachidonic acid metabolism and eicosanoid production in human saphenous vein endothelial cells. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11880240/ · DOI 10.1016/s1388-1981(01)00198-6

evidence_access

Primary abstract

experimental_model

Human platelet preparation.

limitations

Reversible, timing-dependent effects; no clinical antithrombotic benefit or drug interaction quantified.

nutrient_topic

CLA collection; isomer, preparation, species, exposure and manipulation remain explicit. · Conjugated linoleic acid / CLA isomer family

plain_language

Platelet activation changed in a laboratory assay.

primary_references

Antiplatelet effects of conjugated linoleic acid isomers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10320806/ · DOI 10.1016/s1388-1981(99)00055-4

Conjugated linoleic acid: isomers, signaling, nutrient interactions and discovery (2026-09-19) · lines 270–276

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human platelet preparation. · source_derived_draft · unverified_draft

## cla-platelets-c9 Platelet activation changed in a laboratory assay. The isomer inhibited arachidonic-acid- and collagen-induced platelet aggregation in the 5–7 micromolar I50 range. Model: Human platelet preparation. Limitations: Reversible, timing-dependent effects; no clinical antithrombotic benefit or drug interaction quantified. Evidence access: Primary abstract Antiplatelet effects of conjugated linoleic acid isomers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10320806/ · DOI 10.1016/s1388-1981(99)00055-4

evidence_access

Primary abstract

experimental_model

Human platelet preparation.

limitations

Reversible, timing-dependent effects; no clinical antithrombotic benefit or drug interaction quantified.

nutrient_topic

CLA collection; isomer, preparation, species, exposure and manipulation remain explicit. · Conjugated linoleic acid / CLA isomer family

plain_language

Platelet activation changed in a laboratory assay.

primary_references

Antiplatelet effects of conjugated linoleic acid isomers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10320806/ · DOI 10.1016/s1388-1981(99)00055-4

Conjugated linoleic acid: isomers, signaling, nutrient interactions and discovery (2026-09-19) · lines 278–284

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human platelet preparation. · source_derived_draft · unverified_draft

## cla-platelets-t10 Platelet activation changed in a laboratory assay. The isomer inhibited arachidonic-acid- and collagen-induced platelet aggregation in the 5–7 micromolar I50 range. Model: Human platelet preparation. Limitations: Reversible, timing-dependent effects; no clinical antithrombotic benefit or drug interaction quantified. Evidence access: Primary abstract Antiplatelet effects of conjugated linoleic acid isomers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10320806/ · DOI 10.1016/s1388-1981(99)00055-4

evidence_access

Primary abstract

experimental_model

Human platelet radiotracer assay.

limitations

TXB2 is the measured readout of TXA2 formation.

nutrient_topic

CLA collection; isomer, preparation, species, exposure and manipulation remain explicit. · Conjugated linoleic acid / CLA isomer family

plain_language

Two branches from the same fatty acid responded differently.

primary_references

Antiplatelet effects of conjugated linoleic acid isomers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10320806/ · DOI 10.1016/s1388-1981(99)00055-4

Conjugated linoleic acid: isomers, signaling, nutrient interactions and discovery (2026-09-19) · lines 286–292

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human platelet radiotracer assay. · source_derived_draft · unverified_draft

## cla-txb2 Two branches from the same fatty acid responded differently. The mixture and individual isomers reduced arachidonate-derived TXB2 formation, while platelet 12-HETE formation was not inhibited. Model: Human platelet radiotracer assay. Limitations: TXB2 is the measured readout of TXA2 formation. Evidence access: Primary abstract Antiplatelet effects of conjugated linoleic acid isomers. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10320806/ · DOI 10.1016/s1388-1981(99)00055-4

evidence_span

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experimental_model

Human cyclooxygenase-1 and -2 expressed in cos-1 cells treated with aspirin and with carbon-14 labelled aspirin, with a mutant series at Ser-516

exposure

Aspirin acetylation, with S516A, S516N, S516Q and S516M substitutions

limitations

Identifies the site by direct labelling and explains the isoform difference by active site volume. Recombinant enzyme in a heterologous cell line.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human enzyme

plain_language

Acetylating the second enzyme does not switch it off; it turns it into a machine that makes something else.

primary_references

[asa-p8175750] Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. (1994). https://pubmed.ncbi.nlm.nih.gov/8175750/ DOI: 10.1016/s0021-9258(17)36820-5

tissue_or_cell_type

Recombinant cyclooxygenase

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 208–219

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cyclooxygenase-1 and -2 expressed in cos-1 cells treated with aspirin and with carbon-14 labelled aspirin, with a mutant series at Ser-516 · source_derived_draft · unverified_draft

### asa-cox2-becomes-a-lipoxygenase Aspirin treatment of human cyclooxygenase-1 caused time-dependent inactivation of oxygenase activity, whereas aspirin treatment of cyclooxygenase-2 produced an enzyme which retained oxygenase activity but formed exclusively 15-hydroxyeicosatetraenoic acid instead of prostaglandin H2, exclusively of the 15R configuration, with Km values for arachidonate of native and aspirin-treated cyclooxygenase-2 about the same, suggesting arachidonate binds to both in a similar manner. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: Acetylating the second enzyme does not switch it off; it turns it into a machine that makes something else. organism: Human enzyme tissue_or_cell_type: Recombinant cyclooxygenase experimental_model: Human cyclooxygenase-1 and -2 expressed in cos-1 cells treated with aspirin and with carbon-14 labelled aspirin, with a mutant series at Ser-516 limitations: Identifies the site by direct labelling and explains the isoform difference by active site volume. Recombinant enzyme in a heterologous cell line. exposure: Aspirin acetylation, with S516A, S516N, S516Q and S516M substitutions evidence_span: {"source_cache": "artifacts/aspirin-research/8175750.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ba85af90c62b157cf53032375ca703e8b78eff6ddd22ad627bbd7e65965d8e9", "start_char": 0, "end_char": 1786, "text_sha256": "9ba85af90c62b157cf53032375ca703e8b78eff6ddd22ad627bbd7e65965d8e9"} [asa-p8175750] Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. (1994). https://pubmed.ncbi.nlm.nih.gov/8175750/ DOI: 10.1016/s0021-9258(17)36820-5

evidence_span

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experimental_model

Radiolabelled substrate and LC-MS analysis of aspirin-acetylated COX-2 products, with human leukocytes and platelet aggregation assays

exposure

Aspirin acetylation, with lipopolysaccharide-induced cyclooxygenase-2 in leukocytes and a thromboxane receptor agonist on platelets

limitations

Shows the acetylated enzyme keeps more of its original chemistry than the HETE story implies, and links the product to a measured platelet effect. Isolated cells rather than treated people.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human

plain_language

The rerouted enzyme has not stopped making prostaglandins; it makes mirror-image ones, more slowly.

primary_references

[asa-p30096040] Residual cyclooxygenase activity of aspirin-acetylated COX-2 forms 15 R-prostaglandins that inhibit platelet aggregation. (2019). https://pubmed.ncbi.nlm.nih.gov/30096040/ DOI: 10.1096/fj.201801018r

tissue_or_cell_type

Recombinant enzyme and isolated leukocytes and platelets

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 286–297

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabelled substrate and LC-MS analysis of aspirin-acetylated COX-2 products, with human leukocytes and platelet aggregation assays · source_derived_draft · unverified_draft

### asa-it-still-makes-prostaglandins Acetylated cyclooxygenase-2 also retains cyclooxygenase activity forming predominantly 15R-configuration prostaglandins, 70% or 62% 15R by radiolabelled substrate or LC-MS respectively, and although the Km of arachidonic acid for the acetylated enzyme was about threefold lower than for uninhibited enzyme the catalytic efficiency for prostaglandin formation was reduced tenfold through a decrease in Vmax. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The rerouted enzyme has not stopped making prostaglandins; it makes mirror-image ones, more slowly. organism: Human tissue_or_cell_type: Recombinant enzyme and isolated leukocytes and platelets experimental_model: Radiolabelled substrate and LC-MS analysis of aspirin-acetylated COX-2 products, with human leukocytes and platelet aggregation assays limitations: Shows the acetylated enzyme keeps more of its original chemistry than the HETE story implies, and links the product to a measured platelet effect. Isolated cells rather than treated people. exposure: Aspirin acetylation, with lipopolysaccharide-induced cyclooxygenase-2 in leukocytes and a thromboxane receptor agonist on platelets evidence_span: {"source_cache": "artifacts/aspirin-research/30096040.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2bd9c817ec4fe31752028634955f604eb00829efc93a72d5fc7e22be7f5739b8", "start_char": 0, "end_char": 1666, "text_sha256": "2bd9c817ec4fe31752028634955f604eb00829efc93a72d5fc7e22be7f5739b8"} [asa-p30096040] Residual cyclooxygenase activity of aspirin-acetylated COX-2 forms 15 R-prostaglandins that inhibit platelet aggregation. (2019). https://pubmed.ncbi.nlm.nih.gov/30096040/ DOI: 10.1096/fj.201801018r

evidence_span

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experimental_model

Review of arachidonate metabolism in airway hyperreactivity and aspirin-induced asthma

exposure

Cyclooxygenase inhibition and the proposed diversion of arachidonate into the lipoxygenase pathway

limitations

A review from 1981 setting out the shunting hypothesis. It is recorded as the proposal that later work tested, not as evidence that the proposal is right.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Human

plain_language

The standard explanation: block one pathway and the raw material spills into another that makes bronchoconstrictors.

primary_references

[asa-p6113615] Lipoxygenase pathway and hydroperoxy acids: possible relevance to aspirin-induced asthma and hyperirritability of airways in asthmatics. (1981). https://pubmed.ncbi.nlm.nih.gov/6113615/ DOI: 10.1016/0161-4630(81)90097-5

tissue_or_cell_type

Airway

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 546–557

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of arachidonate metabolism in airway hyperreactivity and aspirin-induced asthma · source_derived_draft · unverified_draft

### asa-shunting-proposed The adverse effect of aspirin in asthmatics is often attributed to inhibition of the synthesis and release of defensive modulatory endogenous prostaglandins in the lungs, removing their negative feedback on allergic mediator release, and in addition work suggests diversion of arachidonic acid metabolism via the lipoxygenase pathway after cyclooxygenase inhibition, leading to formation of hydroperoxy acids and leukotrienes whose accumulation in sensitive individuals could explain the mechanism of aspirin-induced asthma. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The standard explanation: block one pathway and the raw material spills into another that makes bronchoconstrictors. organism: Human tissue_or_cell_type: Airway experimental_model: Review of arachidonate metabolism in airway hyperreactivity and aspirin-induced asthma limitations: A review from 1981 setting out the shunting hypothesis. It is recorded as the proposal that later work tested, not as evidence that the proposal is right. exposure: Cyclooxygenase inhibition and the proposed diversion of arachidonate into the lipoxygenase pathway evidence_span: {"source_cache": "artifacts/aspirin-research/6113615.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "184fc232146a3837f396109d951c9755155f181c524a3ffaa330645138d8a616", "start_char": 0, "end_char": 2083, "text_sha256": "184fc232146a3837f396109d951c9755155f181c524a3ffaa330645138d8a616"} [asa-p6113615] Lipoxygenase pathway and hydroperoxy acids: possible relevance to aspirin-induced asthma and hyperirritability of airways in asthmatics. (1981). https://pubmed.ncbi.nlm.nih.gov/6113615/ DOI: 10.1016/0161-4630(81)90097-5

evidence_span

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experimental_model

Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs

exposure

Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors

limitations

Quantifies how efficient the new activity is, which most descriptions of the switch do not. Purified and recombinant enzyme rather than intact cells.

nutrient_topic

Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. · Aspirin / acetylsalicylic acid

organism

Enzyme

plain_language

The rerouted enzyme works well enough that arachidonate does not pile up and spill into other pathways.

primary_references

[asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. (1997). https://pubmed.ncbi.nlm.nih.gov/9016346/ DOI: 10.1124/mol.51.1.52

tissue_or_cell_type

Cyclooxygenase-2

Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22) · lines 260–271

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs · source_derived_draft · unverified_draft

### asa-the-new-activity-is-efficient Both the S516M mutant and the aspirin-acetylated form of cyclooxygenase-2 synthesise 15(R)-HETE with apparent Km values for arachidonic acid within tenfold of untreated enzyme and with similar time courses of turnover-dependent inactivation, and the conversion of arachidonic acid to 15-HETE by acetylated cyclooxygenase-2 is an efficient process providing a unique mechanism among non-steroidal anti-inflammatory drugs that will not lead to arachidonic acid accumulation or shunting to other biosynthetic pathways. Condition category: normal nutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes. plain_language: The rerouted enzyme works well enough that arachidonate does not pile up and spill into other pathways. organism: Enzyme tissue_or_cell_type: Cyclooxygenase-2 experimental_model: Kinetic characterisation of aspirin-acetylated cyclooxygenase-2 and the S516M mutant against a panel of non-steroidal anti-inflammatory drugs limitations: Quantifies how efficient the new activity is, which most descriptions of the switch do not. Purified and recombinant enzyme rather than intact cells. exposure: Aspirin acetylation and the methionine mutant, tested with indomethacin, diclofenac, meclofenamic acid and selective inhibitors evidence_span: {"source_cache": "artifacts/aspirin-research/9016346.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b", "start_char": 0, "end_char": 1899, "text_sha256": "2cc2efefceabbee7bb4f1052db8fc86ee218409fe56981cf92b707c7b0ef531b"} [asa-p9016346] Altered sensitivity of aspirin-acetylated prostaglandin G/H synthase-2 to inhibition by nonsteroidal anti-inflammatory drugs. (1997). https://pubmed.ncbi.nlm.nih.gov/9016346/ DOI: 10.1124/mol.51.1.52

cell_type

Experimental cell models

experimental_model

Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics

limitations

Not proof of ACSL4 dependence in every ferroptosis model.

organism

Mus musculus

Selenium: literature corrections and mechanism additions · lines 1215–1225

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics · secondary_verified · secondary_verified

## acsl4-activation ACSL4 prepares the fatty acid for membrane incorporation. ACSL4 activates arachidonic acid to arachidonoyl-CoA upstream of phospholipid incorporation. Organism: Mus musculus Cell type: Experimental cell models Experimental model: Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics Limitations: Not proof of ACSL4 dependence in every ferroptosis model. Primary reference: [Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis](https://pubmed.ncbi.nlm.nih.gov/27842066/)