Prostaglandin E2

evidence_access

Primary full text

experimental_model

Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation.

limitations

Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. This is not a demonstrated direct COX-2 catalytic inhibitor.

nutrient_topic

Fulvic acid collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Fulvic acid (heterogeneous humic fraction)

plain_language

The downstream prostaglandin output also fell.

primary_references

Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

Fulvic acid: mixture identity, mineral chemistry, signaling and cross-nutrient mechanisms (2026-09-19) · lines 68–74

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. · source_derived_draft · unverified_draft

## fulvic-acid-pge-output The downstream prostaglandin output also fell. Fulvic pretreatment reduced PGE2 release after homocysteine stimulation. Model: Human primary monocytes and U937 cells; Esther 20% stock diluted to 0.5-10 micrograms/mL, 4-hour pretreatment; homocysteine stimulation. Limitations: Cell exposure does not establish oral exposure, homocysteine removal or cardiovascular benefit. Results text reports homocysteine 200 micromolar, while figure captions say 200 micrograms/mL; dose units are unresolved. Inhibitor concentrations also need original-record clarification. This is not a demonstrated direct COX-2 catalytic inhibitor. Evidence access: Primary full text Fulvic acid attenuates homocysteine-induced cyclooxygenase-2 expression in human monocytes. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25888188/ · DOI 10.1186/s12906-015-0583-x

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

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse bone-cell inhibitor experiments; the paper also reports PGE2 production.

limitations

Not proof that dietary arachidonic acid or a COX-2 drug changes fracture benefit in humans.

nutrient_topic

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

plain_language

Prostaglandin-producing machinery links the response to lipid signaling.

primary_references

Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. · 2009 · https://pubmed.ncbi.nlm.nih.gov/20141614/ · DOI 10.1111/j.1582-4934.2009.00673.x

trigger_kind

machinery_impairment Imported condition classification; unverified.

Strontium: calcium interactions, cellular mechanisms and mineralization (2026-09-19) · lines 110–116

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse bone-cell inhibitor experiments; the paper also reports PGE2 production. · source_derived_draft · unverified_draft

## strontium-cox2-dependence Prostaglandin-producing machinery links the response to lipid signaling. Selective COX-2 inhibition abolished the proliferative and anti-apoptotic strontium responses in wild-type and Casr-knockout osteoblasts. Model: Mouse bone-cell inhibitor experiments; the paper also reports PGE2 production. Limitations: Not proof that dietary arachidonic acid or a COX-2 drug changes fracture benefit in humans. Evidence access: Primary abstract Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate. · 2009 · https://pubmed.ncbi.nlm.nih.gov/20141614/ · DOI 10.1111/j.1582-4934.2009.00673.x

evidence_span

{"source_cache": "artifacts/ibuprofen-research/6595999.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cf73667739f04e5edcaf0e75c1f413cbda7abbfe84b8701b1aeaa347b67809c2", "start_char": 0, "end_char": 2422, "text_sha256": "cf73667739f04e5edcaf0e75c1f413cbda7abbfe84b8701b1aeaa347b67809c2"}

experimental_model

Review of renal cortical prostaglandin physiology with dog bile duct ligation and human volunteer data

exposure

Cyclooxygenase inhibition against a background of raised vasoconstrictor tone

limitations

A review assembling several models rather than one experiment. It states the conditional nature of the renal prostaglandin role, which is the point recorded here.

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

Rat, dog and human

plain_language

These prostaglandins are a reserve the kidney calls on under strain, which is why blocking them is harmless until it is not.

primary_references

[ibu-p6595999] Mechanisms of the nephrotoxicity of non-steroidal anti-inflammatory drugs. (1984). https://pubmed.ncbi.nlm.nih.gov/6595999/ DOI: 10.1007/978-3-642-69132-4_56

tissue_or_cell_type

Renal cortex and glomeruli

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 474–485

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of renal cortical prostaglandin physiology with dog bile duct ligation and human volunteer data · source_derived_draft · unverified_draft

### ibu-a-reserve-not-a-baseline Vasodilatory renal prostaglandins are relatively unimportant under normal circumstances but play a modulatory role after ischaemia or in the presence of increased concentrations of vasoconstrictor substances such as angiotensin II, vasopressin or norepinephrine, indomethacin potentiates the renal actions of angiotensin II in vivo particularly the reduction of renal blood flow and filtration rate, and in dogs after chronic bile duct ligation cyclooxygenase inhibition by indomethacin, ibuprofen, naproxen or sulindac sulfide produced a comparable 50% decrease in both renal blood flow and filtration rate. 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: These prostaglandins are a reserve the kidney calls on under strain, which is why blocking them is harmless until it is not. organism: Rat, dog and human tissue_or_cell_type: Renal cortex and glomeruli experimental_model: Review of renal cortical prostaglandin physiology with dog bile duct ligation and human volunteer data limitations: A review assembling several models rather than one experiment. It states the conditional nature of the renal prostaglandin role, which is the point recorded here. exposure: Cyclooxygenase inhibition against a background of raised vasoconstrictor tone evidence_span: {"source_cache": "artifacts/ibuprofen-research/6595999.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "cf73667739f04e5edcaf0e75c1f413cbda7abbfe84b8701b1aeaa347b67809c2", "start_char": 0, "end_char": 2422, "text_sha256": "cf73667739f04e5edcaf0e75c1f413cbda7abbfe84b8701b1aeaa347b67809c2"} [ibu-p6595999] Mechanisms of the nephrotoxicity of non-steroidal anti-inflammatory drugs. (1984). https://pubmed.ncbi.nlm.nih.gov/6595999/ DOI: 10.1007/978-3-642-69132-4_56

evidence_span

{"source_cache": "artifacts/ibuprofen-research/3303291.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8609926e51d2ad349198eb5f3ad78b6b552e8f4d4fc74d07bb3a58795a86e7a7", "start_char": 0, "end_char": 1757, "text_sha256": "8609926e51d2ad349198eb5f3ad78b6b552e8f4d4fc74d07bb3a58795a86e7a7"}

experimental_model

Review of gastroduodenal defence with isolated mucosal preparations

exposure

Acetylsalicylic acid, fenclofenac, ibuprofen and indomethacin on bicarbonate transport and glycoprotein synthesis

limitations

A review of mechanisms rather than an outcome study. The claim that E-series prostaglandins reverse the effect is what ties it to cyclooxygenase.

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

Human and animal

plain_language

The stomach’s own defences are built by prostaglandins, so blocking them removes the coat rather than adding an acid.

primary_references

[ibu-p3303291] Gastroduodenal mucosal defence mechanisms and the action of non-steroidal anti-inflammatory agents. (1987). https://pubmed.ncbi.nlm.nih.gov/3303291/ DOI: 10.3109/00365528709090947

tissue_or_cell_type

Gastric and duodenal mucosa

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 500–511

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of gastroduodenal defence with isolated mucosal preparations · source_derived_draft · unverified_draft

### ibu-bicarbonate-and-mucus A range of non-steroidal anti-inflammatory agents including acetylsalicylic acid, fenclofenac, ibuprofen and indomethacin inhibit gastric bicarbonate transport in isolated mucosal preparations, effects which can be antagonised by exogenous prostaglandins of the E series, and while the secreted mucus gel overlying the epithelial surface is not affected in the short term a number of these agents inhibit glycoprotein biosynthesis by the epithelial cells, so that loss of this protective coat could be anticipated during chronic exposure as erosion by luminal shear and proteolysis would not be compensated by continued secretion. 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 stomach’s own defences are built by prostaglandins, so blocking them removes the coat rather than adding an acid. organism: Human and animal tissue_or_cell_type: Gastric and duodenal mucosa experimental_model: Review of gastroduodenal defence with isolated mucosal preparations limitations: A review of mechanisms rather than an outcome study. The claim that E-series prostaglandins reverse the effect is what ties it to cyclooxygenase. exposure: Acetylsalicylic acid, fenclofenac, ibuprofen and indomethacin on bicarbonate transport and glycoprotein synthesis evidence_span: {"source_cache": "artifacts/ibuprofen-research/3303291.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8609926e51d2ad349198eb5f3ad78b6b552e8f4d4fc74d07bb3a58795a86e7a7", "start_char": 0, "end_char": 1757, "text_sha256": "8609926e51d2ad349198eb5f3ad78b6b552e8f4d4fc74d07bb3a58795a86e7a7"} [ibu-p3303291] Gastroduodenal mucosal defence mechanisms and the action of non-steroidal anti-inflammatory agents. (1987). https://pubmed.ncbi.nlm.nih.gov/3303291/ DOI: 10.3109/00365528709090947

evidence_span

{"source_cache": "artifacts/ibuprofen-research/8907587.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "99f3a26e6399b5f81c18859b9f62eafcd7aa6fc4e483d97a39e8c35c060a9d75", "start_char": 0, "end_char": 1101, "text_sha256": "99f3a26e6399b5f81c18859b9f62eafcd7aa6fc4e483d97a39e8c35c060a9d75"}

experimental_model

Lipopolysaccharide-challenged human whole blood with prostaglandin E2 and thromboxane B2 as isoform indices

exposure

Lipopolysaccharide induction of cyclooxygenase-2 with a single oral indomethacin dose ex vivo

limitations

Establishes the assay the other records rely on. Indomethacin rather than ibuprofen is the drug dosed here.

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

Human

plain_language

The first enzyme is always there and the second one appears when tissue is provoked; most of these drugs hit the first harder.

primary_references

[ibu-p8907587] A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. (1996). https://pubmed.ncbi.nlm.nih.gov/8907587/ DOI: 10.1007/bf02265118

tissue_or_cell_type

Whole blood and mononuclear cells

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 357–368

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Lipopolysaccharide-challenged human whole blood with prostaglandin E2 and thromboxane B2 as isoform indices · source_derived_draft · unverified_draft

### ibu-most-nsaids-favour-cox1 Incubation of human mononuclear cells with lipopolysaccharide induced a time-dependent increase in cyclooxygenase-2 protein of more than a hundredfold at 24 hours with increased prostaglandin E2 production, while cyclooxygenase-1 protein was present at time zero and not induced, and most non-steroidal anti-inflammatory drugs are more potent at inhibiting cyclooxygenase-1 than cyclooxygenase-2, with five experimental compounds showing greater selectivity for cyclooxygenase-2. 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 first enzyme is always there and the second one appears when tissue is provoked; most of these drugs hit the first harder. organism: Human tissue_or_cell_type: Whole blood and mononuclear cells experimental_model: Lipopolysaccharide-challenged human whole blood with prostaglandin E2 and thromboxane B2 as isoform indices limitations: Establishes the assay the other records rely on. Indomethacin rather than ibuprofen is the drug dosed here. exposure: Lipopolysaccharide induction of cyclooxygenase-2 with a single oral indomethacin dose ex vivo evidence_span: {"source_cache": "artifacts/ibuprofen-research/8907587.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "99f3a26e6399b5f81c18859b9f62eafcd7aa6fc4e483d97a39e8c35c060a9d75", "start_char": 0, "end_char": 1101, "text_sha256": "99f3a26e6399b5f81c18859b9f62eafcd7aa6fc4e483d97a39e8c35c060a9d75"} [ibu-p8907587] A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. (1996). https://pubmed.ncbi.nlm.nih.gov/8907587/ DOI: 10.1007/bf02265118

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ibuprofen-research/12152005.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "314477c44dbb699b0fe3d9ab14eb7da427d88538177b4e4267ef0ad25fd407da", "start_char": 0, "end_char": 1822, "text_sha256": "314477c44dbb699b0fe3d9ab14eb7da427d88538177b4e4267ef0ad25fd407da"}

experimental_model

Population pharmacokinetic study in 21 healthy volunteers across all combinations of CYP2C9 variants

exposure

600 milligrams oral racemic ibuprofen, with thromboxane B2 and prostaglandin E2 measured ex vivo

limitations

Links a genotype to both the drug level and the enzyme effect in the same subjects. Twenty-one volunteers spread across genotype groups, so each group is small.

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

Human

plain_language

People who clear the active half slowly get both more drug and more effect from the same tablet.

primary_references

[ibu-p12152005] Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. (2002). https://pubmed.ncbi.nlm.nih.gov/12152005/ DOI: 10.1067/mcp.2002.125726

tissue_or_cell_type

Plasma, platelets and monocytes

trigger_kind

machinery_impairment Imported condition classification; unverified.

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 214–225

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Population pharmacokinetic study in 21 healthy volunteers across all combinations of CYP2C9 variants · source_derived_draft · unverified_draft

### ibu-slow-clearance-more-effect Population mean S-ibuprofen clearances were 3.25, 2.38 and 1.52 litres per hour in carriers of CYP2C9 genotypes *1/*1, *1/*3 and *3/*3 respectively while the *2 variant had no significant effect, and ex vivo formation of thromboxane B2 reflecting cyclooxygenase-1 inhibition depended significantly on the polymorphism, with maximal inhibition and the area under the effect-time curve larger in carriers of the slow genotypes, the same trend holding for prostaglandin E2. Condition category: machinery_impairment 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: People who clear the active half slowly get both more drug and more effect from the same tablet. organism: Human tissue_or_cell_type: Plasma, platelets and monocytes experimental_model: Population pharmacokinetic study in 21 healthy volunteers across all combinations of CYP2C9 variants limitations: Links a genotype to both the drug level and the enzyme effect in the same subjects. Twenty-one volunteers spread across genotype groups, so each group is small. exposure: 600 milligrams oral racemic ibuprofen, with thromboxane B2 and prostaglandin E2 measured ex vivo evidence_span: {"source_cache": "artifacts/ibuprofen-research/12152005.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "314477c44dbb699b0fe3d9ab14eb7da427d88538177b4e4267ef0ad25fd407da", "start_char": 0, "end_char": 1822, "text_sha256": "314477c44dbb699b0fe3d9ab14eb7da427d88538177b4e4267ef0ad25fd407da"} [ibu-p12152005] Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. (2002). https://pubmed.ncbi.nlm.nih.gov/12152005/ DOI: 10.1067/mcp.2002.125726

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/paracetamol-research/20862299.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2cb3934d80d1a7a6632c49f2007cb6e203b3851706a4ffeb43fda2bb655fa8f2", "start_char": 0, "end_char": 1701, "text_sha256": "2cb3934d80d1a7a6632c49f2007cb6e203b3851706a4ffeb43fda2bb655fa8f2"}

experimental_model

Formalin, tail immersion and von Frey tests in fatty acid amide hydrolase and TRPV1 knockout mice with intracerebroventricular injection

exposure

Oral acetaminophen at a dose lacking hypolocomotor activity, with intracerebroventricular AM404 and capsazepine

limitations

Two separate knockouts and a central antagonist all point the same way, and the dose was chosen to avoid sedation confounding the pain tests. Brain prostaglandin E2 was unchanged at that dose, which is a notable negative.

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

Remove the channel and the painkiller stops working, while putting the metabolite straight into the brain works.

primary_references

[apap-p20862299] TRPV1 in brain is involved in acetaminophen-induced antinociception. (2010). https://pubmed.ncbi.nlm.nih.gov/20862299/ DOI: 10.1371/journal.pone.0012748

tissue_or_cell_type

Brain

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 311–322

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Formalin, tail immersion and von Frey tests in fatty acid amide hydrolase and TRPV1 knockout mice with intracerebroventricular injection · source_derived_draft · unverified_draft

### apap-analgesia-needs-trpv1 The antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity was absent in fatty acid amide hydrolase and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests, that dose did not affect global brain contents of prostaglandin E2 or endocannabinoids, intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the formalin test, and pharmacological inhibition of brain TRPV1 by intracerebroventricular capsazepine abolished the antinociceptive effect of oral acetaminophen. 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: Remove the channel and the painkiller stops working, while putting the metabolite straight into the brain works. organism: Mouse tissue_or_cell_type: Brain experimental_model: Formalin, tail immersion and von Frey tests in fatty acid amide hydrolase and TRPV1 knockout mice with intracerebroventricular injection limitations: Two separate knockouts and a central antagonist all point the same way, and the dose was chosen to avoid sedation confounding the pain tests. Brain prostaglandin E2 was unchanged at that dose, which is a notable negative. exposure: Oral acetaminophen at a dose lacking hypolocomotor activity, with intracerebroventricular AM404 and capsazepine evidence_span: {"source_cache": "artifacts/paracetamol-research/20862299.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2cb3934d80d1a7a6632c49f2007cb6e203b3851706a4ffeb43fda2bb655fa8f2", "start_char": 0, "end_char": 1701, "text_sha256": "2cb3934d80d1a7a6632c49f2007cb6e203b3851706a4ffeb43fda2bb655fa8f2"} [apap-p20862299] TRPV1 in brain is involved in acetaminophen-induced antinociception. (2010). https://pubmed.ncbi.nlm.nih.gov/20862299/ DOI: 10.1371/journal.pone.0012748

evidence_span

{"source_cache": "artifacts/paracetamol-research/4588122.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9", "start_char": 0, "end_char": 2254, "text_sha256": "274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9"}

experimental_model

Cisternal cerebrospinal fluid sampled from unanaesthetised cats during fever and after antipyretics

exposure

Shigella dysenteriae pyrogen given into the third ventricle, cisterna magna or intravenously, with indomethacin, paracetamol and aspirin

limitations

Bioassay on a stomach strip rather than direct measurement, and prostaglandin E-like activity rather than identified prostaglandin E2. It is the record that connects fever to central prostaglandin and to this drug.

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

Cat

plain_language

Fever raises a prostaglandin in the fluid round the brain, and this drug brings both down together.

primary_references

[apap-p4588122] Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. (1973). https://pubmed.ncbi.nlm.nih.gov/4588122/ DOI: 10.1113/jphysiol.1973.sp010346

tissue_or_cell_type

Cerebrospinal fluid and hypothalamus

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 285–296

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cisternal cerebrospinal fluid sampled from unanaesthetised cats during fever and after antipyretics · source_derived_draft · unverified_draft

### apap-antipyresis-follows-central-prostaglandin Prostaglandin E-like activity in cisternal cerebrospinal fluid was usually undetectable or low at normal body temperature and increased, often many-fold, during pyrogen fever irrespective of the route of pyrogen administration, and the antipyretic drugs indomethacin, paracetamol and aspirin injected intraperitoneally during the fever brought down temperature and returned the activity to low levels, with chromatography placing the activity in the zone of the E series prostaglandins, supporting the theory that pyrogens produce fever by increasing prostaglandin synthesis in the preoptic anterior hypothalamic area and that antipyretics of the aspirin type act by inhibiting that synthesis. 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: Fever raises a prostaglandin in the fluid round the brain, and this drug brings both down together. organism: Cat tissue_or_cell_type: Cerebrospinal fluid and hypothalamus experimental_model: Cisternal cerebrospinal fluid sampled from unanaesthetised cats during fever and after antipyretics limitations: Bioassay on a stomach strip rather than direct measurement, and prostaglandin E-like activity rather than identified prostaglandin E2. It is the record that connects fever to central prostaglandin and to this drug. exposure: Shigella dysenteriae pyrogen given into the third ventricle, cisterna magna or intravenously, with indomethacin, paracetamol and aspirin evidence_span: {"source_cache": "artifacts/paracetamol-research/4588122.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9", "start_char": 0, "end_char": 2254, "text_sha256": "274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9"} [apap-p4588122] Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. (1973). https://pubmed.ncbi.nlm.nih.gov/4588122/ DOI: 10.1113/jphysiol.1973.sp010346

evidence_span

{"source_cache": "artifacts/paracetamol-research/12598417.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267", "start_char": 0, "end_char": 1894, "text_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267"}

experimental_model

Human whole blood and isolated monocytes and platelets with parallel prostaglandin E2 and thromboxane B2 measurement

exposure

Acetaminophen at therapeutic plasma concentrations of 100 and 300 micromolar, in whole blood and in isolated cells

limitations

The whole blood against isolated cell comparison shows plasma components matter, and measuring two prostanoids in parallel separates the synthase from the downstream synthase. Ex vivo only.

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

Human

plain_language

In whole blood it nearly abolishes the inflammatory prostaglandin; in isolated cells it manages only sixty per cent.

primary_references

[apap-p12598417] Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells. (2003). https://pubmed.ncbi.nlm.nih.gov/12598417/ DOI: 10.1038/sj.bjp.0705078

tissue_or_cell_type

Monocytes and platelets

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 272–283

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human whole blood and isolated monocytes and platelets with parallel prostaglandin E2 and thromboxane B2 measurement · source_derived_draft · unverified_draft

### apap-plasma-changes-the-answer Acetaminophen inhibited lipopolysaccharide-induced whole blood prostaglandin E2 and thromboxane B2 production with half-maximal inhibitory concentrations of 44 and 94 micromolar, at therapeutic concentrations of 100 and 300 micromolar it reduced prostaglandin E2 more than thromboxane B2, but in isolated monocytes both were maximally reduced by only 60%, and at the same concentrations it caused a similar and incomplete inhibition of platelet prostaglandin E2 and thromboxane B2 during whole blood clotting, so that in the presence of plasma the drug almost completely suppressed inducible prostaglandin E2 biosynthesis through effects on both cyclooxygenase-2 and inducible prostaglandin E synthase. 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 whole blood it nearly abolishes the inflammatory prostaglandin; in isolated cells it manages only sixty per cent. organism: Human tissue_or_cell_type: Monocytes and platelets experimental_model: Human whole blood and isolated monocytes and platelets with parallel prostaglandin E2 and thromboxane B2 measurement limitations: The whole blood against isolated cell comparison shows plasma components matter, and measuring two prostanoids in parallel separates the synthase from the downstream synthase. Ex vivo only. exposure: Acetaminophen at therapeutic plasma concentrations of 100 and 300 micromolar, in whole blood and in isolated cells evidence_span: {"source_cache": "artifacts/paracetamol-research/12598417.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267", "start_char": 0, "end_char": 1894, "text_sha256": "e5796a25a03c77d12e8376a60aa094e481bd0c2ab58b29ddcb70027ab477b267"} [apap-p12598417] Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells. (2003). https://pubmed.ncbi.nlm.nih.gov/12598417/ DOI: 10.1038/sj.bjp.0705078

cross_nutrient

Prostaglandin E2 (additional_signal); Nicotinic acid (trigger)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/benyo2005.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "21dedb52cbd8fccaf810dabec7837e471525e0a5462827b21437d2f7b30c44a2", "start_char": 0, "end_char": 1388, "text_sha256": "21dedb52cbd8fccaf810dabec7837e471525e0a5462827b21437d2f7b30c44a2"}

experimental_model

PUMA-G/Hcar2 and prostaglandin-pathway mouse knockout experiments with bone-marrow transplantation

exposure

Nicotinic acid; receptor or cyclooxygenase deletion; wild-type bone-marrow rescue

limitations

Mouse pharmacological flushing experiment. HCAR2 historically GPR109A/HM74A in humans; mouse receptor PUMA-G. The location of the responsible immune cells was inferred, not every human flush directly measured.

nutrient_topic

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

organism

Mus musculus

plain_language

Nicotinic acid triggers prostaglandin signals that widen skin vessels in this mouse model.

primary_references

[nia-clin-benyo2005] GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. (2005). https://pubmed.ncbi.nlm.nih.gov/16322797/ DOI: 10.1172/jci23626

tissue_or_cell_type

Skin vasculature and hematopoietic cells

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1347–1359

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · PUMA-G/Hcar2 and prostaglandin-pathway mouse knockout experiments with bone-marrow transplantation · source_derived_draft · unverified_draft

### nia-clin-prostaglandin-flush Nicotinic-acid flushing was absent in cyclooxygenase-1-deficient mice and reduced in mice lacking the tested PGD2 or PGE2 receptors, supporting prostaglandin involvement. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Nicotinic acid triggers prostaglandin signals that widen skin vessels in this mouse model. organism: Mus musculus tissue_or_cell_type: Skin vasculature and hematopoietic cells experimental_model: PUMA-G/Hcar2 and prostaglandin-pathway mouse knockout experiments with bone-marrow transplantation limitations: Mouse pharmacological flushing experiment. HCAR2 historically GPR109A/HM74A in humans; mouse receptor PUMA-G. The location of the responsible immune cells was inferred, not every human flush directly measured. exposure: Nicotinic acid; receptor or cyclooxygenase deletion; wild-type bone-marrow rescue cross_nutrient: Prostaglandin E2 (additional_signal); Nicotinic acid (trigger) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/benyo2005.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "21dedb52cbd8fccaf810dabec7837e471525e0a5462827b21437d2f7b30c44a2", "start_char": 0, "end_char": 1388, "text_sha256": "21dedb52cbd8fccaf810dabec7837e471525e0a5462827b21437d2f7b30c44a2"} [nia-clin-benyo2005] GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. (2005). https://pubmed.ncbi.nlm.nih.gov/16322797/ DOI: 10.1172/jci23626

evidence_span

{"source_cache": "artifacts/aspirin-research/1309968.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a81a9ed941df59e6b8aa8c7c730d9a14766e2b8bd358b712ee464ae96c67e4e2", "start_char": 0, "end_char": 1685, "text_sha256": "a81a9ed941df59e6b8aa8c7c730d9a14766e2b8bd358b712ee464ae96c67e4e2"}

experimental_model

Double-blind nasal lavage challenge in ten aspirin-sensitive asthmatics, ten insensitive asthmatics and seven healthy subjects

exposure

12 milligrams of acetylsalicylic acid instilled nasally against saline

limitations

Three groups including two control groups, with mediators measured directly in the target tissue. Radioimmunoassay of nasal lavage fluid, and a small number per group.

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 drug blocks prostaglandins in everyone, but only in the sensitive patients does a flood of leukotrienes follow.

primary_references

[asa-p1309968] Release of peptide leukotriene into nasal secretions after local instillation of aspirin in aspirin-sensitive asthmatic patients. (1992). https://pubmed.ncbi.nlm.nih.gov/1309968/ DOI: 10.1164/ajrccm/145.1.65

tissue_or_cell_type

Nasal mucosa

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 572–583

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind nasal lavage challenge in ten aspirin-sensitive asthmatics, ten insensitive asthmatics and seven healthy subjects · source_derived_draft · unverified_draft

### asa-only-sensitive-patients-release After nasal instillation of 12 milligrams of acetylsalicylic acid, significant levels of peptide leukotrienes were detected in sensitive asthmatic patients at 60 minutes in association with a significant increase in symptoms, with no increase in either insensitive patients or healthy subjects, while inhibition of prostaglandin E2 and F2-alpha release was detected in all three groups; aspirin also inhibited prostaglandin D2 release in insensitive asthmatic patients but not in sensitive patients or healthy subjects. 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 drug blocks prostaglandins in everyone, but only in the sensitive patients does a flood of leukotrienes follow. organism: Human tissue_or_cell_type: Nasal mucosa experimental_model: Double-blind nasal lavage challenge in ten aspirin-sensitive asthmatics, ten insensitive asthmatics and seven healthy subjects limitations: Three groups including two control groups, with mediators measured directly in the target tissue. Radioimmunoassay of nasal lavage fluid, and a small number per group. exposure: 12 milligrams of acetylsalicylic acid instilled nasally against saline evidence_span: {"source_cache": "artifacts/aspirin-research/1309968.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a81a9ed941df59e6b8aa8c7c730d9a14766e2b8bd358b712ee464ae96c67e4e2", "start_char": 0, "end_char": 1685, "text_sha256": "a81a9ed941df59e6b8aa8c7c730d9a14766e2b8bd358b712ee464ae96c67e4e2"} [asa-p1309968] Release of peptide leukotriene into nasal secretions after local instillation of aspirin in aspirin-sensitive asthmatic patients. (1992). https://pubmed.ncbi.nlm.nih.gov/1309968/ DOI: 10.1164/ajrccm/145.1.65