Cyclic adenosine monophosphate

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

magnesium -> CaSR/PTH -> calcium

experimental_model

Dispersed human parathyroid cells from hyperparathyroid tissue

limitations

This is pathway-dependent inhibition, not proof that every cellular adenylyl cyclase fails whenever Mg is low.

nutrient_topic

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

organism

Homo sapiens

plain_language

Low Mg strengthened a signaling arm that reduces the cAMP signal associated with PTH release.

primary_references

[quitterer-2001-magnesium-paradox] Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits (2001). https://pubmed.ncbi.nlm.nih.gov/11102444/ DOI: 10.1074/jbc.M007727200

tissue_or_cell_type

Parathyroid cells in vitro

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 433–443

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dispersed human parathyroid cells from hyperparathyroid tissue · source_derived_draft · unverified_draft

### very-low-mg-enhances-casr-camp-inhibition Low Mg enhanced CaSR-associated inhibition of cAMP in the tested parathyroid and receptor-expression cell systems. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low Mg strengthened a signaling arm that reduces the cAMP signal associated with PTH release. organism: Homo sapiens tissue_or_cell_type: Parathyroid cells in vitro experimental_model: Dispersed human parathyroid cells from hyperparathyroid tissue limitations: This is pathway-dependent inhibition, not proof that every cellular adenylyl cyclase fails whenever Mg is low. cross_nutrient: magnesium -> CaSR/PTH -> calcium [quitterer-2001-magnesium-paradox] Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits (2001). https://pubmed.ncbi.nlm.nih.gov/11102444/ DOI: 10.1074/jbc.M007727200

evidence_span

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experimental_model

Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle

exposure

Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds

limitations

Measures both cyclic nucleotides in human tissue with reference compounds for each pathway, and reports an effect on the nucleotide the drug is not supposed to touch. It is an isolated tissue study without added nitric oxide drive.

nutrient_topic

Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

organism

Human

plain_language

In this tissue the drug barely moved the messenger it targets and raised the other one instead.

primary_references

[sil-p10654914] Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. (2000). https://pubmed.ncbi.nlm.nih.gov/10654914/ DOI: 10.1016/s0090-4295(99)00371-4

tissue_or_cell_type

Corpus cavernosum and cardiac muscle

Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 392–403

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle · source_derived_draft · unverified_draft

### sil-cyclic-amp-rose-instead In the concentration range 0.01 to 1 micromolar there was only a minor effect of sildenafil on cyclic GMP levels in isolated human cavernous and cardiac tissues, whereas sildenafil significantly increased cyclic AMP in both at physiologic and supraphysiologic concentrations, more pronounced in cavernous than cardiac tissue, and in the range 0.1 to 1.0 micromolar the effect on cyclic AMP in cardiac samples was almost equivalent to that of milrinone, which the authors offer as a potential mechanism for reported cardiovascular effects and as evidence of cross-talk between the two signalling pathways. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In this tissue the drug barely moved the messenger it targets and raised the other one instead. organism: Human tissue_or_cell_type: Corpus cavernosum and cardiac muscle experimental_model: Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle limitations: Measures both cyclic nucleotides in human tissue with reference compounds for each pathway, and reports an effect on the nucleotide the drug is not supposed to touch. It is an isolated tissue study without added nitric oxide drive. exposure: Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds evidence_span: {"source_cache": "artifacts/sildenafil-research/10654914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292", "start_char": 0, "end_char": 1867, "text_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292"} [sil-p10654914] Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. (2000). https://pubmed.ncbi.nlm.nih.gov/10654914/ DOI: 10.1016/s0090-4295(99)00371-4

duration

Not stated here

evidence_access

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

experimental_model

Rat

exposure

Nattokinase

limitations

Reported together with activation of JAK1/STAT1 signalling in the injured region. Neither the adenylate cyclase step nor the receptor upstream of it is identified, and the route of administration for this arm is not stated in the abstract.

organism

Rat

plain_language

Nattokinase significantly increased cyclic AMP levels in the cerebral ischemia model.

primary_references

Mechanisms of Nattokinase in protection of cerebral ischemia. (2014) https://pubmed.ncbi.nlm.nih.gov/25446567/ DOI: 10.1016/j.ejphar.2014.10.024

route

Not stated here

tissue

Injured brain tissue

Nattokinase: what the purified enzyme cleaves, what survives being eaten, and the gap between the two (2026-09-23) · lines 367–367

Original AI-assisted curation built from a supplied entity-first document of 105 entities and 129 claims. Every reference in that document was resolved against live PubMed with its abstract read and its DOI cross-checked on 2026-09-23, and the EFSA novel-food opinion was retrieved and read in full. That check corrected two PMIDs that pointed at unrelated papers, two DOIs, and two papers recorded as carrying no erratum that do carry one; it also reversed three findings the supplied document had stated backwards. Two papers carry a published correction, recorded as such and not as a retraction. Three sources are not indexed in PubMed and are cited by what they have. Laboratory lineages are recorded, so the four papers from one group, the three from another and the two readings of a single applicant dossier cannot be counted as separate lines of support. Study-specific doses, units, populations and limitations retained; activity units are never converted between systems. Not publisher full text. · supports · Rat · source_derived_draft · unverified_draft

Nattokinase significantly increased cyclic AMP levels in the cerebral ischemia model.

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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

experimental_model

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

exposure

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

limitations

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

nutrient_topic

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

organism

Mouse

plain_language

Without locally made hormone the cell cannot even hear the nerve signal properly.

primary_references

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

tissue_or_cell_type

Brown adipose tissue

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 403–414

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

### cold-dio2-camp-defect In Dio2-null brown adipocytes the acute norepinephrine-, CL316,243- or forskolin-induced increases in lipolysis, UCP1 mRNA and oxygen consumption were all reduced because of impaired cAMP generation, and all were completely reversed by a single T3 injection 14 hours earlier. Condition category: nutrient_deficiency nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Without locally made hormone the cell cannot even hear the nerve signal properly. organism: Mouse tissue_or_cell_type: Brown adipose tissue experimental_model: Mice with targeted disruption of the Dio2 gene, with brown adipocyte assays and T3 rescue limitations: The selenoenzyme is the link between thyroid hormone and sympathetic signalling. Plasma T3 was normal in the knockouts, so the defect is local hormone generation, not circulating hormone. exposure: Cold stress, with norepinephrine, CL316,243 or forskolin stimulation, and a single T3 injection evidence_span: {"source_cache": "artifacts/cold-research/11696583.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68", "start_char": 0, "end_char": 1332, "text_sha256": "adbd82ff8c43d8a2718cfa752c9a0607c367648d6573b968eb885c883376dc68"} [cold-p11696583] The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. (2001). https://pubmed.ncbi.nlm.nih.gov/11696583/ DOI: 10.1172/jci13803

evidence_access

Primary abstract

experimental_model

U2OS cAMP biosensor and pathway perturbations.

limitations

Does not exclude high-concentration PDE or calcium-channel effects in other systems.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The clock experiment identified a receptor-linked signaling route.

primary_references

Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 92–98

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · U2OS cAMP biosensor and pathway perturbations. · source_derived_draft · unverified_draft

## caf-clock-camp The clock experiment identified a receptor-linked signaling route. A cAMP biosensor detected increased cAMP; pharmacological and knockdown experiments supported adenosine-receptor signaling rather than RyR or PDE perturbation as sufficient to explain the clock effect. Model: U2OS cAMP biosensor and pathway perturbations. Limitations: Does not exclude high-concentration PDE or calcium-channel effects in other systems. Evidence access: Primary abstract Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

evidence_span

{"source_cache": "artifacts/thc-research/2165569.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db", "start_char": 0, "end_char": 1256, "text_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db"}

experimental_model

Cloning and heterologous expression of a complementary DNA from rat brain

exposure

Cannabinoid binding and adenylate cyclase inhibition in the transfected cells

limitations

The founding cloning paper. It establishes a receptor, which is what displaced the membrane-disruption explanation of cannabinoid action.

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 receptor expressed in cells

plain_language

Cannabis acts on a specific receptor, not by melting cell membranes as was assumed.

primary_references

[thc-p2165569] Structure of a cannabinoid receptor and functional expression of the cloned cDNA. (1990). https://pubmed.ncbi.nlm.nih.gov/2165569/ DOI: 10.1038/346561a0

tissue_or_cell_type

Brain and neural cell lines

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 62–73

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning and heterologous expression of a complementary DNA from rat brain · source_derived_draft · unverified_draft

### thc-cb1-cloned A cloned complementary DNA encoded a G protein-coupled receptor that inhibits adenylate cyclase in a dose-dependent, stereoselective and pertussis-toxin-sensitive manner, is more responsive to psychoactive than to non-psychoactive cannabinoids, and whose messenger RNA is found in the brain regions that have cannabinoid receptors. 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: Cannabis acts on a specific receptor, not by melting cell membranes as was assumed. organism: Rat receptor expressed in cells tissue_or_cell_type: Brain and neural cell lines experimental_model: Cloning and heterologous expression of a complementary DNA from rat brain limitations: The founding cloning paper. It establishes a receptor, which is what displaced the membrane-disruption explanation of cannabinoid action. exposure: Cannabinoid binding and adenylate cyclase inhibition in the transfected cells evidence_span: {"source_cache": "artifacts/thc-research/2165569.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db", "start_char": 0, "end_char": 1256, "text_sha256": "8d92b7104006ccc194ab498aa8f559606353e6ccc4b5aa7af0a9502c9bfc37db"} [thc-p2165569] Structure of a cannabinoid receptor and functional expression of the cloned cDNA. (1990). https://pubmed.ncbi.nlm.nih.gov/2165569/ DOI: 10.1038/346561a0

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

magnesium -> PTH -> calcium

experimental_model

Human hypomagnesemic hypocalcemia clinical study

limitations

Only two challenge studies; urinary cAMP is an organ-response marker, not direct measurement of PTH1R binding or adenylyl-cyclase Mg occupancy.

nutrient_topic

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

organism

Homo sapiens

plain_language

The kidney responded weakly to the PTH challenge, but another hormone/cAMP response remained functional; Mg deficiency did not disable all signaling equally.

primary_references

[rude-1976-human-pth-resistance] Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency (1976). https://pubmed.ncbi.nlm.nih.gov/182417/ DOI: 10.1111/j.1365-2265.1976.tb01947.x

tissue_or_cell_type

Blood; parathyroid-kidney axis

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Magnesium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 337–347

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human hypomagnesemic hypocalcemia clinical study · source_derived_draft · unverified_draft

### mg-deficiency-blunts-renal-pth-camp-response Parathyroid extract produced only a small urinary cAMP response in the two Mg-deficient patients tested, while glucagon-stimulated plasma cAMP responses were preserved. Condition category: nutrient_deficiency nutrient_topic: Magnesium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The kidney responded weakly to the PTH challenge, but another hormone/cAMP response remained functional; Mg deficiency did not disable all signaling equally. organism: Homo sapiens tissue_or_cell_type: Blood; parathyroid-kidney axis experimental_model: Human hypomagnesemic hypocalcemia clinical study limitations: Only two challenge studies; urinary cAMP is an organ-response marker, not direct measurement of PTH1R binding or adenylyl-cyclase Mg occupancy. cross_nutrient: magnesium -> PTH -> calcium [rude-1976-human-pth-resistance] Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency (1976). https://pubmed.ncbi.nlm.nih.gov/182417/ DOI: 10.1111/j.1365-2265.1976.tb01947.x

evidence_access

Primary abstract

experimental_model

Mouse islet and dispersed-cell experiments; paracrine blockers and metabolic inhibitors.

limitations

Cyanide is broad; the experiment does not identify one unique mitochondrial enzyme as the leucine target.

nutrient_topic

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

plain_language

Part of the suppression arose inside the glucagon-producing cell.

primary_references

Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 352–358

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse islet and dispersed-cell experiments; paracrine blockers and metabolic inhibitors. · source_derived_draft · unverified_draft

## alanine-leucine-alpha-camp Part of the suppression arose inside the glucagon-producing cell. Leucine reduced mouse alpha-cell cAMP even when beta/delta-cell paracrine signaling was limited; cyanide blocked the inhibitory response, supporting mitochondrial-metabolism dependence. Model: Mouse islet and dispersed-cell experiments; paracrine blockers and metabolic inhibitors. Limitations: Cyanide is broad; the experiment does not identify one unique mitochondrial enzyme as the leucine target. Evidence access: Primary abstract Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

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experimental_model

Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina

exposure

Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone

limitations

The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series.

nutrient_topic

Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

organism

Human, rabbit and dog

plain_language

With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.

primary_references

[sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

tissue_or_cell_type

Corpus cavernosum, aorta, cardiac trabeculae and retina

trigger_kind

biomarker_context Imported condition classification; unverified.

Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 262–273

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina · source_derived_draft · unverified_draft

### sil-no-effect-without-nitric-oxide Sildenafil is a potent competitive inhibitor of PDE5 with a half-maximal inhibitory concentration of 3.5 nanomolar, selective over PDE1 to PDE4 by 80 to 19,000-fold and over retinal PDE6 by 10-fold, it enhanced cyclic GMP accumulation driven with sodium nitroprusside in rabbit corpus cavernosum without affecting cyclic AMP, and in the absence of nitric oxide drive it had no functional effect on human and rabbit isolated corpus cavernosum but potently potentiated the relaxant effects of nitric oxide on these tissues. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

evidence_span

{"source_cache": "artifacts/melatonin-research/27185156.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "61fcf7c730c1349e5b306e5c9cfcabcb2905290d7f8762cbfba06f2b5fccaded", "start_char": 0, "end_char": 1043, "text_sha256": "61fcf7c730c1349e5b306e5c9cfcabcb2905290d7f8762cbfba06f2b5fccaded"}

experimental_model

Human islet genetics, cell experiments and recall-by-genotype intervention

exposure

Risk G allele, receptor overexpression and melatonin exposure

limitations

Genotype associations, cultured-cell manipulation and human intervention are separate evidence types. Do not generalize islet signaling to every tissue.

nutrient_topic

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

organism

Human islets and volunteers; separate insulin-cell and mouse experiments

plain_language

The receptor signal meets a messenger involved in insulin release.

primary_references

[melatonin-p27185156] Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. (2016). https://pubmed.ncbi.nlm.nih.gov/27185156/ DOI: 10.1016/j.cmet.2016.04.009

tissue_or_cell_type

MTNR1B signaling and insulin secretion

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 1111–1122

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human islet genetics, cell experiments and recall-by-genotype intervention · source_derived_draft · unverified_draft

### melatonin-islet-camp Melatonin lowered cAMP in the insulin-secreting cells in the study. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The receptor signal meets a messenger involved in insulin release. organism: Human islets and volunteers; separate insulin-cell and mouse experiments tissue_or_cell_type: MTNR1B signaling and insulin secretion experimental_model: Human islet genetics, cell experiments and recall-by-genotype intervention limitations: Genotype associations, cultured-cell manipulation and human intervention are separate evidence types. Do not generalize islet signaling to every tissue. exposure: Risk G allele, receptor overexpression and melatonin exposure evidence_span: {"source_cache": "artifacts/melatonin-research/27185156.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "61fcf7c730c1349e5b306e5c9cfcabcb2905290d7f8762cbfba06f2b5fccaded", "start_char": 0, "end_char": 1043, "text_sha256": "61fcf7c730c1349e5b306e5c9cfcabcb2905290d7f8762cbfba06f2b5fccaded"} [melatonin-p27185156] Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. (2016). https://pubmed.ncbi.nlm.nih.gov/27185156/ DOI: 10.1016/j.cmet.2016.04.009

evidence_span

{"source_cache": "artifacts/melatonin-research/7946354.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eed36768519d1c02ed67434eb3dc08eb561de445d3532113e7eaeb2827e021f", "start_char": 0, "end_char": 1054, "text_sha256": "4eed36768519d1c02ed67434eb3dc08eb561de445d3532113e7eaeb2827e021f"}

experimental_model

Receptor cloning, radioligand binding and functional expression

exposure

Heterologous COS-7 binding and NIH3T3 functional assays

limitations

Species differ across experiments. High-affinity radioligand binding is separated from the sheep functional assay.

nutrient_topic

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

organism

Human and sheep MT1 in cells; functional cyclase assay used sheep receptor

plain_language

The receptor connects to an inhibitory signaling system.

primary_references

[melatonin-p7946354] Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. (1994). https://pubmed.ncbi.nlm.nih.gov/7946354/ DOI: 10.1016/0896-6273(94)90055-8

tissue_or_cell_type

Melatonin receptor identification

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 370–381

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Receptor cloning, radioligand binding and functional expression · source_derived_draft · unverified_draft

### melatonin-mt1-sheep-cyclase The sheep MT1 receptor inhibited adenylyl cyclase through a pertussis-toxin-sensitive mechanism in transfected cells. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The receptor connects to an inhibitory signaling system. organism: Human and sheep MT1 in cells; functional cyclase assay used sheep receptor tissue_or_cell_type: Melatonin receptor identification experimental_model: Receptor cloning, radioligand binding and functional expression limitations: Species differ across experiments. High-affinity radioligand binding is separated from the sheep functional assay. exposure: Heterologous COS-7 binding and NIH3T3 functional assays evidence_span: {"source_cache": "artifacts/melatonin-research/7946354.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4eed36768519d1c02ed67434eb3dc08eb561de445d3532113e7eaeb2827e021f", "start_char": 0, "end_char": 1054, "text_sha256": "4eed36768519d1c02ed67434eb3dc08eb561de445d3532113e7eaeb2827e021f"} [melatonin-p7946354] Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. (1994). https://pubmed.ncbi.nlm.nih.gov/7946354/ DOI: 10.1016/0896-6273(94)90055-8

evidence_span

{"source_cache": "artifacts/melatonin-research/7568007.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1873168e5fa570a1dec0bc112045a3bcffda494e92b52f3349c8b1afebbb505f", "start_char": 0, "end_char": 1269, "text_sha256": "1873168e5fa570a1dec0bc112045a3bcffda494e92b52f3349c8b1afebbb505f"}

experimental_model

Human receptor cloning and functional expression

exposure

Radioligand binding and adenylyl cyclase measurements

limitations

Receptor overexpression system; no claim a given oral dose produces the same occupancy in every human tissue.

nutrient_topic

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

organism

Human MT2 expressed in COS-1 and NIH3T3 cells

plain_language

The second receptor can also reduce the signal that generates cAMP.

primary_references

[melatonin-p7568007] Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. (1995). https://pubmed.ncbi.nlm.nih.gov/7568007/ DOI: 10.1073/pnas.92.19.8734

tissue_or_cell_type

Second melatonin receptor subtype

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 383–394

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human receptor cloning and functional expression · source_derived_draft · unverified_draft

### melatonin-mt2-cyclase Human MT2 expression supported melatonin-receptor-mediated inhibition of adenylyl cyclase. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The second receptor can also reduce the signal that generates cAMP. organism: Human MT2 expressed in COS-1 and NIH3T3 cells tissue_or_cell_type: Second melatonin receptor subtype experimental_model: Human receptor cloning and functional expression limitations: Receptor overexpression system; no claim a given oral dose produces the same occupancy in every human tissue. exposure: Radioligand binding and adenylyl cyclase measurements evidence_span: {"source_cache": "artifacts/melatonin-research/7568007.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "1873168e5fa570a1dec0bc112045a3bcffda494e92b52f3349c8b1afebbb505f", "start_char": 0, "end_char": 1269, "text_sha256": "1873168e5fa570a1dec0bc112045a3bcffda494e92b52f3349c8b1afebbb505f"} [melatonin-p7568007] Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. (1995). https://pubmed.ncbi.nlm.nih.gov/7568007/ DOI: 10.1073/pnas.92.19.8734

evidence_access

Primary full text

experimental_model

Mouse cells and separate mouse tissue measurements.

limitations

A changed pool does not by itself identify its synthesis or breakdown rate.

nutrient_topic

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

plain_language

Reduced signal breakdown connects enzyme inhibition to cellular signaling.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 198–204

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse cells and separate mouse tissue measurements. · source_derived_draft · unverified_draft

## resveratrol-mouse-camp Reduced signal breakdown connects enzyme inhibition to cellular signaling. Resveratrol increased cAMP in mouse C2C12 myotubes at concentrations up to 50 micromolar; oral gavage also increased measured muscle and adipose cAMP in mice. Model: Mouse cells and separate mouse tissue measurements. Limitations: A changed pool does not by itself identify its synthesis or breakdown rate. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

evidence_access

Primary full text

experimental_model

Cell-free cyclic-nucleotide hydrolysis assay.

limitations

Retains preparation identity: do not infer an unreported isoform/species or a human effective dose.

nutrient_topic

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

plain_language

Slower cAMP breakdown can extend a signaling pulse.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 206–212

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free cyclic-nucleotide hydrolysis assay. · source_derived_draft · unverified_draft

## resveratrol-pde1 Slower cAMP breakdown can extend a signaling pulse. Resveratrol inhibited the tested recombinant PDE1 preparation with approximate IC50 6 micromolar. Model: Cell-free cyclic-nucleotide hydrolysis assay. Limitations: Retains preparation identity: do not infer an unreported isoform/species or a human effective dose. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

evidence_access

Primary full text

experimental_model

Cell-free cyclic-nucleotide hydrolysis assay.

limitations

Retains preparation identity: do not infer an unreported isoform/species or a human effective dose.

nutrient_topic

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

plain_language

Slower cAMP breakdown can extend a signaling pulse.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 214–220

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free cyclic-nucleotide hydrolysis assay. · source_derived_draft · unverified_draft

## resveratrol-pde3 Slower cAMP breakdown can extend a signaling pulse. Resveratrol inhibited the tested recombinant PDE3 preparation with approximate IC50 10 micromolar. Model: Cell-free cyclic-nucleotide hydrolysis assay. Limitations: Retains preparation identity: do not infer an unreported isoform/species or a human effective dose. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

evidence_access

Primary full text

experimental_model

Cell-free cyclic-nucleotide hydrolysis assay.

limitations

Retains preparation identity: do not infer an unreported isoform/species or a human effective dose.

nutrient_topic

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

plain_language

Slower cAMP breakdown can extend a signaling pulse.

primary_references

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 222–228

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free cyclic-nucleotide hydrolysis assay. · source_derived_draft · unverified_draft

## resveratrol-pde4 Slower cAMP breakdown can extend a signaling pulse. Resveratrol inhibited the tested recombinant PDE4 preparation with approximate IC50 14 micromolar. Model: Cell-free cyclic-nucleotide hydrolysis assay. Limitations: Retains preparation identity: do not infer an unreported isoform/species or a human effective dose. Evidence access: Primary full text Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22304913/ · DOI 10.1016/j.cell.2012.01.017

evidence_access

Primary full text

experimental_model

Isolated rat Leydig cells, 60-minute incubations.

limitations

cAMP involvement is supported by co-change, not an exclusive pathway demonstrated by blocking or rescue.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

A second rat experiment located a response in steroid-producing cells.

primary_references

The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19860889/ · DOI 10.1186/1477-7827-7-120

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 376–382

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated rat Leydig cells, 60-minute incubations. · source_derived_draft · unverified_draft

## d-aspartate-rat-leydig A second rat experiment located a response in steroid-producing cells. Rat Leydig cells incubated with 0.1 or 1 mM D-aspartate showed increased measured testosterone and cAMP. Model: Isolated rat Leydig cells, 60-minute incubations. Limitations: cAMP involvement is supported by co-change, not an exclusive pathway demonstrated by blocking or rescue. Evidence access: Primary full text The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19860889/ · DOI 10.1186/1477-7827-7-120

cross_nutrient

Nicotinic acid (agonist); Cyclic adenosine monophosphate (measured_signal)

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

Nicotinic acid can act as a receptor signal as well as a vitamin precursor, switching down a cellular signaling molecule.

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 1291–1303

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-hcar2-camp Nicotinic-acid activation of GPR109A/HCAR2 in the human cell-line assay lowered cAMP through a pertussis-toxin-sensitive pathway. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Nicotinic acid can act as a receptor signal as well as a vitamin precursor, switching down a cellular signaling molecule. 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: Nicotinic acid (agonist); Cyclic adenosine monophosphate (measured_signal) 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

evidence_span

{"source_cache": "artifacts/cold-research/7738011.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1c5506f21f40d6674727a5fc3344f2b02f7fc9f2f1e911fd04bfecfc2399175", "start_char": 0, "end_char": 2592, "text_sha256": "b1c5506f21f40d6674727a5fc3344f2b02f7fc9f2f1e911fd04bfecfc2399175"}

experimental_model

Immortalized mouse brown adipocyte cell lines with selective beta-adrenergic agonists and antagonists

exposure

Norepinephrine, the beta-3 selective agonist CL316,243, and subtype-selective antagonists

limitations

A cell-line dissection of receptor subtypes. The additive cAMP response indicates the subtypes are not redundant, but these are immortalized cells.

nutrient_topic

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

organism

Mouse cell lines

plain_language

Three different receptors for the same messenger all feed the heat gene, and together they do more than any one alone.

primary_references

[cold-p7738011] Regulation of the uncoupling protein gene (Ucp) by beta 1, beta 2, and beta 3-adrenergic receptor subtypes in immortalized brown adipose cell lines. (1995). https://pubmed.ncbi.nlm.nih.gov/7738011/ DOI: 10.1074/jbc.270.18.10723

tissue_or_cell_type

Brown adipocytes

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 364–375

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immortalized mouse brown adipocyte cell lines with selective beta-adrenergic agonists and antagonists · source_derived_draft · unverified_draft

### cold-beta-receptors-ucp1 UCP1 expression could be induced by any of the beta-1, beta-2 or beta-3 adrenergic receptor subtypes, but the greatest response came from stimulating all three simultaneously, and beta-3 stimulation did not prevent norepinephrine from further raising adenylyl cyclase activity, suggesting an additive cAMP response. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Three different receptors for the same messenger all feed the heat gene, and together they do more than any one alone. organism: Mouse cell lines tissue_or_cell_type: Brown adipocytes experimental_model: Immortalized mouse brown adipocyte cell lines with selective beta-adrenergic agonists and antagonists limitations: A cell-line dissection of receptor subtypes. The additive cAMP response indicates the subtypes are not redundant, but these are immortalized cells. exposure: Norepinephrine, the beta-3 selective agonist CL316,243, and subtype-selective antagonists evidence_span: {"source_cache": "artifacts/cold-research/7738011.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1c5506f21f40d6674727a5fc3344f2b02f7fc9f2f1e911fd04bfecfc2399175", "start_char": 0, "end_char": 2592, "text_sha256": "b1c5506f21f40d6674727a5fc3344f2b02f7fc9f2f1e911fd04bfecfc2399175"} [cold-p7738011] Regulation of the uncoupling protein gene (Ucp) by beta 1, beta 2, and beta 3-adrenergic receptor subtypes in immortalized brown adipose cell lines. (1995). https://pubmed.ncbi.nlm.nih.gov/7738011/ DOI: 10.1074/jbc.270.18.10723

evidence_span

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

experimental_model

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

exposure

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

limitations

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

nutrient_topic

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

organism

Mouse

plain_language

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

primary_references

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

tissue_or_cell_type

Brown adipose tissue

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

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

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

evidence_span

{"source_cache": "artifacts/cold-research/7628361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64", "start_char": 0, "end_char": 2080, "text_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64"}

experimental_model

Brown and white adipose tissue of hypothyroid and T3-treated rats

exposure

Hypothyroidism, T3 replacement and T3 excess

limitations

The reciprocal regulation in the two tissues is the informative part. A post-receptor cAMP defect persisted after receptor numbers were corrected, so receptor count is not the whole story.

nutrient_topic

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

organism

Rat

plain_language

Thyroid hormone tunes how loudly each fat depot hears the nerve signal, in opposite directions.

primary_references

[cold-p7628361] Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. (1995). https://pubmed.ncbi.nlm.nih.gov/7628361/ DOI: 10.1210/endo.136.8.7628361

tissue_or_cell_type

Brown and white adipose tissue

Cold water immersion: cold sensing, heat production, the catecholamine axis and what repeated exposure changes (2026-09-19) · lines 429–440

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Brown and white adipose tissue of hypothyroid and T3-treated rats · source_derived_draft · unverified_draft

### cold-thyroid-beta3-regulation In brown adipose tissue of hypothyroid rats beta-3 adrenergic receptor number and mRNA increased 4- to 6-fold while both fell in white adipose tissue, T3 injection reverted the changes within 24 hours, and T3 excess caused a greater than 90% reduction of beta-3 receptor mRNA in brown fat but a 5-fold increase in white fat. Condition category: normal nutrient_topic: Cold water immersion research collection; topical membership is not evidence of a direct clinical effect, and a therapeutic exposure is not a dietary intake. plain_language: Thyroid hormone tunes how loudly each fat depot hears the nerve signal, in opposite directions. organism: Rat tissue_or_cell_type: Brown and white adipose tissue experimental_model: Brown and white adipose tissue of hypothyroid and T3-treated rats limitations: The reciprocal regulation in the two tissues is the informative part. A post-receptor cAMP defect persisted after receptor numbers were corrected, so receptor count is not the whole story. exposure: Hypothyroidism, T3 replacement and T3 excess evidence_span: {"source_cache": "artifacts/cold-research/7628361.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64", "start_char": 0, "end_char": 2080, "text_sha256": "ee7ba7cfa7ae3387c067f33a03ad9c212801437175f6cb656d5e86b482ed8d64"} [cold-p7628361] Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. (1995). https://pubmed.ncbi.nlm.nih.gov/7628361/ DOI: 10.1210/endo.136.8.7628361

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

45 lithium-treated patients versus 42 on other psychotropics; desmopressin challenge.

limitations

Observational comparison cannot remove all confounding; urinary AQP2 is a marker, not a full tissue inventory.

nutrient_topic

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

plain_language

Human kidney findings connect the cellular route to water balance.

primary_references

Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18596116/ · DOI 10.2215/CJN.01640408

trigger_kind

biomarker_context Imported condition classification; unverified.

Lithium: metal-sensitive enzymes, transport and cross-nutrient mechanisms (2026-09-19) · lines 336–342

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 45 lithium-treated patients versus 42 on other psychotropics; desmopressin challenge. · source_derived_draft · unverified_draft

## lithium-human-concentration Human kidney findings connect the cellular route to water balance. Urine-concentrating impairment and lower urinary AQP2/cAMP correlated with lithium-treatment duration in patients. Model: 45 lithium-treated patients versus 42 on other psychotropics; desmopressin challenge. Limitations: Observational comparison cannot remove all confounding; urinary AQP2 is a marker, not a full tissue inventory. Evidence access: Primary abstract Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18596116/ · DOI 10.2215/CJN.01640408

dose

Indicaxanthin; forskolin, IBMX and other pharmacological probes, exact concentrations not in accessed abstract

duration

Acute responses; exact interval not in accessed abstract

evidence_access

Primary PubMed abstract.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Isolated mouse ileal longitudinal muscle

limitations

PDE involvement is inferred pharmacologically, not established by an isoform-specific binding or purified-enzyme assay; no clinical motility treatment is tested.

nutrient_topic

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

organism

Isolated mouse ileal longitudinal muscle

plain_language

Adding indicaxanthin increased basal and forskolin-stimulated cAMP in mouse ileal muscle.

primary_references

Inhibitory effects of indicaxanthin on mouse ileal contractility: analysis of the mechanism of action. (2011). https://pubmed.ncbi.nlm.nih.gov/21371457/ DOI: 10.1016/j.ejphar.2011.02.034

route

Ex vivo organ-bath addition

tissue

Organ-bath smooth muscle

Indicaxanthin: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 96–105

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 · Isolated mouse ileal longitudinal muscle · source_derived_draft · unverified_draft

## indicaxanthin-ileal-camp Adding indicaxanthin increased basal and forskolin-stimulated cAMP in mouse ileal muscle. Model/species: Isolated mouse ileal longitudinal muscle Tissue: Organ-bath smooth muscle Exposure: Indicaxanthin; forskolin, IBMX and other pharmacological probes, exact concentrations not in accessed abstract Route: Ex vivo organ-bath addition Duration: Acute responses; exact interval not in accessed abstract Limits: PDE involvement is inferred pharmacologically, not established by an isoform-specific binding or purified-enzyme assay; no clinical motility treatment is tested. Primary reference: Inhibitory effects of indicaxanthin on mouse ileal contractility: analysis of the mechanism of action. (2011). https://pubmed.ncbi.nlm.nih.gov/21371457/ DOI: 10.1016/j.ejphar.2011.02.034 Access: Primary PubMed abstract.

evidence_access

Primary abstract

experimental_model

Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges.

limitations

Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The adapted cells responded more strongly to an adenosine agonist.

primary_references

Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 156–162

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. · source_derived_draft · unverified_draft

## caf-neutrophil-camp The adapted cells responded more strongly to an adenosine agonist. After caffeine exposure, NECA stimulation produced greater cAMP accumulation. Model: Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. Limitations: Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial. Evidence access: Primary abstract Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

evidence_access

Full-text methods 2.14 and results 3.2, Figure 3B; Europe PMC PMC5750604

experimental_model

LXFL529L cytosolic preparation, predominantly PDE4; radioactive cAMP assay.

limitations

Mixed preparation, not a pure PDE isoform or evidence of equivalent inhibition after a normal beverage.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A high-concentration enzyme effect is separate from receptor antagonism.

primary_references

Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29113064/ · DOI 10.3390/medicines4040080

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 404–410

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · LXFL529L cytosolic preparation, predominantly PDE4; radioactive cAMP assay. · source_derived_draft · unverified_draft

## caf-pde A high-concentration enzyme effect is separate from receptor antagonism. Caffeine inhibited measured cAMP-PDE activity by up to about 40% at 250–500 micrograms/mL in the reported assay. Model: LXFL529L cytosolic preparation, predominantly PDE4; radioactive cAMP assay. Limitations: Mixed preparation, not a pure PDE isoform or evidence of equivalent inhibition after a normal beverage. Evidence access: Full-text methods 2.14 and results 3.2, Figure 3B; Europe PMC PMC5750604 Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29113064/ · DOI 10.3390/medicines4040080

dose

6-Gingerol 10 micromolar followed by forskolin 100 micromolar

duration

30 min gingerol followed by 10 min forskolin

evidence_access

Primary open full text, results, figure legends and methods, plus PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Neutrophils isolated from healthy human donors

limitations

Potentiation of a forskolin-stimulated signal is not proof of the same magnitude under basal conditions.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Neutrophils isolated from healthy human donors

plain_language

6-Gingerol pretreatment increased the forskolin-stimulated intracellular cAMP response in human neutrophils.

primary_references

Antineutrophil properties of natural gingerols in models of lupus. (2021). https://pubmed.ncbi.nlm.nih.gov/33373329/ DOI: 10.1172/jci.insight.138385

route

Ex vivo exposure

tissue

Human neutrophil cytosol

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 459–468

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Neutrophils isolated from healthy human donors · source_derived_draft · unverified_draft

## gingerols-6-neutrophil-camp 6-Gingerol pretreatment increased the forskolin-stimulated intracellular cAMP response in human neutrophils. Model/species: Neutrophils isolated from healthy human donors Tissue: Human neutrophil cytosol Exposure: 6-Gingerol 10 micromolar followed by forskolin 100 micromolar Route: Ex vivo exposure Duration: 30 min gingerol followed by 10 min forskolin Limits: Potentiation of a forskolin-stimulated signal is not proof of the same magnitude under basal conditions. Primary reference: Antineutrophil properties of natural gingerols in models of lupus. (2021). https://pubmed.ncbi.nlm.nih.gov/33373329/ DOI: 10.1172/jci.insight.138385 Access: Primary open full text, results, figure legends and methods, plus PubMed metadata.

dose

6-Gingerol 10 micromolar; rolipram 0.1 micromolar comparator

duration

1 h at 37 degrees C

evidence_access

Primary open full text, results, figure legends and methods, plus PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Lysates of human donor neutrophils

limitations

Mixed cAMP-PDE activity was measured; similarity to rolipram does not establish isoform selectivity.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Lysates of human donor neutrophils

plain_language

Adding 6-gingerol reduced human neutrophil lysate cAMP-PDE activity by about 40 percent.

primary_references

Antineutrophil properties of natural gingerols in models of lupus. (2021). https://pubmed.ncbi.nlm.nih.gov/33373329/ DOI: 10.1172/jci.insight.138385

route

Ex vivo lysate assay

tissue

Neutrophil enzyme preparation

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 448–457

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Lysates of human donor neutrophils · source_derived_draft · unverified_draft

## gingerols-6-neutrophil-pde Adding 6-gingerol reduced human neutrophil lysate cAMP-PDE activity by about 40 percent. Model/species: Lysates of human donor neutrophils Tissue: Neutrophil enzyme preparation Exposure: 6-Gingerol 10 micromolar; rolipram 0.1 micromolar comparator Route: Ex vivo lysate assay Duration: 1 h at 37 degrees C Limits: Mixed cAMP-PDE activity was measured; similarity to rolipram does not establish isoform selectivity. Primary reference: Antineutrophil properties of natural gingerols in models of lupus. (2021). https://pubmed.ncbi.nlm.nih.gov/33373329/ DOI: 10.1172/jci.insight.138385 Access: Primary open full text, results, figure legends and methods, plus PubMed metadata.

dose

6-Gingerol 10 micromolar with forskolin or cAMP stimulation

duration

Kinase assay incubation 90 min; cellular pretreatment interval not resolved here

evidence_access

Primary open full text, results, figure legends and methods, plus PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Neutrophils isolated from healthy human donors

limitations

Activity response, not demonstrated direct binding of gingerol to PKA.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Neutrophils isolated from healthy human donors

plain_language

6-Gingerol enhanced measured PKA activity in the stimulated human-neutrophil experiments.

primary_references

Antineutrophil properties of natural gingerols in models of lupus. (2021). https://pubmed.ncbi.nlm.nih.gov/33373329/ DOI: 10.1172/jci.insight.138385

route

Ex vivo exposure and lysate kinase assay

tissue

Human neutrophil PKA activity assay

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 470–479

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Neutrophils isolated from healthy human donors · source_derived_draft · unverified_draft

## gingerols-6-neutrophil-pka 6-Gingerol enhanced measured PKA activity in the stimulated human-neutrophil experiments. Model/species: Neutrophils isolated from healthy human donors Tissue: Human neutrophil PKA activity assay Exposure: 6-Gingerol 10 micromolar with forskolin or cAMP stimulation Route: Ex vivo exposure and lysate kinase assay Duration: Kinase assay incubation 90 min; cellular pretreatment interval not resolved here Limits: Activity response, not demonstrated direct binding of gingerol to PKA. Primary reference: Antineutrophil properties of natural gingerols in models of lupus. (2021). https://pubmed.ncbi.nlm.nih.gov/33373329/ DOI: 10.1172/jci.insight.138385 Access: Primary open full text, results, figure legends and methods, plus PubMed metadata.

dose

Ginger constituent enzyme assay; study used 100 micromolar in tissue experiments, enzyme-assay exposure details not resolved here

duration

Not specified in accessed abstract

evidence_access

Primary PubMed abstract.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Purified PDE4D and PLC beta enzyme preparations

limitations

Preparation species and PLC beta isoform are unresolved; do not label these as a proven specific human tissue target.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Purified PDE4D and PLC beta enzyme preparations

plain_language

6-Gingerol inhibited the purified PDE4D preparation in the airway-mechanism study.

primary_references

Active components of ginger potentiate β-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins. (2014). https://pubmed.ncbi.nlm.nih.gov/23962082/ DOI: 10.1165/rcmb.2013-0133OC

route

In vitro addition

tissue

Cell-free enzyme assays

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 195–204

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Purified PDE4D and PLC beta enzyme preparations · source_derived_draft · unverified_draft

## gingerols-6-pde4d 6-Gingerol inhibited the purified PDE4D preparation in the airway-mechanism study. Model/species: Purified PDE4D and PLC beta enzyme preparations Tissue: Cell-free enzyme assays Exposure: Ginger constituent enzyme assay; study used 100 micromolar in tissue experiments, enzyme-assay exposure details not resolved here Route: In vitro addition Duration: Not specified in accessed abstract Limits: Preparation species and PLC beta isoform are unresolved; do not label these as a proven specific human tissue target. Primary reference: Active components of ginger potentiate β-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins. (2014). https://pubmed.ncbi.nlm.nih.gov/23962082/ DOI: 10.1165/rcmb.2013-0133OC Access: Primary PubMed abstract.

dose

Ginger constituent enzyme assay; study used 100 micromolar in tissue experiments, enzyme-assay exposure details not resolved here

duration

Not specified in accessed abstract

evidence_access

Primary PubMed abstract.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Purified PDE4D and PLC beta enzyme preparations

limitations

Preparation species and PLC beta isoform are unresolved; do not label these as a proven specific human tissue target.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Purified PDE4D and PLC beta enzyme preparations

plain_language

8-Gingerol inhibited the purified PDE4D preparation in the airway-mechanism study.

primary_references

Active components of ginger potentiate β-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins. (2014). https://pubmed.ncbi.nlm.nih.gov/23962082/ DOI: 10.1165/rcmb.2013-0133OC

route

In vitro addition

tissue

Cell-free enzyme assays

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 217–226

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Purified PDE4D and PLC beta enzyme preparations · source_derived_draft · unverified_draft

## gingerols-8-pde4d 8-Gingerol inhibited the purified PDE4D preparation in the airway-mechanism study. Model/species: Purified PDE4D and PLC beta enzyme preparations Tissue: Cell-free enzyme assays Exposure: Ginger constituent enzyme assay; study used 100 micromolar in tissue experiments, enzyme-assay exposure details not resolved here Route: In vitro addition Duration: Not specified in accessed abstract Limits: Preparation species and PLC beta isoform are unresolved; do not label these as a proven specific human tissue target. Primary reference: Active components of ginger potentiate β-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins. (2014). https://pubmed.ncbi.nlm.nih.gov/23962082/ DOI: 10.1165/rcmb.2013-0133OC Access: Primary PubMed abstract.

dose

100 mg whole-ginger extract, approximately 20 mg gingerols daily

duration

7 days; sampling baseline, day 7 and day 14

evidence_access

Primary open full text, results, figure legends and methods, plus PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Healthy volunteers: 9 Michigan participants and 8 Colorado participants

limitations

Small before/after cohorts without placebo; shared research program, not two independent laboratory replications. Individual gingerol attribution and clinical disease benefit are unproven.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Healthy volunteers: 9 Michigan participants and 8 Colorado participants

plain_language

Seven days of whole-ginger extract intake was associated with higher neutrophil cAMP in the healthy-volunteer cohorts.

primary_references

Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans. (2023). https://pubmed.ncbi.nlm.nih.gov/37737262/ DOI: 10.1172/jci.insight.172011

route

Oral mixed extract

tissue

Blood neutrophils, PBMCs and plasma

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 492–501

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Healthy volunteers: 9 Michigan participants and 8 Colorado participants · source_derived_draft · unverified_draft

## gingerols-human-extract-camp Seven days of whole-ginger extract intake was associated with higher neutrophil cAMP in the healthy-volunteer cohorts. Model/species: Healthy volunteers: 9 Michigan participants and 8 Colorado participants Tissue: Blood neutrophils, PBMCs and plasma Exposure: 100 mg whole-ginger extract, approximately 20 mg gingerols daily Route: Oral mixed extract Duration: 7 days; sampling baseline, day 7 and day 14 Limits: Small before/after cohorts without placebo; shared research program, not two independent laboratory replications. Individual gingerol attribution and clinical disease benefit are unproven. Primary reference: Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans. (2023). https://pubmed.ncbi.nlm.nih.gov/37737262/ DOI: 10.1172/jci.insight.172011 Access: Primary open full text, results, figure legends and methods, plus PubMed metadata.

dose

100 mg whole-ginger extract, approximately 20 mg gingerols daily

duration

7 days; sampling baseline, day 7 and day 14

evidence_access

Primary open full text, results, figure legends and methods, plus PubMed metadata.

evidence_scope

literature_reviewed; model-specific source-derived curation, not universally established human effects

experimental_model

Healthy volunteers: 9 Michigan participants and 8 Colorado participants

limitations

Small before/after cohorts without placebo; shared research program, not two independent laboratory replications. Individual gingerol attribution and clinical disease benefit are unproven.

nutrient_topic

Gingerols collection; each molecular form and experimental preparation remains explicit. · Gingerols

organism

Healthy volunteers: 9 Michigan participants and 8 Colorado participants

plain_language

The ginger pilot study did not find a significant increase in PBMC cAMP.

primary_references

Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans. (2023). https://pubmed.ncbi.nlm.nih.gov/37737262/ DOI: 10.1172/jci.insight.172011

route

Oral mixed extract

tissue

Blood neutrophils, PBMCs and plasma

Gingerols: mechanisms, molecular forms and cross-actor connections (2026-09-20) · lines 503–512

Original AI-assisted curation of thirteen primary research papers; study-specific PubMed/DOI links and limitations retained. Not publisher full text. · supports · Healthy volunteers: 9 Michigan participants and 8 Colorado participants · source_derived_draft · unverified_draft

## gingerols-human-extract-pbmc-null The ginger pilot study did not find a significant increase in PBMC cAMP. Model/species: Healthy volunteers: 9 Michigan participants and 8 Colorado participants Tissue: Blood neutrophils, PBMCs and plasma Exposure: 100 mg whole-ginger extract, approximately 20 mg gingerols daily Route: Oral mixed extract Duration: 7 days; sampling baseline, day 7 and day 14 Limits: Small before/after cohorts without placebo; shared research program, not two independent laboratory replications. Individual gingerol attribution and clinical disease benefit are unproven. Primary reference: Ginger intake suppresses neutrophil extracellular trap formation in autoimmune mice and healthy humans. (2023). https://pubmed.ncbi.nlm.nih.gov/37737262/ DOI: 10.1172/jci.insight.172011 Access: Primary open full text, results, figure legends and methods, plus PubMed metadata.