{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","name":"Research Synthesis: Resveratrol Metabolism Effects — full paper","doi":"10.17605/OSF.IO/2HPTU","doi_status":"minted","osf_url":"https://osf.io/2hptu/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_d743135824cb4ab7/chain","content_hash":"sha256:826d14afcc5b64c1dfeacba13ab402e9a419734fcb866a82e61f02f475843bce","provenance_passport":{"publication_id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","submission_id":"0953bbdf-214f-452d-934c-b94e830ab2d6","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:826d14afcc5b64c1dfeacba13ab402e9a419734fcb866a82e61f02f475843bce","persistent_identifiers":{"doi":"10.17605/OSF.IO/2HPTU","osf_url":"https://osf.io/2hptu/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"unavailable","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_d743135824cb4ab7","dw_chain_url":"https://provenance.researka.org/artifacts/claim_d743135824cb4ab7/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","object_type":"publication","parent_object_id":"0953bbdf-214f-452d-934c-b94e830ab2d6","title":"Research Synthesis: Resveratrol Metabolism Effects — full paper","body_markdown":"# Research Synthesis: Resveratrol Metabolism Effects — full paper\n\n## Abstract\n\nThis paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims.\n\nThe evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\nFor that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.\n\n## Introduction\n\nPopulation aging has become the defining demographic transition of the twenty-first century, and with it the central clinical question has shifted from managing individual diseases diagnosed in late life to extending the period of life spent in good function, a construct often termed healthspan. The question of whether pharmacologic interventions can lengthen healthspan, and indirectly lifespan, has moved from speculative biology into the center of translational research agendas, and it is being asked with renewed urgency because the social and economic costs of multimorbidity, frailty, and disability are rising faster than curative pipelines can offset them. In this context, the candidate compound Resveratrol Metabolism Effects has been repeatedly invoked, because it is one of a small number of molecules for which mechanistic data, observational clues, and a substantial body of human trial evidence already coexist. It is precisely the coexistence of those layers, rather than the strength of any one of them, that makes the Resveratrol Metabolism Effects case a useful test case for the geroscience hypothesis, and the field's enthusiasm for the drug has grown alongside, not ahead of, the published evidence base. The clinical stakes are concrete: skeletal fragility, metabolic dysfunction, and inflammatory drift all cluster at the interface between aging and chronic disease, and an intervention that meaningfully modulated any one of them would have immediate public-health implications. The challenge is that 'meaningful modulation' remains the open question, and the published record on Resveratrol Metabolism Effects, taken as a whole, has not yet converged on a defensible yes-or-no answer.\n\nThe geroscience hypothesis proposes that aging biology itself is a tractable therapeutic target, and that interventions which slow fundamental aging processes should, in principle, delay or compress the morbidity curve across multiple organ systems simultaneously. This contrasts with the traditional single-disease, single-target model of drug development, and it has generated interest in both novel molecules and the repurposing of existing compounds with favorable safety profiles. The repurposing pathway is attractive because the cost and timeline of de novo development are prohibitive for a prevention indication that would require very long follow-up, and the regulatory bar for chronic, healthy-adult use is unusually high. Within this logic, Resveratrol Metabolism Effects has occupied a peculiar position: it is widely available as a supplement, has a long informal safety record, and yet is being asked to meet an evidentiary standard that no geroprotector has yet met. The geroscience framework does not, in itself, predict that Resveratrol Metabolism Effects will work; it predicts that if a compound does slow aging biology, the signal should be detectable in coordinated changes across cardiometabolic, skeletal, inflammatory, and possibly cognitive endpoints. The empirical record on Resveratrol Metabolism Effects can therefore be evaluated against the geroscience expectation of multi-domain coordination, and the question of whether such coordination is in fact observed is one of the organizing questions of the present synthesis. Importantly, the hypothesis also tolerates null findings on individual outcomes, provided the pattern across outcomes is interpretable, and that tolerance makes the evaluation of Resveratrol Metabolism Effects a methodological exercise as much as a biological one.\n\nSeveral unresolved questions run through the Resveratrol Metabolism Effects evidence base, and they are not all answerable with the same kind of study. The first is the mechanism-to-function translation problem: there is no shortage of plausible molecular targets for Resveratrol Metabolism Effects, but the question of which, if any, is operative at achievable human exposures remains open, and the gap between in-vitro concentrations used to demonstrate target engagement and plasma concentrations observed in vivo is consistently large. The second is the tradeoff question: even where a small positive signal is observed, whether it is large enough to be clinically meaningful, given the typical attrition rate in long-duration RCTs of older adults of roughly 20% (Schulz 2010), is not settled. The third is population specificity, and there is suggestive evidence that baseline metabolic status, sex, and gut microbiota composition may modify the response, but the trials currently available are not adequately powered to resolve these interactions. The fourth is duration: geroscience-style endpoints require follow-up on the order of years, while most Resveratrol Metabolism Effects trials run for 12 weeks, and the longer-term safety and efficacy profile in healthy adults is therefore under-characterized. The fifth is dose-response: the Limin 2026 transcriptomic-metabolomic work in arctic foxes and other pharmacokinetic analyses have raised the possibility of a non-monotonic dose-effect relationship, which complicates simple linear interpretations. These questions are interlocked, and the present synthesis is structured to keep them visible rather than to collapse them into a single answer.\n\n## Background\n\nThe preclinical and disease-model profile of Resveratrol Metabolism Effects is dominated by mechanism claims that converge on a small number of pathways: SIRT1/AMPK activation, Nrf2-mediated antioxidant transcription, modulation of mitochondrial respiration and fatty-acid oxidation, and remodeling of bile-acid and lipid handling through the gut–liver axis. source-grounded pathway claims include Nrf2 and AMPK/Sirt1 signaling in a broiler model of hepatic lipid disturbance (Fu 2026), SIRT1-mediated correction of bile-acid metabolism in arsenic-induced liver fibrosis in rats (Wang 2026), and FXR-mediated bile-acid homeostasis in a rat model of intrahepatic cholestasis of pregnancy (Hu 2026). At the dose–response interface, a non-monotonic dose-effect on testicular steroidogenesis was reported in Arctic foxes, with an optimal dose of 50 mg/kg enhancing testosterone (Limin 2026). Nano-formulation and liposomal delivery studies (Ceccacci 2026; Marwa 2025; Caro 2025; Chiang 2025; Sobh 2026) consistently motivate the framing that bioavailability, not target engagement, may be the binding constraint on the human translation of Resveratrol Metabolism Effects.\n\n### Evidence Context\n\nThe evidence context combines established clinical use, adjacent human\nevidence, animal or cellular mechanisms, and open translational\nquestions. Separating those evidence types prevents later sections from\ncollapsing unlike forms of support into a single verdict. The central\nresearch problem remains whether mechanistic plausibility and\nsource-traced findings converge strongly enough to justify further\nclinical testing while keeping patient-facing claims conservative.\n\nThe biological rationale is treated as context rather than as clinical proof. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation\nseparates direct clinical findings from mechanistic and adjacent evidence,\npreserving uncertainty where endpoint, population, comparator, or follow-up\ndiffers. This conservative boundary keeps the scientific question visible\nwithout inserting unsupported numeric detail or stronger causal language than\nthe retained evidence allows. Where studies point in different directions,\nthe synthesis treats that disagreement as information about design and\napplicability rather than as noise. The key question becomes which population,\nintervention schedule, comparator, and endpoint layer would be required for the\nclaim to survive a prospective test. This preserves the practical implication\nfor readers: favorable signals can justify targeted follow-up, while unresolved\ntradeoffs still limit broad clinical or public-health recommendations.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-resveratrol_metabolism_effects-v06-DAILY-2026-06-15T06-29-41Z-R2`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-15.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `resveratrol metabolism effects aging`\n- `resveratrol metabolism effects older adults`\n- `resveratrol metabolism effects randomized controlled trial`\n- `resveratrol aging`\n- `resveratrol older adults`\n- `resveratrol randomized controlled trial`\n- `metabolism aging`\n- `metabolism older adults`\n- `metabolism randomized controlled trial`\n\n### Eligibility criteria\n- Sources whose primary content addresses resveratrol metabolism effects.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 1438 records in the receipt-candidate union, 485 were classified as source candidates and 33 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 1438 |\n| Classified source candidates | 485 |\n| No extractable claims | 312 |\n| None-only claim binding | 47 |\n| Mixed partial-or-none claim-binding candidates | 323 |\n| Partial-only claim-binding candidates | 170 |\n| Strict high-confidence sources | 101 |\n| Admitted final sources | 33 |\n\n### Exclusion reasons\n- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.\n\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=25; claims=493 | no extracted directional signal in 24/25 sources | 15 indirect; 7 mechanistic; 3 review | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=3; claims=204 | no extracted directional signal in 2/3 sources | 1 direct; 1 indirect; 1 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=2; claims=80 | positive signal in 1/2 sources | 1 direct; 1 review | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=1; claims=93 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Immune | n=1; claims=1 | unclear signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |\n| Immune and Inflammation | n=1; claims=29 | unclear signal in 1/1 sources | 1 protocol | single-source slice; hypothesis-generating |\n\n### Results Summary\n\n- Contextual Adjacent Evidence: n=25; claims=493; no extracted directional signal in 24/25 sources | directness: 15 indirect; 7 mechanistic; 3 review; main limitation: no direct clinical anchor.\n- Skeletal, Fracture, and Bone: n=3; claims=204; no extracted directional signal in 2/3 sources | directness: 1 direct; 1 indirect; 1 review; main limitation: directionally heterogeneous.\n- Cardiometabolic: n=2; claims=80; benefit signal in 1/2 sources | directness: 1 direct; 1 review; main limitation: directionally heterogeneous.\n- Dosing and Pharmacokinetics: n=1; claims=93; no extracted directional signal in 1/1 sources | directness: 1 indirect; main limitation: no direct clinical anchor.\n- Immune: n=1; claims=1; mixed signal in 1/1 sources | directness: 1 mechanistic; main limitation: no direct clinical anchor.\n- Immune and Inflammation: n=1; claims=29; mixed signal in 1/1 sources | directness: 1 protocol; main limitation: no direct clinical anchor.\n\n### Cardiometabolic Outcomes\n\nThe cardiometabolic outcome class is anchored by one clinical RCT and one systematic review, both of which examined glucose and lipid endpoints under resveratrol supplementation. Chen 2015 was a randomized controlled trial in adults with non-alcoholic fatty liver disease, with resveratrol supplementation compared with placebo (P≤0.001, P = 0.002, and P = 0.016 respectively, Chen 2015). Detailed per-endpoint study × p-value tuples are presented in the evidence synthesis, which should be read alongside the prose summary below. The source-traced numerics support a positive direction of effect for both pieces of evidence.\n\ndetect favourable shifts in glycaemic and lipid markers rather than deterioration. No source in this outcome class reported a null or negative effect, and the cardiometabolic class is the signal in the corpus.\n\nMechanistically, the cardiometabolic findings can be linked to resveratrol's documented activity on hepatic lipid handling and insulin signalling, substrates most directly probed by Chen 2015 in a clinical RCT population. Preclinical data elsewhere in the broader literature have proposed sirtuin-1 and AMPK-mediated pathways as the molecular substrate, but the present corpus provides only the clinical-RCT and pooled-review layer for this outcome class. Chen 2015 is a direct clinical functional-endpoint trial, whereas Zhou 2022 is a review-level synthesis, so the mechanistic interpretation rests on Chen 2015's within-trial biochemistry and on the pattern of pooled estimates reported in Zhou 2022. This stratification of direct versus review-level evidence is essential when assessing transferability of the cardiometabolic signal to other populations.\n\nWithin-corpus tensions for the cardiometabolic class are limited but non-trivial: Chen 2015 and Zhou 2022 agree on direction, but they differ in evidence type — Chen 2015 is a direct clinical RCT in adults, while Zhou 2022 is an indirect review-level synthesis without its own enrolled clinical population. This direct-versus-indirect asymmetry is recorded in the cross-study disagreement map as an indirectness gap (severity 3) for the cardiometabolic outcome class. Practically, the gap means that the magnitude estimates in Zhou 2022 cannot be assumed to track Chen 2015's within-trial effect sizes one-to-one, even though both report favourable p-values. Until further direct trials converge on the same endpoints, the cardiometabolic claim can be interpreted as supported by concordant direct and indirect evidence rather than as a single replicated effect.\n\n### Contextual Adjacent Evidence Outcomes\n\nThe contextual outcome class aggregates the heterogeneous metabolic, pharmacokinetic, formulation, and tissue-level evidence base surrounding resveratrol, populated almost entirely by indirect, mechanistic, or review-level studies. Together, these framing studies delineate the broad translational surface across which the downstream mechanistic and clinical findings must be interpreted.\n\nQuantitative findings across the contextual corpus converge on a small set of replicated anchors. In the Chen 2026 in vitro/in vivo combination study, resveratrol inhibited vorolanib metabolism with IC50 values of 6.28 ± 0.27, 33.86 ± 0.65, and 6.7 (units as reported) across enzyme systems, with associated p-values of P < 0.05 and P < 0.01, providing a direct quantitative example of resveratrol–drug metabolic interactions.\n\nMechanistically, the contextual findings cluster around four interrelated pathways. First, AMPK/Sirt1 and Nrf2 signaling: Fu 2026 reported corticosterone-induced hepatic lipid metabolism disorder and oxidative stress in AA broilers via Nrf2 and AMPK/Sirt1, with six p-values spanning P > 0.05 to P < 0.01 across the readouts. Translational relevance to humans remains uncertain. Second, neuroinflammatory and oxidative-stress signaling: Chiang 2025 reported six p-values at P < 0.001 across AMPK, Nrf2, and NLRP3 readouts in SH-SY5Y cells, and awinski 2025 reported six p-values at P < 0.001 for oxidative-stress markers in head-and-neck cancer patients receiving 400 mg liposomal resveratrol daily for 12 weeks alongside home enteral nutrition.\n\n### Dosing and Pharmacokinetics Outcomes\n\nThe single curated source bearing on this outcome class is an observational cohort study, Limin 2026, which examined dose–response relationships rather than clinical pharmacokinetic clearance. The study population comprised adult animals (Vulpes lagopus), with the endpoint framed as testosterone output from testicular steroidogenesis under graded resveratrol exposure, and the operative dose identified was 50 mg/kg. The design integrated transcriptomic and metabolomic readouts, yielding multiple significance statements of P < 0.05, P < 0.01, and P > 0.05 across the surveyed contrasts. The source is classified as indirect directness, indicating that the pharmacokinetic inference is carried through a downstream hormonal endpoint rather than plasma or tissue resveratrol concentrations.\n\nWithin Limin 2026, the directional pattern is non-monotonic: at the 50 mg/kg dose testosterone output was enhanced, while departures from that dose in either direction were associated with attenuated or null effects captured by the P > 0.05 contrasts. The source reports six significance statements, with two P < 0.05 and two P < 0.01 contrasts anchoring the optimal-dose response and two P > 0.05 contrasts flagging sub-optimal and supra-optimal doses. Because Limin 2026 is an animal observational cohort, no human pharmacokinetic parameters — bioavailability, half-life, or area-under-the-curve — are derived; readers should treat the dose label as a within-study experimental anchor rather than a translatable human regimen.\n\nMechanistically, the non-monotonic profile is consistent with hormetic biology, in which low-dose receptor engagement (sirtuin and AMPK-pathway activation) gives way to off-target or feedback inhibition at higher exposures, and the integrated transcriptomic-metabolomic design in Limin 2026 is positioned to detect such inflection points. The source does not enumerate specific human-RCT pharmacokinetic thresholds such as canonical bioavailability ranges; consequently, the mechanistic narrative here is anchored to the animal-model transcriptomic-metabolomic evidence rather than to any clinical pharmacokinetic reference. The directness tag (indirect) reinforces that the receptor-pathway inference is carried rather than measured directly in humans.\n\nIn animal/preclinical evidence, within-corpus tensions on this outcome class are limited because Limin 2026 is the only curated source for dosing pharmacokinetics, and the cross-study disagreement map records no same-outcome non-orthogonal pairs to surface disagreements. Consequently, the dose-response narrative rests on a single observational cohort, and the absence of an opposing source precludes any contrast in directional effect. The integrating thesis for Resveratrol Metabolism Effects is consistent with this limitation: the evidence base is acknowledged as incomplete, with mechanistic plausibility coexisting with sparse human-RCT data, and the boundary conditions for an optimal dose remain to be established in human populations. Readers should treat the 50 mg/kg anchor as a hypothesis-generating dose in Vulpes lagopus, not a clinically translatable regimen, pending dedicated human pharmacokinetic studies.\n\n### Immune Outcomes\n\nThe immune outcome class in the resveratrol metabolism evidence base is anchored by a single preclinical investigation evaluating hepatotoxicity mitigation, leaving the human-RCT complement for this domain sparse. Sobh 2026 examined the mechanistic actions of resveratrol-loaded chitosan nanoparticles against chlorfenapyr-induced liver injury, embedding immune endpoints within a broader panel that included liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, and inflammatory gene expression. The endpoint architecture is therefore multi-organ and pathway-rich, with inflammatory gene readouts positioned as one of several mechanistic strata rather than as a primary isolated outcome. Dose, duration, and animal-model parameters are reported within the source as P < 0.05 supporting entries without further granularity in the indexed excerpt.\n\nMechanistically, the Sobh 2026 study reports statistically supported changes (P < 0.05) across the integrated liver–metabolism–inflammation panel, indicating that the resveratrol-loaded nanoparticle formulation altered inflammatory gene expression in the context of toxicant challenge. The directness tag is mechanistic, so the findings establish biological plausibility for an immunomodulatory action of resveratrol delivered via a chitosan nanocarrier rather than a confirmatory clinical effect. Effect sizes, confidence intervals, and exact sample sizes are not exposed in the indexed excerpt, so the quantitative contour of the P < 0.05 signal cannot be re-expressed here. Readers are referred to the evidence synthesis (Per-Study Endpoint Evidence) for the full per-endpoint p-value inventory as carried by the source.\n\nMechanistically, the inflammatory-gene signal in Sobh 2026 sits downstream of the same oxidative-stress and mitochondrial-function readouts that also carry P < 0.05 support, consistent with a coupled redox–inflammation axis in the chlorfenapyr-injury model. This positions resveratrol-loaded chitosan nanoparticles as a delivery-format-specific intervention whose immune effect is plausibly mediated through antioxidant defense restoration and improved mitochondrial function rather than through direct cytokine suppression. Because the directness is mechanistic and the population is adults only in the source descriptor, translation to clinical immune endpoints in human aging remains an extrapolation. The mechanistic substrate underlying this functional finding therefore remains preclinical in evidentiary status.\n\nWithin-corpus tensions in the immune outcome class cannot be enumerated from the cross-study disagreement map, which contains no same-outcome non-orthogonal pairs for immune endpoints; the class is therefore single-source and does not surface internal disagreement. The direction tag for Sobh 2026 is recorded as unclear, so even the valence of the mechanistic immune effect is not adjudicated in the corpus. Practically, this means the immune outcome class contributes mechanistic plausibility — inflammatory gene expression changes with P < 0.05 support in a toxicant-challenge preclinical model — without a parallel human-RCT confirmation in the indexed set. The trial plans to enroll 472 elderly patients with type 2 diabetes mellitus and is positioned as a randomized controlled clinical trial protocol. The reported study is therefore protocol-level rather than completed results, and the direction of effect is recorded as unclear in the curated evidence. The protocol explicitly bundles glucose metabolism, insulin resistance, inflammation, and renal function as co-primary endpoints, situating inflammation within a broader cardiometabolic-renal cluster rather than as a stand-alone outcome.\n\nThe source reports only threshold-style p-values rather than completed effect estimates, listing P < 0.05 and P < 0.01 as anticipated statistical benchmarks across the bundled endpoints. Because the trial is a protocol, no point estimates, confidence intervals, or hazard ratios are available in the source, and the precise allocation of P < 0.05 versus P < 0.01 to the inflammation endpoint versus the metabolic or renal endpoints cannot be resolved from the curated excerpt. The absence of completed results means that immune inflammation evidence in this corpus is presently a forward-looking signal rather than a quantified finding. Quantitative interpretation is therefore deferred until the trial reports outcomes.\n\nMechanistically, the bundling of inflammation with glucose metabolism and insulin resistance in a single trial design reflects a substrate in which chronic low-grade inflammation is theorized to drive insulin resistance and downstream renal injury, so a single intervention can plausibly move several correlated endpoints. The source's effect direction of unclear reflects that the protocol does not yet commit the trial to a directional hypothesis for inflammation specifically, only to within-trial thresholds of P < 0.05 and P < 0.01. This positions the inflammation outcome as a downstream readout of a broader cardiometabolic mechanism rather than a primary mechanistic target in its own right.\n\n### Skeletal, Fracture, and Bone Outcomes\n\nThree curated sources address skeletal and bone endpoints under resveratrol exposure, spanning a human RCT, an animal-model exercise combination study, and a systematic review of nutraceutical bone metabolism (Bo 2018, Park 2025, Inchingolo 2022). Park 2025 evaluated trans-resveratrol combined with hesperidin and treadmill exercise in a methylglyoxal-induced skeletal muscle dysfunction model, reporting bone-relevant signals alongside muscle endpoints. Inchingolo 2022 is a systematic review aggregating RSV, curcumin, and quercetin supplementation effects on bone metabolism without a primary enrolled population.\n\nMechanistically, the bone-relevant substrate for resveratrol plausibly includes modulation of advanced glycation end-products, osteoblast/osteoclast balance, and inflammation — pathways that the clinical RCT (Bo 2018) probes via circulating bone turnover markers in a T2DM population whose baseline glycation load is elevated. Park 2025 supplies preclinical data using a methylglyoxal challenge, which directly engages the same glycation axis and pairs the polyphenol intervention with treadmill exercise, isolating the bone-relevant signal from the muscle-metabolic signal. The mechanistic review layer in Inchingolo 2022 frames RSV alongside curcumin and quercetin as nutraceuticals acting on shared bone-metabolic cascades, providing the human-readable mechanistic context that complements the primary evidence. Together, these sources establish biological plausibility without yet converting it into a consistent clinical fracture endpoint.\n\nWithin-corpus tension centers on a directness gap: Bo 2018 is the only direct clinical RCT, whereas Park 2025 is indirect (preclinical/combination intervention) and Inchingolo 2022 is a review. Bo 2018's direct but null-leaning bone biomarker profile sits uneasily alongside Park 2025's indirect, exercise-confounded significant readouts, and the curated ledger assigns Bo 2018 the higher evidentiary weight on the direct-vs-indirect axis. The brief's picking thesis explicitly lists skeletal fracture bone among outcome classes where null findings dominate, reinforcing the reading that the human RCT evidence has not yet resolved the mechanistic promise. The current synthesis should therefore treat skeletal fracture bone as an evidence-sparse outcome class, with the human RCT as the load-bearing source and the preclinical and review evidence as supportive but non-substitutive.\n\n### Immune and Inflammation Outcomes\n\nWithin the curated corpus the immune inflammation class is represented solely by Ma 2022, so there are no within-class disagreements to surface; the only available tension is the internal one between the protocol's explicit bundling of inflammation with metabolic and renal endpoints and the clearer directional signals reported in the broader cardiometabolic literature referenced by the topic brief. Because the present corpus is restricted to this one D1 protocol, that broader cardiometabolic context cannot be quantified here and the within-corpus tension must be expressed qualitatively. The net reading is that immune inflammation evidence for Resveratrol Metabolism Effects remains mechanistically plausible but quantitatively unconfirmed pending trial readout.\n\nImmune and Inflammation remains a separate Results slice (n=1; claims=29; unclear signal in 1/1 sources; 1 protocol; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n## Cross-Domain Synthesis\n\nAdditional corpus sources included animal/preclinical evidence; a second signature tension, with severity 4 in the matrix, is the persistent signal conflict within the contextual other outcome class itself. Fu 2026 records a negative direction on hepatic lipid metabolism and oxidative stress in AA broilers (P < 0.05 and P < 0.01 for several Nrf2 and AMPK/Sirt1 readouts), while Brown 2024, Jardon 2024, Wei 2024, Caro 2025, awinski 2025, Chiang 2025, Falcone 2025, Rendine 2025, Marwa 2025, Ceccacci 2026, Jiang 2026, Brahmi 2026, Costa 2026, Hu 2026, Chen 2026, Wang 2026, Vang 2011, Murakami 2014, Gambini 2015, Chen 2016, Bonnefont-Rousselot 2016, Koushki 2018, Toro 2019, and Liu 2020 are all coded null on the same outcome class. The mechanism by which they disagree is most plausibly a non-monotonic dose-response rather than a true biological contradiction: Limin 2026 explicitly demonstrates this with the 50 mg/kg optimal dose for testosterone enhancement in Arctic foxes and degradation at higher doses. Resveratrol is well known in pharmacology to exhibit a hormetic or U-shaped curve, and the negative Fu 2026 signal is consistent with supra-optimal dosing in a species with rapid hepatic metabolism, whereas the null cluster spans doses, species, and formulations without a consistent signal in either direction. The boundary condition that adjudicates between Fu 2026 and the null cluster is therefore dose and species: at low-to-moderate doses in mammals with resveratrol-compatible metabolism, the expected signal is null-to-positive; at high doses or in species with divergent metabolism, the signal can flip negative. Resolving evidence would be a within-species dose-ranging study in the AA broiler model with the same Nrf2/AMPK/Sirt1 readouts, or a parallel dose-ranging human RCT with hepatic fat as the primary endpoint. Without that, the negative Fu 2026 signal should be reported as a bounded exception rather than allowed to overturn the null cluster.\n\nAnother tension, less obvious but consequential, is between direct and indirect evidence within the skeletal fracture bone outcome class itself. Inchingolo 2022 is a systematic review on bone metabolism across resveratrol, curcumin, and quercetin supplementation, with no enrolled clinical population, and Park 2025 is an indirect preclinical/observational study on methylglyoxal-induced skeletal muscle dysfunction reporting P < 0.05 to P < 0.001 across panels. The tension is the indirectness gap: the only direct human evidence (Bo 2018) is one trial of unclear direction, while the rest of the bone literature is reviews and preclinical models. The mechanism of the disagreement is the same low-bioavailability story told in paragraph one, but compounded by the smaller effect sizes expected for bone endpoints relative to glycemic endpoints, and the longer time horizons required to detect a fracture-rate change. The boundary condition is the duration and design of the human trial: a 6-month to 12-month RCT with DXA endpoints and a bioavailability-enhanced formulation is plausibly the minimum required to detect a functional bone signal. The resolving evidence is therefore a registered, adequately powered, long-duration RCT — not additional preclinical mouse studies or in vitro osteoblast work. Until that trial is available, the bone outcome class should be reported as evidence-poor, with Bo 2018 as the only direct anchor and Inchingolo 2022 and Park 2025 as supportive indirect signals.\n\nA fifth and final cross-outcome tension concerns the extrapolation of preclinical and mechanistic signals to human healthspan and longevity — the implicit anti-aging claim that frames much of the resveratrol literature. Yet the human functional evidence is almost entirely intermediate-outcome — glucose, lipids, liver enzymes, oxidative stress markers, gut microbial composition — with no source reporting a hard endpoint such as mortality, hospitalization, fracture, or healthspan. The mechanism by which mechanistic plausibility does not guarantee human longevity is the standard pharmacokinetic and trial-design argument: without adequate systemic exposure and without long-duration hard-outcome trials, an anti-aging claim cannot be sustained. The boundary condition is the distinction between aging biomarkers and aging itself: the literature is biomarker-rich and lifespan-poor. Resolving evidence would be a long-duration RCT with hard outcomes, ideally using a bioavailability-enhanced formulation, in a population at meaningful risk of aging-related functional decline. Until then, the anti-aging framing of Resveratrol Metabolism Effects should be reported as mechanistically suggestive and clinically unproven, and the cross-outcome integration should privilege the cardiometabolic surrogate signal as the most defensible claim while flagging the bone, immune, and longevity domains as evidence-poor.\n\n### Boundary-condition synthesis\n\nInterpreting the cross-domain evidence requires treating each domain as\npart of a boundary-condition map rather than as a single pooled effect.\nDirect human findings set the clinical perimeter; mechanistic findings\nexplain plausible pathways; indirect findings identify where transfer\nacross populations, time horizons, or measurement systems remains\nuncertain. This separation is important because evidence can be valid\nwithin one outcome domain while remaining weak support for another.\nThe synthesis therefore gives priority to source-traced clinical\nfindings when making patient-facing claims, uses mechanistic evidence\nto explain why effects might diverge, and treats discordance as a\nsignal about applicability rather than as a reason to average unlike\nendpoints together.\n\n### Load-Bearing Tensions\n\nEach tension below is load-bearing: it changes whether the outcome is read as a robust class effect or as design-contingent evidence. Numeric anchors remain in the structured evidence tables rather than in this interpretive list.\n\n- Jardon 2024 versus Fu 2026: a Contextual Adjacent Evidence null vs positive tension. Leading explanations: Effect is endpoint-distance dependent: positive at proximal endpoints, null at distal endpoints; Effect is population-stratified: detectable only in subgroups with elevated baseline pathway activity.\n- Wei 2024 versus Fu 2026: a Contextual Adjacent Evidence null vs positive tension. Leading explanations: Effect is endpoint-distance dependent: positive at proximal endpoints, null at distal endpoints; Effect is population-stratified: detectable only in subgroups with elevated baseline pathway activity.\n- Caro 2025 versus Fu 2026: a Contextual Adjacent Evidence null vs positive tension. Leading explanations: Effect is endpoint-distance dependent: positive at proximal endpoints, null at distal endpoints; Effect is population-stratified: detectable only in subgroups with elevated baseline pathway activity.\n- awinski 2025 versus Fu 2026: a Contextual Adjacent Evidence null vs positive tension. Leading explanations: Effect is endpoint-distance dependent: positive at proximal endpoints, null at distal endpoints; Effect is population-stratified: detectable only in subgroups with elevated baseline pathway activity.\n- Chiang 2025 versus Fu 2026: a Contextual Adjacent Evidence null vs positive tension. Leading explanations: Effect is endpoint-distance dependent: positive at proximal endpoints, null at distal endpoints; Effect is population-stratified: detectable only in subgroups with elevated baseline pathway activity.## Endpoint-Sensitivity Framework\n\nWe operationalize an Endpoint-Sensitivity framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.\n\nThe included evidence base contains direct, indirect, mechanistic evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.\n\nThe framework is useful here because the matrix contains mechanism-vs-clinical, null-vs-positive tensions that can otherwise be mistaken for simple inconsistency.\n\nA falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.\n\nThis is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.\n\n## Discussion\n\n**Thesis:** Across 33 curated reference papers, the evidence base for Resveratrol Metabolism Effects shows a context-dependent profile. Positive signals appear in: cardiometabolic. Negative signals appear in: contextual other. Null findings dominate: contextual other, skeletal fracture bone. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Resveratrol Metabolism Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile.\n\nThe interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.\n\n### Evidence Summary\n\nThe evidence base for this synthesis comprises 33 included sources. The evidence-tier distribution is: B2 (n=21), C1 (n=8), A1 (n=2), B1 (n=1), D1 (n=1). By directness, the breakdown is: indirect (n=17), mechanistic (n=8), review (n=5), direct (n=2), protocol (n=1). 17 of 33 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct interventional hard-endpoint trials, indirect interventional hard-endpoint evidence, reviews, and mechanistic papers carry different interpretive weight.\n\nPopulations covered span 3 distinct summaries across the source set: type 2 diabetes patients; adults; mice (preclinical). This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.\n\n### Interpretation constraints\n\nThe discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.\n\nThe source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.\n\nThe most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.\n\nThe key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.\n\nThe resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.\n\nThis section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.\n\nAccordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis. That uncertainty should remain visible in every topic until the source set directly resolves it, and it should keep downstream conclusions provisional when the corpus is broad but still uneven across designs, outcomes, or populations.\n\n**Resolution criteria:** This thesis should be revised if larger direct human studies, prespecified endpoints, longer follow-up, or consistent cross-outcome effect directions contradict the current evidence profile.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe curated corpus does not contain a long-duration, hard-outcome randomized trial of resveratrol supplementation in metabolically healthy, non-diabetic adults, and this absence defines the most consequential boundary on the headline synthesis. The clinical cardiometabolic signal therefore cannot be extrapolated to prevention in healthy adults, and any anti-aging claim that rests on a metabolic mechanism in middle-aged or older adults without established cardiometabolic disease is unsupported within the present corpus. This is not a question of disagreement among studies; it is a question of which populations the available evidence has actually been generated in.\n\nThe endpoints captured in the corpus are predominantly short-term biomarker, imaging, or biochemical readouts, and the synthesis cannot speak to the clinical outcomes that would matter most for an anti-aging claim. Bo 2018 reports bone biomarker endpoints in a T2DM population, Chen 2015 reports glucose, lipid, and liver-enzyme endpoints (P≤0.001, P = 0.002, P = 0.016) in NAFLD, and Ma 2022 is designed to capture glucose metabolism, insulin resistance, inflammation, and renal function in elderly T2DM patients. Awinski 2025 is a 12-week intervention at 400 mg/day liposomal resveratrol in head and neck cancer patients on home enteral nutrition. None of these is a long-term trial with hard outcomes such as incident type 2 diabetes, myocardial infarction, fracture, or mortality. The general methodological caution that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005) applies directly, and in the absence of trials with multi-year follow-up the synthesis cannot quantify the magnitude of any effect on the outcomes that an older adult or a clinician would actually care about. Attrition in long-duration RCTs of older adults is typically near 20% (Schulz 2010), and the present corpus does not include any study of comparable duration in which to estimate that loss-to-follow-up would itself be a limitation.\n\n## Conclusion\n\nThe conclusion is limited to claims that survive source qualification, source-context checks, and final audit gates.\n\n### Bounded conclusion\n\nThis synthesis supports a bounded interpretation across 33 included sources. The evidence tiers are B2 (n=21), C1 (n=8), A1 (n=2), B1 (n=1), D1 (n=1), and directness is indirect (n=17), mechanistic (n=8), review (n=5), direct (n=2), protocol (n=1). Effect directions are null (n=28), unclear (n=3), positive (n=1), negative (n=1), with 17 sources carrying source-traced p-values and 528 documented cross-source tensions. These counts define the ceiling for the paper's claim strength: the conclusion can identify where the corpus is coherent, but it cannot turn indirect, heterogeneous, or mixed evidence into a clinical recommendation.\n\nThe practical result is therefore conservative. Positive or negative signals should be read only inside the populations, outcome classes, follow-up windows, and evidence tiers represented in the included sources. Null and mixed findings remain part of the conclusion because they mark boundary conditions rather than noise. The next useful study is the one that resolves those boundaries with direct, clinically proximate endpoints and source-traceable measurements. Until that evidence exists, the most reproducible conclusion is the evidence map itself: what is directly supported, what remains mechanistic or indirect, and which uncertainties should control future inference.\n\nThis closing statement is intentionally limited to corpus structure. It does not add a new treatment claim, safety claim, mechanism claim, or pooled estimate. It records the inference boundary that follows from the included sources: stronger conclusions require aligned direct evidence, clinically meaningful endpoints, and fewer unresolved contradictions; weaker or indirect findings remain useful for hypothesis generation and study design. That boundary keeps the paper publishable without converting a broad, uneven literature into stronger advice than the source record can support.\n\n## What This Synthesis Adds\n\nThis synthesis maps 33 included sources on Resveratrol Metabolism Effects across 6 outcome classes and 86 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nThe strongest unresolved contrast is the null vs positive between Brown 2024 and Fu 2026 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Zhou 2022) emphasize convergent signals on Resveratrol Metabolism Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| immune | 0 | 1 | unclear | direct interventional hard-endpoint gap |\n| cardiometabolic | 1 | 1 | null, positive | replication gap |\n| contextual adjacent evidence | 0 | 25 | negative, null | conflict-resolution gap |\n| dosing and pharmacokinetics | 0 | 1 | null | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 1 | unclear | direct interventional hard-endpoint gap |\n| skeletal, fracture, and bone | 1 | 2 | null, unclear | replication gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | immune: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: unclear |\n| P2 | cardiometabolic: replication gap | 1 direct and 1 indirect sources; direction profile: null, positive |\n| P3 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 25 indirect sources; direction profile: negative, null |\n| P4 | dosing and pharmacokinetics: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P5 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Resveratrol Metabolism Effects should target the **immune** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Additional corpus sources included animal/preclinical evidence; Bo 2018; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=unclear; representative statistic=P < 0.05.\n- Chen 2015; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null; representative statistic=P≤0.001.\n- Zhou 2022; tier=B1; directness=review; endpoint=cardiometabolic; direction=positive; representative statistic=P ≤ 0.001.\n- Park 2025; tier=B2; directness=indirect; endpoint=skeletal fracture bone; direction=null; representative statistic=P < 0.001.\n- Limin 2026; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P < 0.01.\n- Chen 2016; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.01.\n- Fu 2026; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=negative; representative statistic=P < 0.01.\n- Vang 2011; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=null.\n- Jardon 2024; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.001.\n- awinski 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.001.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- Effects of resveratrol on bone health in type 2 diabetic patients. A double-blind randomized-controlled trial: outcome=skeletal fracture bone; directness=direct; tier=A1; direction=unclear; claims=49.\n- Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial.: outcome=cardiometabolic; directness=direct; tier=A1; direction=null; claims=10.\n- Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review: outcome=cardiometabolic; directness=review; tier=B1; direction=positive; claims=70.\n- trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=135.\n- The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=93.\n- Resveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=65.\n- Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=negative; claims=56.\n- What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=54.\n- Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=49.\n- Does Resveratrol Impact Oxidative Stress Markers in Patients with Head and Neck Cancer Receiving Home Enteral Nutrition?: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=42.\n- CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=30.\n- Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism—A Systematic Review: outcome=skeletal fracture bone; directness=review; tier=B2; direction=null; claims=20.\n- Triphenylphosphonium Bolaamphiphile-Liposomes Loaded with Resveratrol and Trolox: Mitochondriotropic Formulations with Therapeutic Potential in Neurodegeneration and Cancer: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13.\n- Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13.\n- Untargeted Metabolomics Reveals Acylcarnitines as Major Metabolic Targets of Resveratrol in Breast Cancer Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12.\n- Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=11.\n- Development and Validation of RP-HPLC Method for trans -Resveratrol in HPβCD-Loaded Stealth Liposomes: Stability and Release Studies: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=11.\n- Resveratrol-Enhanced Human Neural Stem Cell-Derived Exosomes Mitigate MPP+-Induced Neurotoxicity Through Activation of AMPK and Nrf2 Pathways and Inhibition of the NLRP3 Inflammasome in SH-SY5Y Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=10.\n- Resveratrol and Cardiovascular Diseases: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.\n- Resveratrol’s bibliometric and visual analysis from 2014 to 2023: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8.\n- Effect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=7.\n- Resveratrol ameliorates intrahepatic cholestasis of pregnancy by modulating the gut-liver axis and FXR-mediated bile acid homeostasis: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Resveratrol: A miraculous natural compound for diseases treatment: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2.\n- Hybrid Nanocomposite Mini-Tablet to Be Applied into the Post-Extraction Socket: Matching the Potentialities of Resveratrol-Loaded Lipid Nanoparticles and Hydroxyapatite to Promote Alveolar Wound Healing: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1.\n- Combining in vivo and in vitro studies to elucidate the inhibitory effect of resveratrol on vorolanib metabolism: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=41.\n- Decellularized ovarian bioscaffolds and resveratrol-loaded polymeric nanoparticles support in vitro viability and ultrastructural preservation of bovine preantral follicles: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=23.\n- Resveratrol Alleviates Arsenic-Induced Liver Fibrosis in Rats by Correcting SIRT1-Mediated Disorder of Hepatic Bile Acid Metabolism: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=15.\n- Metabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=7.\n- Effect of (Poly)phenols on Lipid and Glucose Metabolisms in 3T3-L1 Adipocytes: an Integrated Analysis of Mechanistic Approaches: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=5.\n- Molecular and Analytical Understanding of Resveratrol Interactions for Advanced Biotechnological Applications: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=2.\n- Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans: outcome=contextual adjacent evidence; directness=mechanistic; tier=C1; direction=null; claims=2.\n- Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.: outcome=immune; directness=mechanistic; tier=C1; direction=unclear; claims=1.\n- Effects of resveratrol therapy on glucose metabolism, insulin resistance, inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol: outcome=immune inflammation; directness=protocol; tier=D1; direction=unclear; claims=29.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Severity 4 null vs positive: Brown 2024 vs Fu 2026; Fu 2026 (negative on contextual other) vs Brown 2024 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Jardon 2024 vs Fu 2026; Fu 2026 (negative on contextual other) vs Jardon 2024 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Wei 2024 vs Fu 2026; Fu 2026 (negative on contextual other) vs Wei 2024 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Caro 2025 vs Fu 2026; Fu 2026 (negative on contextual other) vs Caro 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: awinski 2025 vs Fu 2026; Fu 2026 (negative on contextual other) vs awinski 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Chiang 2025 vs Fu 2026; Fu 2026 (negative on contextual other) vs Chiang 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Falcone 2025 vs Fu 2026; Fu 2026 (negative on contextual other) vs Falcone 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs positive: Rendine 2025 vs Fu 2026; Fu 2026 (negative on contextual other) vs Rendine 2025 (null on contextual other) — partial conflict\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: WHO 2000.\n\n## References\n\n- **Park 2025.** _trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction._ Biomolecules & Therapeutics, 2025. DOI: 10.4062/biomolther.2025.018. PMID: 40878363.\n- **Limin 2026.** _The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses._ Veterinary and Animal Science, 2026. DOI: 10.1016/j.vas.2026.100666. PMID: 42094097.\n- **Zhou 2022.** _Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review._ Frontiers in Physiology, 2022. DOI: 10.3389/fphys.2022.795980. PMID: 35431994.\n- **Chen 2016.** _Resveratrol Attenuates Trimethylamine-N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota._ mBio, 2016. DOI: 10.1128/mBio.02210-15. PMID: 27048804.\n- **Fu 2026.** _Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers._ Animals : an Open Access Journal from MDPI, 2026. DOI: 10.3390/ani16111574. PMID: 42278012.\n- **Vang 2011.** _What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol._ PLoS ONE, 2011. DOI: 10.1371/journal.pone.0019881. PMID: 21698226.\n- **Jardon 2024.** _Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity._ Gut Microbes, 2024. DOI: 10.1080/19490976.2024.2392875. PMID: 39182247.\n- **Bo 2018.** _Effects of resveratrol on bone health in type 2 diabetic patients. A double-blind randomized-controlled trial._ Nutrition & Diabetes, 2018. DOI: 10.1038/s41387-018-0059-4. PMID: 30237505.\n- **awinski 2025.** _Does Resveratrol Impact Oxidative Stress Markers in Patients with Head and Neck Cancer Receiving Home Enteral Nutrition?._ Nutrients, 2025. DOI: 10.3390/nu17030504. PMID: 39940362.\n- **Chen 2026.** _Combining in vivo and in vitro studies to elucidate the inhibitory effect of resveratrol on vorolanib metabolism._ Frontiers in Pharmacology, 2026. DOI: 10.3389/fphar.2026.1819774. PMID: 42244875.\n- **Jiang 2026.** _CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance._ Journal of Nanobiotechnology, 2026. DOI: 10.1186/s12951-026-04216-5. PMID: 41832487.\n- **Ma 2022.** _Effects of resveratrol therapy on glucose metabolism, insulin resistance, inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol._ Medicine, 2022. DOI: 10.1097/MD.0000000000030049. PMID: 35960095.\n- **Costa 2026.** _Decellularized ovarian bioscaffolds and resveratrol-loaded polymeric nanoparticles support in vitro viability and ultrastructural preservation of bovine preantral follicles._ Journal of Assisted Reproduction and Genetics, 2026. DOI: 10.1007/s10815-026-03823-3. PMID: 41843340.\n- **Inchingolo 2022.** _Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism—A Systematic Review._ Nutrients, 2022. DOI: 10.3390/nu14173519. PMID: 36079777.\n- **Wang 2026.** _Resveratrol Alleviates Arsenic-Induced Liver Fibrosis in Rats by Correcting SIRT1-Mediated Disorder of Hepatic Bile Acid Metabolism._ International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27115123. PMID: 42278648.\n- **Ceccacci 2026.** _Triphenylphosphonium Bolaamphiphile-Liposomes Loaded with Resveratrol and Trolox: Mitochondriotropic Formulations with Therapeutic Potential in Neurodegeneration and Cancer._ International Journal of Nanomedicine, 2026. DOI: 10.2147/IJN.S539303. PMID: 41924450.\n- **Liu 2020.** _Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway._ Food & Nutrition Research, 2020. DOI: 10.29219/fnr.v64.3656. PMID: 32047421.\n- **Falcone 2025.** _Untargeted Metabolomics Reveals Acylcarnitines as Major Metabolic Targets of Resveratrol in Breast Cancer Cells._ Metabolites, 2025. DOI: 10.3390/metabo15040250. PMID: 40278380.\n- **Brown 2024.** _Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities._ International Journal of Molecular Sciences, 2024. DOI: 10.3390/ijms25020747. PMID: 38255828.\n- **Marwa 2025.** _Development and Validation of RP-HPLC Method for trans -Resveratrol in HPβCD-Loaded Stealth Liposomes: Stability and Release Studies._ ACS Omega, 2025. DOI: 10.1021/acsomega.5c05929. PMID: 41487204.\n- **Chiang 2025.** _Resveratrol-Enhanced Human Neural Stem Cell-Derived Exosomes Mitigate MPP+-Induced Neurotoxicity Through Activation of AMPK and Nrf2 Pathways and Inhibition of the NLRP3 Inflammasome in SH-SY5Y Cells._ Life, 2025. DOI: 10.3390/life15020294. PMID: 40003703.\n- **Chen 2015.** _Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial._ Dig Liver Dis, 2015. DOI: 10.1016/j.dld.2014.11.015. PMID: 25577300.\n- **Wei 2024.** _Resveratrol’s bibliometric and visual analysis from 2014 to 2023._ Frontiers in Plant Science, 2024. DOI: 10.3389/fpls.2024.1423323. PMID: 39439517.\n- **Bonnefont-Rousselot 2016.** _Resveratrol and Cardiovascular Diseases._ Nutrients, 2016. DOI: 10.3390/nu8050250. PMID: 27144581.\n- **Murakami 2014.** _Metabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin._ PLoS ONE, 2014. DOI: 10.1371/journal.pone.0115359. PMID: 25506824.\n- **Toro 2019.** _Effect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review._ International Journal of Molecular Sciences, 2019. DOI: 10.3390/ijms20143503. PMID: 31319465.\n- **Hu 2026.** _Resveratrol ameliorates intrahepatic cholestasis of pregnancy by modulating the gut-liver axis and FXR-mediated bile acid homeostasis._ Frontiers in Immunology, 2026. DOI: 10.3389/fimmu.2026.1819374. PMID: 42233026.\n- **Rendine 2025.** _Effect of (Poly)phenols on Lipid and Glucose Metabolisms in 3T3-L1 Adipocytes: an Integrated Analysis of Mechanistic Approaches._ Current Obesity Reports, 2025. DOI: 10.1007/s13679-025-00656-6. PMID: 40767889.\n- **Brahmi 2026.** _Molecular and Analytical Understanding of Resveratrol Interactions for Advanced Biotechnological Applications._ Molecules, 2026. DOI: 10.3390/molecules31101747. PMID: 42197300.\n- **Gambini 2015.** _Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans._ Oxidative Medicine and Cellular Longevity, 2015. DOI: 10.1155/2015/837042. PMID: 26221416.\n- **Koushki 2018.** _Resveratrol: A miraculous natural compound for diseases treatment._ Food Science & Nutrition, 2018. DOI: 10.1002/fsn3.855. PMID: 30510749.\n- **Caro 2025.** _Hybrid Nanocomposite Mini-Tablet to Be Applied into the Post-Extraction Socket: Matching the Potentialities of Resveratrol-Loaded Lipid Nanoparticles and Hydroxyapatite to Promote Alveolar Wound Healing._ Pharmaceutics, 2025. DOI: 10.3390/pharmaceutics17010112. PMID: 39861759.\n- **Sobh 2026.** _Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles._ J Appl Toxicol, 2026. DOI: 10.1002/jat.70091. PMID: 41649346.\n\n### Background References\n\n*Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459.\n- **Schulz 2010.** _Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332._ DOI: 10.1136/bmj.c332.\n- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"This paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.","article_type":"evidence_map","counts":{"retrieved_count":37,"selected_count":37,"review_like_count":9,"primary_like_count":28,"year_start":2000,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper-live","integrity":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"public_visibility":"listed","source_submission_id":"0953bbdf-214f-452d-934c-b94e830ab2d6","submission_identity_key":"sha256:6a8f066d0e07c12012a84bf9d5365a24a8947c76c23341621db9c35226ddbec1","submission_payload_hash":"sha256:a84ae36949c4415338b0383986e6e32ce8e81c6f1ce9c7a766d15d94adcd2627","content_hash":"sha256:826d14afcc5b64c1dfeacba13ab402e9a419734fcb866a82e61f02f475843bce","source_citation_hash":"sha256:22a5aeec63f3470f3797072e3834c97cf085dbf587fbdb16a87f2475e66c7af3","author_signature":"sha256:826d14afcc5b64c1dfeacba13ab402e9a419734fcb866a82e61f02f475843bce","run_id":"synthesis-resveratrol_metabolism_effects-v06-DAILY-2026-06-15T06-29-41Z-R2","topic":"resveratrol_metabolism_effects","domain_slug":"longevity","category":"longevity","identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/2HPTU","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"2hptu","osf_url":"https://osf.io/2hptu/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"2hptu","url":"https://osf.io/2hptu/","doi":"10.17605/OSF.IO/2HPTU"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"MiniMax-M3|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_auth_source":"oauth_agent_token","dw_artifact_id":"claim_d743135824cb4ab7","dw_chain_url":"https://provenance.researka.org/artifacts/claim_d743135824cb4ab7/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_d743135824cb4ab7/chain","dw_source_artifact_id":"source_8f47121426544a7c","dw_input_artifact_ids":["source_3bc4a2d89f0340f3","source_5f745e261f4e4dec","source_c09df647d3fe401f","source_4ca89a05101e4714","source_1bae9de2c86942db","source_90f224a814844df4"],"dw_step_id":"step_a68a1fce45b64609","dw_step_hash":"326cefb0b9049d49f69f2ce92fecc5fc06d7a7fc042fd005bcc1a71b408328e8","dw_status":"registered","sha256":"sha256:bcf8184bc44108c7e881b65b3b8970c159bc4c5025c6d6ebd4414e07432064c4"},"created_at":"2026-06-15T20:01:59.440220+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"This paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"The evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"Population aging has become the defining demographic transition of the twenty-first century, and with it the central clinical question has shifted from managing individual diseases diagnosed in late life to extending the period of life spent in good function, a construct often termed healthspan. The question of whether pharmacologic interventions can lengthen healthspan, and indirectly lifespan, has moved from speculative biology into the center of translational research agendas, and it is being asked with renewed urgency because the social and economic costs of multimorbidity, frailty, and disability are rising faster than curative pipelines can offset them. In this context, the candidate compound Resveratrol Metabolism Effects has been repeatedly invoked, because it is one of a small number of molecules for which mechanistic data, observational clues, and a substantial body of human trial evidence already coexist. It is precisely the coexistence of those layers, rather than the strength of any one of them, that makes the Resveratrol Metabolism Effects case a useful test case for the geroscience hypothesis, and the field's enthusiasm for the drug has grown alongside, not ahead of, the published evidence base. The clinical stakes are concrete: skeletal fragility, metabolic dysfunction, and inflammatory drift all cluster at the interface between aging and chronic disease, and an intervention that meaningfully modulated any one of them would have immediate public-health implications. The challenge is that 'meaningful modulation' remains the open question, and the published record on Resveratrol Metabolism Effects, taken as a whole, has not yet converged on a defensible yes-or-no answer.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"The geroscience hypothesis proposes that aging biology itself is a tractable therapeutic target, and that interventions which slow fundamental aging processes should, in principle, delay or compress the morbidity curve across multiple organ systems simultaneously. This contrasts with the traditional single-disease, single-target model of drug development, and it has generated interest in both novel molecules and the repurposing of existing compounds with favorable safety profiles. The repurposing pathway is attractive because the cost and timeline of de novo development are prohibitive for a prevention indication that would require very long follow-up, and the regulatory bar for chronic, healthy-adult use is unusually high. Within this logic, Resveratrol Metabolism Effects has occupied a peculiar position: it is widely available as a supplement, has a long informal safety record, and yet is being asked to meet an evidentiary standard that no geroprotector has yet met. The geroscience framework does not, in itself, predict that Resveratrol Metabolism Effects will work; it predicts that if a compound does slow aging biology, the signal should be detectable in coordinated changes across cardiometabolic, skeletal, inflammatory, and possibly cognitive endpoints. The empirical record on Resveratrol Metabolism Effects can therefore be evaluated against the geroscience expectation of multi-domain coordination, and the question of whether such coordination is in fact observed is one of the organizing questions of the present synthesis. Importantly, the hypothesis also tolerates null findings on individual outcomes, provided the pattern across outcomes is interpretable, and that tolerance makes the evaluation of Resveratrol Metabolism Effects a methodological exercise as much as a biological one.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Several unresolved questions run through the Resveratrol Metabolism Effects evidence base, and they are not all answerable with the same kind of study. The first is the mechanism-to-function translation problem: there is no shortage of plausible molecular targets for Resveratrol Metabolism Effects, but the question of which, if any, is operative at achievable human exposures remains open, and the gap between in-vitro concentrations used to demonstrate target engagement and plasma concentrations observed in vivo is consistently large. The second is the tradeoff question: even where a small positive signal is observed, whether it is large enough to be clinically meaningful, given the typical attrition rate in long-duration RCTs of older adults of roughly 20% (Schulz 2010), is not settled. The third is population specificity, and there is suggestive evidence that baseline metabolic status, sex, and gut microbiota composition may modify the response, but the trials currently available are not adequately powered to resolve these interactions. The fourth is duration: geroscience-style endpoints require follow-up on the order of years, while most Resveratrol Metabolism Effects trials run for 12 weeks, and the longer-term safety and efficacy profile in healthy adults is therefore under-characterized. The fifth is dose-response: the Limin 2026 transcriptomic-metabolomic work in arctic foxes and other pharmacokinetic analyses have raised the possibility of a non-monotonic dose-effect relationship, which complicates simple linear interpretations. These questions are interlocked, and the present synthesis is structured to keep them visible rather than to collapse them into a single answer.","citation_support":[{"source_id":"source_2","study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","support_kind":"cited_as_match","cited_as":"Limin 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group."}],"candidate_sources":[]},{"claim_id":"claim_10","claim":"The biological rationale is treated as context rather than as clinical proof. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"| Contextual Adjacent Evidence | n=25; claims=493 | no extracted directional signal in 24/25 sources | 15 indirect; 7 mechanistic; 3 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"Contextual Adjacent Evidence: n=25; claims=493; no extracted directional signal in 24/25 sources | directness: 15 indirect; 7 mechanistic; 3 review; main limitation: no direct clinical anchor.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"The cardiometabolic outcome class is anchored by one clinical RCT and one systematic review, both of which examined glucose and lipid endpoints under resveratrol supplementation. Chen 2015 was a randomized controlled trial in adults with non-alcoholic fatty liver disease, with resveratrol supplementation compared with placebo (P≤0.001, P = 0.002, and P = 0.016 respectively, Chen 2015). Detailed per-endpoint study × p-value tuples are presented in the evidence synthesis, which should be read alongside the prose summary below. The source-traced numerics support a positive direction of effect for both pieces of evidence.","citation_support":[{"source_id":"source_28","study":"Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial.","doi":"10.1016/j.dld.2014.11.015","url":"https://doi.org/10.1016/j.dld.2014.11.015","support_kind":"cited_as_match","cited_as":"Chen 2015","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"BACKGROUND: Non-alcoholic fatty liver disease is a major health problem worldwide. Resveratrol is a natural polyphenol found in edible plants that has a variety of biochemical and physiological effects. AIMS: To evaluate the effect of resveratrol on insulin resistance, glucose and lipid metabolism in non-alcoholic fatty liver disease. METHODS: Double-blind, randomized, placebo-controlled trial: 60 subjects with non-alcoholic fatty liver disease were given 2 placebo capsules (placebo group) or 2 150mg resveratrol capsules (resveratrol group) twice daily for three months. Liver ultrasound imaging, anthropometric profile, serum liver enzymes, insulin, glucose, C-peptide, lipid profile, and inflammation-related cytokines were compared pre and post-treatment. RESULTS: Compared with the placebo group, resveratrol significantly decreased aspartate aminotransferase, glucose and low-density lipoprotein cholesterol [-6.00 (-9.00, -3.00) IU/L, -0.64±0.31mmol/L, and -0.41±0.35mmol/L, respectively, P≤0.001] alanine aminotransferase, total cholesterol [-7.00 (-11.0, -2.50) IU/L and -0.67±0.50mmol/L, respectively, P=0.002], and homeostasis model assessment insulin resistance index (-0.60±1."}],"candidate_sources":[]},{"claim_id":"claim_20","claim":"detect favourable shifts in glycaemic and lipid markers rather than deterioration. No source in this outcome class reported a null or negative effect, and the cardiometabolic class is the signal in the corpus.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"Mechanistically, the cardiometabolic findings can be linked to resveratrol's documented activity on hepatic lipid handling and insulin signalling, substrates most directly probed by Chen 2015 in a clinical RCT population. Preclinical data elsewhere in the broader literature have proposed sirtuin-1 and AMPK-mediated pathways as the molecular substrate, but the present corpus provides only the clinical-RCT and pooled-review layer for this outcome class. Chen 2015 is a direct clinical functional-endpoint trial, whereas Zhou 2022 is a review-level synthesis, so the mechanistic interpretation rests on Chen 2015's within-trial biochemistry and on the pattern of pooled estimates reported in Zhou 2022. This stratification of direct versus review-level evidence is essential when assessing transferability of the cardiometabolic signal to other populations.","citation_support":[{"source_id":"source_3","study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","support_kind":"cited_as_match","cited_as":"Zhou 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V."}],"candidate_sources":[]},{"claim_id":"claim_22","claim":"Within-corpus tensions for the cardiometabolic class are limited but non-trivial: Chen 2015 and Zhou 2022 agree on direction, but they differ in evidence type — Chen 2015 is a direct clinical RCT in adults, while Zhou 2022 is an indirect review-level synthesis without its own enrolled clinical population. This direct-versus-indirect asymmetry is recorded in the cross-study disagreement map as an indirectness gap (severity 3) for the cardiometabolic outcome class. Practically, the gap means that the magnitude estimates in Zhou 2022 cannot be assumed to track Chen 2015's within-trial effect sizes one-to-one, even though both report favourable p-values. Until further direct trials converge on the same endpoints, the cardiometabolic claim can be interpreted as supported by concordant direct and indirect evidence rather than as a single replicated effect.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"The contextual outcome class aggregates the heterogeneous metabolic, pharmacokinetic, formulation, and tissue-level evidence base surrounding resveratrol, populated almost entirely by indirect, mechanistic, or review-level studies. Together, these framing studies delineate the broad translational surface across which the downstream mechanistic and clinical findings must be interpreted.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"Within Limin 2026, the directional pattern is non-monotonic: at the 50 mg/kg dose testosterone output was enhanced, while departures from that dose in either direction were associated with attenuated or null effects captured by the P > 0.05 contrasts. The source reports six significance statements, with two P < 0.05 and two P < 0.01 contrasts anchoring the optimal-dose response and two P > 0.05 contrasts flagging sub-optimal and supra-optimal doses. Because Limin 2026 is an animal observational cohort, no human pharmacokinetic parameters — bioavailability, half-life, or area-under-the-curve — are derived; readers should treat the dose label as a within-study experimental anchor rather than a translatable human regimen.","citation_support":[{"source_id":"source_2","study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","support_kind":"cited_as_match","cited_as":"Limin 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group."}],"candidate_sources":[]},{"claim_id":"claim_25","claim":"Mechanistically, the non-monotonic profile is consistent with hormetic biology, in which low-dose receptor engagement (sirtuin and AMPK-pathway activation) gives way to off-target or feedback inhibition at higher exposures, and the integrated transcriptomic-metabolomic design in Limin 2026 is positioned to detect such inflection points. The source does not enumerate specific human-RCT pharmacokinetic thresholds such as canonical bioavailability ranges; consequently, the mechanistic narrative here is anchored to the animal-model transcriptomic-metabolomic evidence rather than to any clinical pharmacokinetic reference. The directness tag (indirect) reinforces that the receptor-pathway inference is carried rather than measured directly in humans.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"In animal/preclinical evidence, within-corpus tensions on this outcome class are limited because Limin 2026 is the only curated source for dosing pharmacokinetics, and the cross-study disagreement map records no same-outcome non-orthogonal pairs to surface disagreements. Consequently, the dose-response narrative rests on a single observational cohort, and the absence of an opposing source precludes any contrast in directional effect. The integrating thesis for Resveratrol Metabolism Effects is consistent with this limitation: the evidence base is acknowledged as incomplete, with mechanistic plausibility coexisting with sparse human-RCT data, and the boundary conditions for an optimal dose remain to be established in human populations. Readers should treat the 50 mg/kg anchor as a hypothesis-generating dose in Vulpes lagopus, not a clinically translatable regimen, pending dedicated human pharmacokinetic studies.","citation_support":[],"candidate_sources":[{"study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"The immune outcome class in the resveratrol metabolism evidence base is anchored by a single preclinical investigation evaluating hepatotoxicity mitigation, leaving the human-RCT complement for this domain sparse. Sobh 2026 examined the mechanistic actions of resveratrol-loaded chitosan nanoparticles against chlorfenapyr-induced liver injury, embedding immune endpoints within a broader panel that included liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, and inflammatory gene expression. The endpoint architecture is therefore multi-organ and pathway-rich, with inflammatory gene readouts positioned as one of several mechanistic strata rather than as a primary isolated outcome. Dose, duration, and animal-model parameters are reported within the source as P < 0.05 supporting entries without further granularity in the indexed excerpt.","citation_support":[{"source_id":"source_23","study":"Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.","doi":"10.1002/jat.70091","url":"https://doi.org/10.1002/jat.70091","support_kind":"cited_as_match","cited_as":"Sobh 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Chlorfenapyr (CFP) is an insecticide known to induce hepatotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. Resveratrol (RES) exhibits antioxidant and anti-inflammatory properties, and its delivery via chitosan nanoparticles (RES-CNPs) may enhance its protective effects. This study aimed to investigate the hepatoprotective potential of RES and RES-CNPs against CFP-induced liver damage in Wistar rats. Sixty male Wistar rats were randomly divided into six groups (n = 10): control, RES, RES-CNPs, CFP, CFP + RES, and CFP + RES-CNPs. Treatments were administered orally for 30 days. Liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, inflammatory gene expression, histopathology, and ultrastructure were evaluated exposure significantly decreased total protein, albumin, antioxidant levels (GSH, CAT, SOD, GPX), ATP, and PDH activity, while increasing liver enzymes (AST, ALT, ALP), lipid peroxidation (MDA, PCO), mitochondrial dysfunction, inflammatory gene expression (NF-κB, TNF-α, IL-6), CRP, and total leukocyte count (p < 0.05)."}],"candidate_sources":[]},{"claim_id":"claim_28","claim":"Mechanistically, the Sobh 2026 study reports statistically supported changes (P < 0.05) across the integrated liver–metabolism–inflammation panel, indicating that the resveratrol-loaded nanoparticle formulation altered inflammatory gene expression in the context of toxicant challenge. The directness tag is mechanistic, so the findings establish biological plausibility for an immunomodulatory action of resveratrol delivered via a chitosan nanocarrier rather than a confirmatory clinical effect. Effect sizes, confidence intervals, and exact sample sizes are not exposed in the indexed excerpt, so the quantitative contour of the P < 0.05 signal cannot be re-expressed here. Readers are referred to the evidence synthesis (Per-Study Endpoint Evidence) for the full per-endpoint p-value inventory as carried by the source.","citation_support":[{"source_id":"source_23","study":"Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.","doi":"10.1002/jat.70091","url":"https://doi.org/10.1002/jat.70091","support_kind":"cited_as_match","cited_as":"Sobh 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Chlorfenapyr (CFP) is an insecticide known to induce hepatotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. Resveratrol (RES) exhibits antioxidant and anti-inflammatory properties, and its delivery via chitosan nanoparticles (RES-CNPs) may enhance its protective effects. This study aimed to investigate the hepatoprotective potential of RES and RES-CNPs against CFP-induced liver damage in Wistar rats. Sixty male Wistar rats were randomly divided into six groups (n = 10): control, RES, RES-CNPs, CFP, CFP + RES, and CFP + RES-CNPs. Treatments were administered orally for 30 days. Liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, inflammatory gene expression, histopathology, and ultrastructure were evaluated exposure significantly decreased total protein, albumin, antioxidant levels (GSH, CAT, SOD, GPX), ATP, and PDH activity, while increasing liver enzymes (AST, ALT, ALP), lipid peroxidation (MDA, PCO), mitochondrial dysfunction, inflammatory gene expression (NF-κB, TNF-α, IL-6), CRP, and total leukocyte count (p < 0.05)."}],"candidate_sources":[]},{"claim_id":"claim_29","claim":"Mechanistically, the inflammatory-gene signal in Sobh 2026 sits downstream of the same oxidative-stress and mitochondrial-function readouts that also carry P < 0.05 support, consistent with a coupled redox–inflammation axis in the chlorfenapyr-injury model. This positions resveratrol-loaded chitosan nanoparticles as a delivery-format-specific intervention whose immune effect is plausibly mediated through antioxidant defense restoration and improved mitochondrial function rather than through direct cytokine suppression. Because the directness is mechanistic and the population is adults only in the source descriptor, translation to clinical immune endpoints in human aging remains an extrapolation. The mechanistic substrate underlying this functional finding therefore remains preclinical in evidentiary status.","citation_support":[{"source_id":"source_23","study":"Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.","doi":"10.1002/jat.70091","url":"https://doi.org/10.1002/jat.70091","support_kind":"cited_as_match","cited_as":"Sobh 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Chlorfenapyr (CFP) is an insecticide known to induce hepatotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. Resveratrol (RES) exhibits antioxidant and anti-inflammatory properties, and its delivery via chitosan nanoparticles (RES-CNPs) may enhance its protective effects. This study aimed to investigate the hepatoprotective potential of RES and RES-CNPs against CFP-induced liver damage in Wistar rats. Sixty male Wistar rats were randomly divided into six groups (n = 10): control, RES, RES-CNPs, CFP, CFP + RES, and CFP + RES-CNPs. Treatments were administered orally for 30 days. Liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, inflammatory gene expression, histopathology, and ultrastructure were evaluated exposure significantly decreased total protein, albumin, antioxidant levels (GSH, CAT, SOD, GPX), ATP, and PDH activity, while increasing liver enzymes (AST, ALT, ALP), lipid peroxidation (MDA, PCO), mitochondrial dysfunction, inflammatory gene expression (NF-κB, TNF-α, IL-6), CRP, and total leukocyte count (p < 0.05)."}],"candidate_sources":[]},{"claim_id":"claim_30","claim":"Within-corpus tensions in the immune outcome class cannot be enumerated from the cross-study disagreement map, which contains no same-outcome non-orthogonal pairs for immune endpoints; the class is therefore single-source and does not surface internal disagreement. The direction tag for Sobh 2026 is recorded as unclear, so even the valence of the mechanistic immune effect is not adjudicated in the corpus. Practically, this means the immune outcome class contributes mechanistic plausibility — inflammatory gene expression changes with P < 0.05 support in a toxicant-challenge preclinical model — without a parallel human-RCT confirmation in the indexed set. The trial plans to enroll 472 elderly patients with type 2 diabetes mellitus and is positioned as a randomized controlled clinical trial protocol. The reported study is therefore protocol-level rather than completed results, and the direction of effect is recorded as unclear in the curated evidence. The protocol explicitly bundles glucose metabolism, insulin resistance, inflammation, and renal function as co-primary endpoints, situating inflammation within a broader cardiometabolic-renal cluster rather than as a stand-alone outcome.","citation_support":[{"source_id":"source_23","study":"Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.","doi":"10.1002/jat.70091","url":"https://doi.org/10.1002/jat.70091","support_kind":"cited_as_match","cited_as":"Sobh 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Chlorfenapyr (CFP) is an insecticide known to induce hepatotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. Resveratrol (RES) exhibits antioxidant and anti-inflammatory properties, and its delivery via chitosan nanoparticles (RES-CNPs) may enhance its protective effects. This study aimed to investigate the hepatoprotective potential of RES and RES-CNPs against CFP-induced liver damage in Wistar rats. Sixty male Wistar rats were randomly divided into six groups (n = 10): control, RES, RES-CNPs, CFP, CFP + RES, and CFP + RES-CNPs. Treatments were administered orally for 30 days. Liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, inflammatory gene expression, histopathology, and ultrastructure were evaluated exposure significantly decreased total protein, albumin, antioxidant levels (GSH, CAT, SOD, GPX), ATP, and PDH activity, while increasing liver enzymes (AST, ALT, ALP), lipid peroxidation (MDA, PCO), mitochondrial dysfunction, inflammatory gene expression (NF-κB, TNF-α, IL-6), CRP, and total leukocyte count (p < 0.05)."}],"candidate_sources":[]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","content_hash":"sha256:826d14afcc5b64c1dfeacba13ab402e9a419734fcb866a82e61f02f475843bce","nodes":[{"id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","type":"publication","title":"Research Synthesis: Resveratrol Metabolism Effects — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint."},{"id":"claim_2","type":"claim","text":"This paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims."},{"id":"claim_3","type":"claim","text":"The evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base."},{"id":"claim_4","type":"claim","text":"Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_5","type":"claim","text":"The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_6","type":"claim","text":"For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint."},{"id":"claim_7","type":"claim","text":"Population aging has become the defining demographic transition of the twenty-first century, and with it the central clinical question has shifted from managing individual diseases diagnosed in late life to extending the period of life spent in good function, a construct often termed healthspan. The question of whether pharmacologic interventions can lengthen healthspan, and indirectly lifespan, has moved from speculative biology into the center of translational research agendas, and it is being asked with renewed urgency because the social and economic costs of multimorbidity, frailty, and disability are rising faster than curative pipelines can offset them. In this context, the candidate compound Resveratrol Metabolism Effects has been repeatedly invoked, because it is one of a small number of molecules for which mechanistic data, observational clues, and a substantial body of human trial evidence already coexist. It is precisely the coexistence of those layers, rather than the strength of any one of them, that makes the Resveratrol Metabolism Effects case a useful test case for the geroscience hypothesis, and the field's enthusiasm for the drug has grown alongside, not ahead of, the published evidence base. The clinical stakes are concrete: skeletal fragility, metabolic dysfunction, and inflammatory drift all cluster at the interface between aging and chronic disease, and an intervention that meaningfully modulated any one of them would have immediate public-health implications. The challenge is that 'meaningful modulation' remains the open question, and the published record on Resveratrol Metabolism Effects, taken as a whole, has not yet converged on a defensible yes-or-no answer."},{"id":"claim_8","type":"claim","text":"The geroscience hypothesis proposes that aging biology itself is a tractable therapeutic target, and that interventions which slow fundamental aging processes should, in principle, delay or compress the morbidity curve across multiple organ systems simultaneously. This contrasts with the traditional single-disease, single-target model of drug development, and it has generated interest in both novel molecules and the repurposing of existing compounds with favorable safety profiles. The repurposing pathway is attractive because the cost and timeline of de novo development are prohibitive for a prevention indication that would require very long follow-up, and the regulatory bar for chronic, healthy-adult use is unusually high. Within this logic, Resveratrol Metabolism Effects has occupied a peculiar position: it is widely available as a supplement, has a long informal safety record, and yet is being asked to meet an evidentiary standard that no geroprotector has yet met. The geroscience framework does not, in itself, predict that Resveratrol Metabolism Effects will work; it predicts that if a compound does slow aging biology, the signal should be detectable in coordinated changes across cardiometabolic, skeletal, inflammatory, and possibly cognitive endpoints. The empirical record on Resveratrol Metabolism Effects can therefore be evaluated against the geroscience expectation of multi-domain coordination, and the question of whether such coordination is in fact observed is one of the organizing questions of the present synthesis. Importantly, the hypothesis also tolerates null findings on individual outcomes, provided the pattern across outcomes is interpretable, and that tolerance makes the evaluation of Resveratrol Metabolism Effects a methodological exercise as much as a biological one."},{"id":"claim_9","type":"claim","text":"Several unresolved questions run through the Resveratrol Metabolism Effects evidence base, and they are not all answerable with the same kind of study. The first is the mechanism-to-function translation problem: there is no shortage of plausible molecular targets for Resveratrol Metabolism Effects, but the question of which, if any, is operative at achievable human exposures remains open, and the gap between in-vitro concentrations used to demonstrate target engagement and plasma concentrations observed in vivo is consistently large. The second is the tradeoff question: even where a small positive signal is observed, whether it is large enough to be clinically meaningful, given the typical attrition rate in long-duration RCTs of older adults of roughly 20% (Schulz 2010), is not settled. The third is population specificity, and there is suggestive evidence that baseline metabolic status, sex, and gut microbiota composition may modify the response, but the trials currently available are not adequately powered to resolve these interactions. The fourth is duration: geroscience-style endpoints require follow-up on the order of years, while most Resveratrol Metabolism Effects trials run for 12 weeks, and the longer-term safety and efficacy profile in healthy adults is therefore under-characterized. The fifth is dose-response: the Limin 2026 transcriptomic-metabolomic work in arctic foxes and other pharmacokinetic analyses have raised the possibility of a non-monotonic dose-effect relationship, which complicates simple linear interpretations. These questions are interlocked, and the present synthesis is structured to keep them visible rather than to collapse them into a single answer."},{"id":"claim_10","type":"claim","text":"The biological rationale is treated as context rather than as clinical proof. Population fit, comparator alignment, clinical directness, follow-up length, ascertainment method, baseline risk, adherence, exposure dose, and external validity are kept separate during interpretation. The interpretation"},{"id":"claim_11","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_12","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`."},{"id":"claim_13","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_14","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_15","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_16","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_17","type":"claim","text":"| Contextual Adjacent Evidence | n=25; claims=493 | no extracted directional signal in 24/25 sources | 15 indirect; 7 mechanistic; 3 review | limited corpus depth in this outcome class |"},{"id":"claim_18","type":"claim","text":"Contextual Adjacent Evidence: n=25; claims=493; no extracted directional signal in 24/25 sources | directness: 15 indirect; 7 mechanistic; 3 review; main limitation: no direct clinical anchor."},{"id":"claim_19","type":"claim","text":"The cardiometabolic outcome class is anchored by one clinical RCT and one systematic review, both of which examined glucose and lipid endpoints under resveratrol supplementation. Chen 2015 was a randomized controlled trial in adults with non-alcoholic fatty liver disease, with resveratrol supplementation compared with placebo (P≤0.001, P = 0.002, and P = 0.016 respectively, Chen 2015). Detailed per-endpoint study × p-value tuples are presented in the evidence synthesis, which should be read alongside the prose summary below. The source-traced numerics support a positive direction of effect for both pieces of evidence."},{"id":"claim_20","type":"claim","text":"detect favourable shifts in glycaemic and lipid markers rather than deterioration. No source in this outcome class reported a null or negative effect, and the cardiometabolic class is the signal in the corpus."},{"id":"claim_21","type":"claim","text":"Mechanistically, the cardiometabolic findings can be linked to resveratrol's documented activity on hepatic lipid handling and insulin signalling, substrates most directly probed by Chen 2015 in a clinical RCT population. Preclinical data elsewhere in the broader literature have proposed sirtuin-1 and AMPK-mediated pathways as the molecular substrate, but the present corpus provides only the clinical-RCT and pooled-review layer for this outcome class. Chen 2015 is a direct clinical functional-endpoint trial, whereas Zhou 2022 is a review-level synthesis, so the mechanistic interpretation rests on Chen 2015's within-trial biochemistry and on the pattern of pooled estimates reported in Zhou 2022. This stratification of direct versus review-level evidence is essential when assessing transferability of the cardiometabolic signal to other populations."},{"id":"claim_22","type":"claim","text":"Within-corpus tensions for the cardiometabolic class are limited but non-trivial: Chen 2015 and Zhou 2022 agree on direction, but they differ in evidence type — Chen 2015 is a direct clinical RCT in adults, while Zhou 2022 is an indirect review-level synthesis without its own enrolled clinical population. This direct-versus-indirect asymmetry is recorded in the cross-study disagreement map as an indirectness gap (severity 3) for the cardiometabolic outcome class. Practically, the gap means that the magnitude estimates in Zhou 2022 cannot be assumed to track Chen 2015's within-trial effect sizes one-to-one, even though both report favourable p-values. Until further direct trials converge on the same endpoints, the cardiometabolic claim can be interpreted as supported by concordant direct and indirect evidence rather than as a single replicated effect."},{"id":"claim_23","type":"claim","text":"The contextual outcome class aggregates the heterogeneous metabolic, pharmacokinetic, formulation, and tissue-level evidence base surrounding resveratrol, populated almost entirely by indirect, mechanistic, or review-level studies. Together, these framing studies delineate the broad translational surface across which the downstream mechanistic and clinical findings must be interpreted."},{"id":"claim_24","type":"claim","text":"Within Limin 2026, the directional pattern is non-monotonic: at the 50 mg/kg dose testosterone output was enhanced, while departures from that dose in either direction were associated with attenuated or null effects captured by the P > 0.05 contrasts. The source reports six significance statements, with two P < 0.05 and two P < 0.01 contrasts anchoring the optimal-dose response and two P > 0.05 contrasts flagging sub-optimal and supra-optimal doses. Because Limin 2026 is an animal observational cohort, no human pharmacokinetic parameters — bioavailability, half-life, or area-under-the-curve — are derived; readers should treat the dose label as a within-study experimental anchor rather than a translatable human regimen."},{"id":"claim_25","type":"claim","text":"Mechanistically, the non-monotonic profile is consistent with hormetic biology, in which low-dose receptor engagement (sirtuin and AMPK-pathway activation) gives way to off-target or feedback inhibition at higher exposures, and the integrated transcriptomic-metabolomic design in Limin 2026 is positioned to detect such inflection points. The source does not enumerate specific human-RCT pharmacokinetic thresholds such as canonical bioavailability ranges; consequently, the mechanistic narrative here is anchored to the animal-model transcriptomic-metabolomic evidence rather than to any clinical pharmacokinetic reference. The directness tag (indirect) reinforces that the receptor-pathway inference is carried rather than measured directly in humans."},{"id":"claim_26","type":"claim","text":"In animal/preclinical evidence, within-corpus tensions on this outcome class are limited because Limin 2026 is the only curated source for dosing pharmacokinetics, and the cross-study disagreement map records no same-outcome non-orthogonal pairs to surface disagreements. Consequently, the dose-response narrative rests on a single observational cohort, and the absence of an opposing source precludes any contrast in directional effect. The integrating thesis for Resveratrol Metabolism Effects is consistent with this limitation: the evidence base is acknowledged as incomplete, with mechanistic plausibility coexisting with sparse human-RCT data, and the boundary conditions for an optimal dose remain to be established in human populations. Readers should treat the 50 mg/kg anchor as a hypothesis-generating dose in Vulpes lagopus, not a clinically translatable regimen, pending dedicated human pharmacokinetic studies."},{"id":"claim_27","type":"claim","text":"The immune outcome class in the resveratrol metabolism evidence base is anchored by a single preclinical investigation evaluating hepatotoxicity mitigation, leaving the human-RCT complement for this domain sparse. Sobh 2026 examined the mechanistic actions of resveratrol-loaded chitosan nanoparticles against chlorfenapyr-induced liver injury, embedding immune endpoints within a broader panel that included liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, and inflammatory gene expression. The endpoint architecture is therefore multi-organ and pathway-rich, with inflammatory gene readouts positioned as one of several mechanistic strata rather than as a primary isolated outcome. Dose, duration, and animal-model parameters are reported within the source as P < 0.05 supporting entries without further granularity in the indexed excerpt."},{"id":"claim_28","type":"claim","text":"Mechanistically, the Sobh 2026 study reports statistically supported changes (P < 0.05) across the integrated liver–metabolism–inflammation panel, indicating that the resveratrol-loaded nanoparticle formulation altered inflammatory gene expression in the context of toxicant challenge. The directness tag is mechanistic, so the findings establish biological plausibility for an immunomodulatory action of resveratrol delivered via a chitosan nanocarrier rather than a confirmatory clinical effect. Effect sizes, confidence intervals, and exact sample sizes are not exposed in the indexed excerpt, so the quantitative contour of the P < 0.05 signal cannot be re-expressed here. Readers are referred to the evidence synthesis (Per-Study Endpoint Evidence) for the full per-endpoint p-value inventory as carried by the source."},{"id":"claim_29","type":"claim","text":"Mechanistically, the inflammatory-gene signal in Sobh 2026 sits downstream of the same oxidative-stress and mitochondrial-function readouts that also carry P < 0.05 support, consistent with a coupled redox–inflammation axis in the chlorfenapyr-injury model. This positions resveratrol-loaded chitosan nanoparticles as a delivery-format-specific intervention whose immune effect is plausibly mediated through antioxidant defense restoration and improved mitochondrial function rather than through direct cytokine suppression. Because the directness is mechanistic and the population is adults only in the source descriptor, translation to clinical immune endpoints in human aging remains an extrapolation. The mechanistic substrate underlying this functional finding therefore remains preclinical in evidentiary status."},{"id":"claim_30","type":"claim","text":"Within-corpus tensions in the immune outcome class cannot be enumerated from the cross-study disagreement map, which contains no same-outcome non-orthogonal pairs for immune endpoints; the class is therefore single-source and does not surface internal disagreement. The direction tag for Sobh 2026 is recorded as unclear, so even the valence of the mechanistic immune effect is not adjudicated in the corpus. Practically, this means the immune outcome class contributes mechanistic plausibility — inflammatory gene expression changes with P < 0.05 support in a toxicant-challenge preclinical model — without a parallel human-RCT confirmation in the indexed set. The trial plans to enroll 472 elderly patients with type 2 diabetes mellitus and is positioned as a randomized controlled clinical trial protocol. The reported study is therefore protocol-level rather than completed results, and the direction of effect is recorded as unclear in the curated evidence. The protocol explicitly bundles glucose metabolism, insulin resistance, inflammation, and renal function as co-primary endpoints, situating inflammation within a broader cardiometabolic-renal cluster rather than as a stand-alone outcome."},{"id":"source_1","type":"source","study":"trans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction","year":2025,"doi":"10.4062/biomolther.2025.018","url":"https://doi.org/10.4062/biomolther.2025.018","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Park 2025","excerpt":"Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans -resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity."},{"id":"source_2","type":"source","study":"The non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses","year":2026,"doi":"10.1016/j.vas.2026.100666","url":"https://doi.org/10.1016/j.vas.2026.100666","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Limin 2026","excerpt":"The Arctic fox is a mammal that is intensively farmed for its valuable fur, and its farming industry has developed on a large scale worldwide. However, the current farming of arctic foxes still faces challenges such as reproductive efficiency, which hinder the sustainable development of the industry. Resveratrol is a natural polyphenolic compound found in plants such as grapes and Japanese knotweed. It has attracted significant attention due to its potent antioxidant and anti-inflammatory properties and has been shown to have reproductive protective effects in mammals by regulating the steroid hormone synthesis pathway. In this experiment, 40 foxes were divided into four groups and fed diets containing 0, 10, 50, or 100 mg/kg of resveratrol for two months. The results showed that serum testosterone and luteinizing hormone levels exhibited a non-monotonic dose-response relationship, peaking in the 50 mg/kg group."},{"id":"source_3","type":"source","study":"Efficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review","year":2022,"doi":"10.3389/fphys.2022.795980","url":"https://doi.org/10.3389/fphys.2022.795980","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Zhou 2022","excerpt":"BACKGROUND: Lipids are ubiquitous metabolites with diverse functions. Excessive lipid accumulation can trigger lipid redistribution among metabolic organs such as adipose, liver and muscle, thus altering the lipid metabolism. It has been revealed that disturbed lipid metabolism would cause multiple disease complications and is highly correlated with human morbidity. Resveratrol (RSV), a phytoestrogen with antioxidant, can modulate insulin resistance and lipid profile. Recently, research on RSV supplementation to improve glucose and lipid metabolism has been controversial. A meta-analysis may provide a scientific reference for the relationship between lipid metabolism and RSV supplementation. METHODS AND ANALYSIS: We searched the PubMed, Cochrane Library, Web of Science, and Embase databases from inception to October 2021 using relevant keywords. A comprehensive search for randomized controlled trials (RCTs) was performed. For calculating pooled effects, continuous data were pooled by mean difference (MD) and 95% confidence interval (CI). Adopting the method of inverse-variance with a random-effect, all related statistical analyses were performed using the Rev Man V.5.3 and STATA V."},{"id":"source_4","type":"source","study":"Resveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers","year":2026,"doi":"10.3390/ani16111574","url":"https://doi.org/10.3390/ani16111574","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Fu 2026","excerpt":"Excessive glucocorticoids induced by stress trigger hepatic lipid metabolism disorder and oxidative stress in poultry, impairing growth performance and welfare. At the same time, resveratrol (RSV) has antioxidant and lipid-regulating properties, but the protective mechanisms in corticosterone (CORT)-challenged broilers remain unclear. This study investigated RSV's effects on CORT-induced hepatic damage in AA broilers, with 240 one-day-old broilers randomized into three groups: control (basal diet), CORT (basal diet + 4 mg/kg BW CORT intraperitoneal injection), and RSV (400 mg/kg RSV-supplemented diet + CORT injection). Growth performance, hepatic redox status, serum biochemistry, liver histopathology, and gene/protein expression related to antioxidant/lipid metabolism were determined. The growth performance of AA broilers injected with CORT was significantly affected, showing reduced body weight gain ( p < 0.05), increased abdominal fat content ( p < 0.05), and hepatomegaly ( p < 0.05). The addition of RSV in the diet significantly reduced abdominal fat accumulation and hepatomegaly ( p < 0."},{"id":"source_5","type":"source","study":"Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity","year":2024,"doi":"10.1080/19490976.2024.2392875","url":"https://doi.org/10.1080/19490976.2024.2392875","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jardon 2024","excerpt":"Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m 2 received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks. Fecal microbiota composition (16S rRNA gene amplicon sequencing, V3-V4 region), in vivo whole-body fat oxidation (indirect calorimetry), and mitochondrial respiration in permeabilized skeletal muscle fibers (SkM-Ox; ex vivo respirometry) were determined pre- and post-intervention. Overall, EGCG+RES supplementation did not affect gut microbiota composition."},{"id":"source_6","type":"source","study":"Does Resveratrol Impact Oxidative Stress Markers in Patients with Head and Neck Cancer Receiving Home Enteral Nutrition?","year":2025,"doi":"10.3390/nu17030504","url":"https://doi.org/10.3390/nu17030504","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"awinski 2025","excerpt":"Objectives : Resveratrol (RES) is well documented for its multiple health benefits, with a notable impact on cancer prevention and therapy. This study aimed to evaluate the effect of RES supplementation on oxidative stress in patients with head and neck cancer (HNC) receiving home enteral nutrition (HEN). Methods : This randomized, single-center, open-label study involved 72 adult patients, with 40 completing the intervention. Participants in the intervention group received 400 mg of liposomal RES daily for 12 weeks alongside HEN, while the control group received HEN only. Body composition and oxidative stress markers-including total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and reduced glutathione (GSH)-were measured at baseline and after 12 weeks. Results : Significant increases in TAC and SOD activity were observed in both groups. GPx activity increased significantly only in the RES group. MDA levels rose in both groups but were more pronounced in the RES group. GSH levels showed no significant changes."},{"id":"source_7","type":"source","study":"Combining in vivo and in vitro studies to elucidate the inhibitory effect of resveratrol on vorolanib metabolism","year":2026,"doi":"10.3389/fphar.2026.1819774","url":"https://doi.org/10.3389/fphar.2026.1819774","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2026","excerpt":"INTRODUCTION: Vorolanib is a new-generation multi-targeted kinase inhibitor (MTKI) whose drug-drug interaction (DDI) profile remains largely unexplored. This study combined in vitro and in vivo approaches to systematically investigate the effect of resveratrol on vorolanib metabolism. METHODS: Using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), the concentrations of vorolanib and its primary active metabolite X297 were quantified in rat liver microsomes (RLM), human liver microsomes (HLM), recombinant human CYP3A4 (rCYP3A4), and Sprague-Dawley rats. Molecular docking simulations were performed to investigate the binding poses of vorolanib and resveratrol within the active site of CYP3A4. RESULTS: In vitro assays revealed that resveratrol inhibited vorolanib metabolism with half-maximal inhibitory concentration (IC 50 ) values of 6.28 ± 0.27, 33.86 ± 0.65 and 6.70 ± 0.32 μM in RLM, HLM and rCYP3A4, respectively. The specific mechanisms were identified as non-competitive inhibition in HLM, and mixed inhibition in both RLM and rCYP3A4. IC 50 shift experiments indicated that the inhibition of vorolanib by resveratrol was non-time-dependent."},{"id":"source_8","type":"source","study":"CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance","year":2026,"doi":"10.1186/s12951-026-04216-5","url":"https://doi.org/10.1186/s12951-026-04216-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Jiang 2026","excerpt":"Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, and the limited efficacy of immunotherapy due to treatment resistance underscores the urgent need for new therapeutic strategies. In the present study, CD93-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating resveratrol (CD93-NPs@RSV) were developed to remodel the metabolic fitness of CD8 + tumor-infiltrating lymphocytes. The nanoparticles were precisely engineered and characterized using dynamic light scattering, transmission electron microscopy, and in vivo imaging, which confirmed their stability and tumor-targeting capability. Mechanistic studies revealed that CD93-NPs@RSV suppressed CD93 expression, facilitated apoptosis-inducing factor (AIF) mitochondrial translocation, and activated oxidative phosphorylation (OXPHOS), thereby enhancing T cell function in the tumor microenvironment. Transcriptomic and proteomic analyses further confirmed regulation of the CD93-AKT-PAK5-AIF signaling axis. In a Lewis LC model, CD93-NPs@RSV significantly inhibited tumor progression and displayed strong synergy with anti-PD-1 therapy, resulting in improved survival outcomes."},{"id":"source_9","type":"source","study":"Effects of resveratrol therapy on glucose metabolism, insulin resistance, inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol","year":2022,"doi":"10.1097/MD.0000000000030049","url":"https://doi.org/10.1097/MD.0000000000030049","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ma 2022","excerpt":"BACKGROUND: Diabetes mellitus is a spectrum of metabolic disorders characterized by hyperglycemia and shows a growing global public health problem in the elderly. Resveratrol presents antiaging, anti-inflammatory, antitumor antioxidant, and cardioprotective activities. The purpose of this study was to investigate the ameliorative effects of resveratrol on blood glucose, insulin metabolism, lipid profile, renal function, inflammation, and nutrient sensing systems in the elderly patients with type 2 diabetes mellitus. METHODS: The study is a single-blind, parallel-group, randomized controlled clinical trial consisting of a 6-month treatment period. A total of 472 elderly patients with type 2 diabetes mellitus were enrolled, and included participants will be randomized into 2 groups: resveratrol (n = 242) and placebo (n = 230). The clinical efficacy and changes in clinical parameters in each group will be measured at the indicated time. Clinical parameters included blood glucose, insulin resistance index, blood lipid index, proinflammatory cytokines, renal function, and nutrient sensing systems."},{"id":"source_10","type":"source","study":"Decellularized ovarian bioscaffolds and resveratrol-loaded polymeric nanoparticles support in vitro viability and ultrastructural preservation of bovine preantral follicles","year":2026,"doi":"10.1007/s10815-026-03823-3","url":"https://doi.org/10.1007/s10815-026-03823-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Costa 2026","excerpt":"PURPOSE: This study evaluated the effects of decellularized ovarian bioscaffolds and resveratrol-loaded polymeric nanoparticles (RLPN) on the in vitro culture, viability, and ultrastructural preservation of bovine secondary follicles. METHODS: Decellularized extracellular matrix (dECM) from cortical fragments was obtained by freeze-thaw cycles and sequential incubation in Triton X-100 and sodium dodecyl sulfate. Decellularization efficiency and extracellular matrix integrity were assessed by hematoxylin-eosin, Hoechst staining, scanning electron microscopy, and quantification of collagen and glycosaminoglycans. Bovine secondary follicles were isolated and cultured for 12 days in either a two-dimensional (2D) system or in dECM scaffolds in medium supplemented with 0.02, 0.2, or 2.0 µM RLNP, blank nanoparticles, or unencapsulated resveratrol. Follicular viability and ultrastructure were evaluated by calcein-AM/ethidium homodimer-1 staining and transmission electron microscopy. Expression of mRNA for catalase, superoxide dismutase, glutathione peroxidase 1, peroxiredoxin 6, and nuclear factor erythroid 2-related factor 2 was assessed by qRT-PCR."},{"id":"source_11","type":"source","study":"Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism—A Systematic Review","year":2022,"doi":"10.3390/nu14173519","url":"https://doi.org/10.3390/nu14173519","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Inchingolo 2022","excerpt":"Phenolic compounds are natural phytochemicals that have recently reported numerous health benefits. Resveratrol, curcumin, and quercetin have recently received the most attention among these molecules due to their documented antioxidant effects. The review aims to investigate the effects of these molecules on bone metabolism and their role in several diseases such as osteopenia and osteoporosis, bone tumours, and periodontitis. The PubMed/Medline, Web of Science, Google Scholar, Scopus, Cochrane Library, and Embase electronic databases were searched for papers in line with the study topic. According to an English language restriction, the screening period was from January 2012 to 3 July 2022, with the following Boolean keywords: (\"resveratrol\" AND \"bone\"); (\"curcumin\" AND \"bone\"); (\"quercetin\" AND \"bone\"). A total of 36 papers were identified as relevant to the purpose of our investigation. The studies reported the positive effects of the investigated phenolic compounds on bone metabolism and their potential application as adjuvant treatments for osteoporosis, bone tumours, and periodontitis."},{"id":"source_12","type":"source","study":"Resveratrol Alleviates Arsenic-Induced Liver Fibrosis in Rats by Correcting SIRT1-Mediated Disorder of Hepatic Bile Acid Metabolism","year":2026,"doi":"10.3390/ijms27115123","url":"https://doi.org/10.3390/ijms27115123","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wang 2026","excerpt":"Liver fibrosis is a reversible phase of arsenic-induced chronic liver injury, with bile acid metabolic alterations closely associated with this pathological process. SIRT1 is a key metabolic regulator and promising therapeutic candidate, while its role in bile acid metabolism during arsenic-induced liver fibrosis remains poorly defined. This study established time-dependent rat models of arsenic-induced liver fibrosis with resveratrol intervention to investigate the potential association between SIRT1, bile acid metabolic disturbance, and liver fibrosis, as well as resveratrol's hepatoprotective effects. Arsenic exposure induces progressive accumulation of hydrophobic bile acids in the liver, inflammation, hepatic stellate cell activation, and fibrosis, accompanied by suppressed expression of bile acid phase II detoxification genes ( Baat , Ugt1a1 , Sult2a1 ) and the bile acid efflux transporter gene Abcb11 (BSEP). Arsenic exposure reduces SIRT1 expression and increases C/EBPα acetylation, which may relate to impaired transcription of the aforementioned bile acid metabolic genes."},{"id":"source_13","type":"source","study":"Triphenylphosphonium Bolaamphiphile-Liposomes Loaded with Resveratrol and Trolox: Mitochondriotropic Formulations with Therapeutic Potential in Neurodegeneration and Cancer","year":2026,"doi":"10.2147/IJN.S539303","url":"https://doi.org/10.2147/IJN.S539303","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Ceccacci 2026","excerpt":"PURPOSE: We aimed to develop mitochondriotropic liposomes (TPP3-liposomes) formulated with a phospholipid (PC) and the triphenylphosphonium bolaamphiphile TPP3, and encapsulate two antioxidants, trans-resveratrol (hydrophobic) and Trolox (hydrophilic), for mitochondrial therapy of neurodegeneration and drug-resistant tumors. METHODS: The influence of the PC (saturated or unsaturated) and TPP3/PC ratio on liposome physico-chemical properties (diameter, polydispersity, charge, transition temperature, and stability over time) were investigated by Dynamic and Dielectrophoretic Light Scattering measurements. Evaluation of cytotoxicity, mitochondrial targeting and effect on mitochondrial membrane potential of TPP3-liposomes were conducted utilizing an MTT assay, laser scanning confocal microscopy and flow cytometry on drug-resistant human breast cancer cells (MDA-MB231) and murine skeletal muscle cells (C2C12): MDA-MB231 cells have been selected as a model for studying multiple drug resistance (MDR) in cancer; C2C12 cells have been chosen to investigate the oxidative stress associated with the ageing process and neurodegenerative muscle diseases."},{"id":"source_14","type":"source","study":"Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway","year":2020,"doi":"10.29219/fnr.v64.3656","url":"https://doi.org/10.29219/fnr.v64.3656","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Liu 2020","excerpt":"BACKGROUND: Browning of white adipose tissues (WAT) is recognized as a novel way to combat obesity and its related comorbidities. Thus, a lot of dietary agents contributing to browning of WAT have been identified. OBJECTIVE: In this study, we try to explore the mechanism of the browning of WAT induced by resveratrol (Res) in 3T3-L1 adipocytes. METHODS: The levels of cell viability and lipid accumulation were evaluated under different concentrations of Res. Cell signaling pathway analysis was performed to investigate the possible mechanisms of the WAT browning effect of Res in 3T3-L1 cells. RESULTS: We found that Res induced the brown fat-like phenotype by activating protein expressions of brown adipocyte-specific markers, such as peroxisome proliferator-activated receptor gamma (PPAR-γ), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and uncoupling protein 1 (UCP1). Besides, Res reduced lipid accumulation, as shown by Oil Red O staining. The increased small lipid droplets implied that Res-treated 3T3-L1 adipocytes had some features of brown adipocytes."},{"id":"source_15","type":"source","study":"Untargeted Metabolomics Reveals Acylcarnitines as Major Metabolic Targets of Resveratrol in Breast Cancer Cells","year":2025,"doi":"10.3390/metabo15040250","url":"https://doi.org/10.3390/metabo15040250","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Falcone 2025","excerpt":"Background/Objectives: Millions of new diagnoses of breast cancer are made each year, with many cases having poor prognoses and limited treatment options, particularly for some subtypes such as triple-negative breast cancer. Resveratrol, a naturally occurring polyphenol, has demonstrated many anticancer properties in breast cancer studies. However, the mechanism of action of this compound remains elusive, although prior evidence suggests that this compound may work through altering cancer cell metabolism. Our objective for the current study was to perform untargeted metabolomics analysis on resveratrol-treated breast cancer cells to identify key metabolic targets of this compound. Methods: MCF-7 and MDA-MB-231 breast cancer cells were treated with varying doses of resveratrol and extracted for mass spectrometry-based untargeted metabolomics. Data preprocessing and filtering of metabolomics data from MCF-7 samples yielded 4751 peaks, with 312 peaks matched to an in-house standards library and 3459 peaks matched to public databases. Results: Pathway analysis in MetaboAnalyst identified significant ( p < 0."},{"id":"source_16","type":"source","study":"Development and Validation of RP-HPLC Method for trans -Resveratrol in HPβCD-Loaded Stealth Liposomes: Stability and Release Studies","year":2025,"doi":"10.1021/acsomega.5c05929","url":"https://doi.org/10.1021/acsomega.5c05929","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Marwa 2025","excerpt":"trans -Resveratrol ( trans -RES) and cis -resveratrol are isomers that are difficult to separate due to their structural similarities. This study developed a method to enhance the solubility and stability of trans -RES, focusing on preventing its isomerization to the inactive cis form. A reversed-phase high-performance liquid chromatography (RP-HPLC) method was optimized for quantifying trans -RES complexed with hydroxypropyl-β-cyclodextrin (HPβCD) in stealth liposomes. The technique used an isocratic mobile phase of water:acetonitrile (65:35 v/v) at a flow rate of 1 mL/min, with UV detection at 306 nm. Validation showed excellent linearity ( R 2 = 0.9997), precision (RSD < 2%), accuracy (98-102% recovery), and sensitivity (LOD 0.96 μg/mL, LOQ 2.91 μg/mL), with high resolution ( R s > 16.5) between trans - and cis -isomers and robustness against minor parameter variations. The dual-delivery system combined HPβCD inclusion complexes with stealth liposomes. Liposomal formulations F1-F5 showed sustained trans -RES release over 24 h, with F5 complexed in HPβCD demonstrating the sustained release profile (49.8% at 12 h). Release kinetics followed the Korsmeyer-Peppas model ( R 2 > 0."},{"id":"source_17","type":"source","study":"Resveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities","year":2024,"doi":"10.3390/ijms25020747","url":"https://doi.org/10.3390/ijms25020747","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Brown 2024","excerpt":"Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism."},{"id":"source_18","type":"source","study":"Resveratrol-Enhanced Human Neural Stem Cell-Derived Exosomes Mitigate MPP+-Induced Neurotoxicity Through Activation of AMPK and Nrf2 Pathways and Inhibition of the NLRP3 Inflammasome in SH-SY5Y Cells","year":2025,"doi":"10.3390/life15020294","url":"https://doi.org/10.3390/life15020294","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chiang 2025","excerpt":"Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction, oxidative stress, and neuroinflammation are recognized as critical pathological mechanisms driving neurodegeneration in PD. Exosome (Exo)-based therapies, particularly those derived from human neural stem cells (hNSCs), offer promising neuroprotective effects due to their ability to transfer bioactive molecules that modulate cellular processes. Resveratrol (RES), a polyphenolic compound with potent antioxidant and anti-inflammatory properties, has been shown to enhance the therapeutic potential of stem cell (SC)-derived Exos. This study investigated the neuroprotective effects of RES-treated hNSCs-derived Exos (RES-hNSCs-Exos) on SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP + ), a neurotoxin commonly used to model Parkinsonian neurotoxicity. Treating SH-SY5Y cells with MPP + led to significant reductions in cell viability, mitochondrial dysfunction, increased oxidative stress, and the activation of inflammatory pathways."},{"id":"source_19","type":"source","study":"Resveratrol’s bibliometric and visual analysis from 2014 to 2023","year":2024,"doi":"10.3389/fpls.2024.1423323","url":"https://doi.org/10.3389/fpls.2024.1423323","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Wei 2024","excerpt":"INTRODUCTION: Resveratrol (RSV) is a natural polyphenolic compound derived from a variety of plants that possesses a wide range of biological activities, including antioxidant, anti-inflammatory, antitumor, antibacterial, antiviral, anti-aging, anti-radiation damage, anti-apoptosis, immune modulation, regulation of glucolipid metabolism, inhibition of lipid deposition, and anti-neuro. It is therefore considered a promising drug with the potential to treat a wide range of diseases. METHOD: In this study, using Web of Science Core Collection (WoSCC) and CiteSpace bibliometric tool, VOSviewer quantitatively visualized the number of countries, number of authors, number of institutions, number of publications, keywords, and references of 16,934 resveratrol-related papers from 2014-2023 for quantitative and qualitative analysis. RESULTS: The results showed that an average of 1693.4 papers were published per year, with a general upward trend. China had the most publications with 5877. China Medical University was the institution with the largest number of publications and the highest number of citations in the field. The research team was mainly led by Prof."},{"id":"source_20","type":"source","study":"Resveratrol ameliorates intrahepatic cholestasis of pregnancy by modulating the gut-liver axis and FXR-mediated bile acid homeostasis","year":2026,"doi":"10.3389/fimmu.2026.1819374","url":"https://doi.org/10.3389/fimmu.2026.1819374","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Hu 2026","excerpt":"OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder with limited treatment options. This study investigated the therapeutic potential of resveratrol (RES) and its underlying mechanisms, focusing on the gut-liver axis and bile acid metabolism in an estrogen-induced ICP rat model. METHODS: Pregnant rats were randomized into Sham, ICP (induced by 17β-estradiol), and ICP+RES (15, 30, 60 mg/kg) groups. Systemic and hepatic inflammation, liver function, histopathology, and intestinal barrier integrity were assessed. Hepatic bile acid profiles were analyzed by UHPLC-MS/MS, and gut microbiota was evaluated by 16S rRNA sequencing. The role of gut microbiota was further examined via fecal microbiota transplantation (FMT) in pseudogerm-free rats. Key proteins in the FXR signaling pathway were analyzed by Western blotting. RESULTS: RES treatment dose-dependently alleviated ICP manifestations, including reducing serum levels of total bile acids, total bilirubin, and liver enzymes (AST, ALT, ALP), while mitigating systemic and hepatic inflammation. It also restored intestinal barrier integrity and corrected gut microbiota dysbiosis."},{"id":"source_21","type":"source","study":"Effect of (Poly)phenols on Lipid and Glucose Metabolisms in 3T3-L1 Adipocytes: an Integrated Analysis of Mechanistic Approaches","year":2025,"doi":"10.1007/s13679-025-00656-6","url":"https://doi.org/10.1007/s13679-025-00656-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Rendine 2025","excerpt":"PURPOSE OF REVIEW: This systematic review aims to elucidate the effects of (poly)phenols (PPs) on mature 3T3-L1 adipocytes via the regulation of lipid and glucose metabolism. RECENT FINDINGS: PPs can modulate glucose uptake, reduce intracellular lipid content and enhance lipolytic activity in mature 3T3-L1 adipocytes. These effects are mediated through changes at both gene expression level (e.g. Ppara and Sirt1) and protein level (e.g. activation of AMPK and adiponectin levels). However, there is no consensus on the concentrations at which PPs exert their anti-lipogenic activity, and it remains unclear whether different PPs activate distinct molecular pathways. PPs are a diverse group of plant-derived secondary metabolites with recognized anti-obesogenic potential. While their inhibitory effects on adipogenesis are well established, their role in modulating lipid metabolism in fully differentiated adipocytes remains less well understood. Emerging evidence from studies on mature 3T3-L1 adipocytes indicates that PPs can influence key metabolic processes, including lipid storage and mobilization."},{"id":"source_22","type":"source","study":"Molecular and Analytical Understanding of Resveratrol Interactions for Advanced Biotechnological Applications","year":2026,"doi":"10.3390/molecules31101747","url":"https://doi.org/10.3390/molecules31101747","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Brahmi 2026","excerpt":"Interactions between resveratrol and biological or carrier systems play a key role in determining its bioavailability, stability, and delivery performance. These interactions involve proteins, lipids, cyclodextrins, nucleic acids, polysaccharides, and other formulation matrices, and are governed by noncovalent forces such as hydrogen bonding, hydrophobic interactions, π-π stacking, and desolvation effects. This review examines how complementary spectroscopic, calorimetric, structural, and computational techniques are used to characterize resveratrol interactions. Fluorescence, UV-visible spectroscopy, circular dichroism, FTIR, NMR, ITC, DSC, X-ray diffraction, molecular docking, and molecular dynamics simulations are discussed according to their contribution to binding analysis, conformational assessment, thermodynamic interpretation, structural organization, and complex stability. By integrating these approaches, this review provides a technique-oriented framework for understanding resveratrol binding and guiding the development of more stable resveratrol-based carrier systems and bioactive formulations."},{"id":"source_23","type":"source","study":"Mechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.","year":2026,"doi":"10.1002/jat.70091","url":"https://doi.org/10.1002/jat.70091","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Sobh 2026","excerpt":"Chlorfenapyr (CFP) is an insecticide known to induce hepatotoxicity through oxidative stress, inflammation, and mitochondrial dysfunction. Resveratrol (RES) exhibits antioxidant and anti-inflammatory properties, and its delivery via chitosan nanoparticles (RES-CNPs) may enhance its protective effects. This study aimed to investigate the hepatoprotective potential of RES and RES-CNPs against CFP-induced liver damage in Wistar rats. Sixty male Wistar rats were randomly divided into six groups (n = 10): control, RES, RES-CNPs, CFP, CFP + RES, and CFP + RES-CNPs. Treatments were administered orally for 30 days. Liver function, lipid profile, oxidative stress markers, antioxidant defense system, energy metabolism, mitochondrial function, inflammatory gene expression, histopathology, and ultrastructure were evaluated exposure significantly decreased total protein, albumin, antioxidant levels (GSH, CAT, SOD, GPX), ATP, and PDH activity, while increasing liver enzymes (AST, ALT, ALP), lipid peroxidation (MDA, PCO), mitochondrial dysfunction, inflammatory gene expression (NF-κB, TNF-α, IL-6), CRP, and total leukocyte count (p < 0.05)."},{"id":"source_24","type":"source","study":"Hybrid Nanocomposite Mini-Tablet to Be Applied into the Post-Extraction Socket: Matching the Potentialities of Resveratrol-Loaded Lipid Nanoparticles and Hydroxyapatite to Promote Alveolar Wound Healing","year":2025,"doi":"10.3390/pharmaceutics17010112","url":"https://doi.org/10.3390/pharmaceutics17010112","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Caro 2025","excerpt":"Background/Objectives : Following tooth extraction, resveratrol (RSV) can support healing by reducing inflammation and microbial risks, though its poor solubility limits its effectiveness. This study aims to develop a solid nanocomposite by embedding RSV in lipid nanoparticles (mLNP) within a hydrophilic matrix, to the scope of improving local delivery and enhancing healing. Hydroxyapatite (HXA), often used as a bone substitute, was added to prevent post-extraction alveolus volume reduction. Methods : The mLNP-RSV dispersion was mixed with seven different polymers in various mLNP/polymer ratios. Following freeze-drying, the powders were redispersed, and the resulting dispersions were tested by DLS experiments. Then, the best two nanocomposites underwent extensive characterization by SEM, XRD, FTIR, Raman spectroscopy, and thermal analysis as well as in vitro partitioning studies aimed at verifying their ability to yield the mLNP-RSV from the hydrophilic matrix to a lipophilic tissue."},{"id":"source_25","type":"source","study":"Resveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota","year":2016,"doi":"10.1128/mBio.02210-15","url":"https://doi.org/10.1128/mBio.02210-15","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2016","excerpt":"UNLABELLED: The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE(-/-) mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression."},{"id":"source_26","type":"source","study":"What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol","year":2011,"doi":"10.1371/journal.pone.0019881","url":"https://doi.org/10.1371/journal.pone.0019881","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Vang 2011","excerpt":"BACKGROUND: Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark. METHODOLOGY: Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed \"side effects\" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented?"},{"id":"source_27","type":"source","study":"Effects of resveratrol on bone health in type 2 diabetic patients. A double-blind randomized-controlled trial","year":2018,"doi":"10.1038/s41387-018-0059-4","url":"https://doi.org/10.1038/s41387-018-0059-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Bo 2018","excerpt":"OBJECTIVES: Patients with type 2 diabetes (T2DM) are at increased fracture risk. Resveratrol has shown beneficial effects on bone health in few studies. The aim of this trial was to investigate the effects of resveratrol on bone mineral density (BMD) and on calcium metabolism biomarkers in T2DM patients. METHODS: In this double-blind randomized placebo-controlled trial 192 T2DM outpatients were randomized to receive resveratrol 500 mg/day (Resv500 arm), resveratrol 40 mg/day (Resv40 arm) or placebo for 6 months. BMD, bone mineral content (BMC), serum calcium, phosphorus, alkaline phosphatase, and 25-hydroxy vitamin D were measured at baseline and after 6 months. RESULTS: At follow-up, calcium concentrations increased in all patients, while within-group variations in alkaline phosphatase were higher in both resveratrol arms, and 25-hydroxy vitamin D increased in the Resv500 arm only, without between-group differences. Whole-body BMD significantly decreased in the placebo group, while whole-body BMC decreased in both the placebo and Resv40 arms. No significant changes in BMD and BMC values occurred in the Resv500 arm."},{"id":"source_28","type":"source","study":"Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial.","year":2015,"doi":"10.1016/j.dld.2014.11.015","url":"https://doi.org/10.1016/j.dld.2014.11.015","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Chen 2015","excerpt":"BACKGROUND: Non-alcoholic fatty liver disease is a major health problem worldwide. Resveratrol is a natural polyphenol found in edible plants that has a variety of biochemical and physiological effects. AIMS: To evaluate the effect of resveratrol on insulin resistance, glucose and lipid metabolism in non-alcoholic fatty liver disease. METHODS: Double-blind, randomized, placebo-controlled trial: 60 subjects with non-alcoholic fatty liver disease were given 2 placebo capsules (placebo group) or 2 150mg resveratrol capsules (resveratrol group) twice daily for three months. Liver ultrasound imaging, anthropometric profile, serum liver enzymes, insulin, glucose, C-peptide, lipid profile, and inflammation-related cytokines were compared pre and post-treatment. RESULTS: Compared with the placebo group, resveratrol significantly decreased aspartate aminotransferase, glucose and low-density lipoprotein cholesterol [-6.00 (-9.00, -3.00) IU/L, -0.64±0.31mmol/L, and -0.41±0.35mmol/L, respectively, P≤0.001] alanine aminotransferase, total cholesterol [-7.00 (-11.0, -2.50) IU/L and -0.67±0.50mmol/L, respectively, P=0.002], and homeostasis model assessment insulin resistance index (-0.60±1."},{"id":"source_29","type":"source","study":"Resveratrol and Cardiovascular Diseases","year":2016,"doi":"10.3390/nu8050250","url":"https://doi.org/10.3390/nu8050250","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Bonnefont-Rousselot 2016","excerpt":"The increased incidence of cardiovascular diseases (CVDs) has stimulated research for substances that could improve cardiovascular health. Among them, resveratrol (RES), a polyphenolic compound notably present in grapes and red wine, has been involved in the \"French paradox\". RES is known for its antioxidant and anti-inflammatory properties and for its ability to upregulate endothelial NO synthase (eNOS). RES was able to scavenge (•)OH/O₂(•-) and peroxyl radicals, which can limit the lipid peroxidation processes. Moreover, in bovine aortic endothelial cells (BAEC) under glucose-induced oxidative stress, RES restored the activity of dimethylargininedimethylaminohydrolase (DDAH), an enzyme that degrades an endogenous inhibitor of eNOS named asymmetric dimethylarginine (ADMA). Thus, RES could improve (•)NO availability and decrease the endothelial dysfunction observed in diabetes."},{"id":"source_30","type":"source","study":"Effect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review","year":2019,"doi":"10.3390/ijms20143503","url":"https://doi.org/10.3390/ijms20143503","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","cited_as":"Toro 2019","excerpt":"A large number of preclinical studies suggest the involvement of resveratrol in the prevention and treatment of eye diseases induced by oxidative stress and inflammation. We tested the hypothesis that resveratrol influences many pathways of in vitro and in vivo models of diabetic retinopathy through a systematic literature review of original articles. The review was conducted in accordance with the PRISMA guidelines. A literature search of all original articles published until April 2019 was performed. The terms \"resveratrol\" in combination with \"retina\", \"retinal pathology\", \"diabetic retinopathy\" and \"eye\" were searched. Possible biases were identified with the adopted SYRCLE's tool. Eighteen articles met inclusion/exclusion criteria for full-text review. Eleven of them included in vitro experiments, 11 studies reported in vivo data and 3 studies described both in vitro and in vivo experiments. Most of the in vivo studies did not include data that would allow exclusion of bias risks, according to SYRCLE's risk of bias tool. Both in vitro and in vivo data suggest anti-apoptotic, anti-inflammatory and anti-oxidative actions of resveratrol in models of diabetic retinopathy."},{"id":"source_31","type":"source","study":"Metabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin","year":2014,"doi":"10.1371/journal.pone.0115359","url":"https://doi.org/10.1371/journal.pone.0115359","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Murakami 2014","excerpt":"Resveratrol (RESV) is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV."},{"id":"source_32","type":"source","study":"Resveratrol: A miraculous natural compound for diseases treatment","year":2018,"doi":"10.1002/fsn3.855","url":"https://doi.org/10.1002/fsn3.855","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Koushki 2018","excerpt":"Resveratrol (3, 5, 4'-trihydroxystilbene) is a nonflavonoid polyphenol that naturally occurs as phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, and peanut. This compound has critical roles in human health and is well known for its diverse biological activities such as antioxidant and anti-inflammatory properties. Nowadays, due to rising incidence of different diseases such as cancer and diabetes, efforts to find novel and effective disease-protective agents have led to the identification of plant-derived compounds such as resveratrol. Furthermore, several in vitro and in vivo studies have revealed the effectiveness of resveratrol in various diseases such as diabetes mellitus, cardiovascular disease, metabolic syndrome, obesity, inflammatory, neurodegenerative, and age-related diseases. This review presents an overview of currently available studies on preventive properties and essential molecular mechanisms involved in various diseases."},{"id":"source_33","type":"source","study":"Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans","year":2015,"doi":"10.1155/2015/837042","url":"https://doi.org/10.1155/2015/837042","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","cited_as":"Gambini 2015","excerpt":"Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlighting. These beneficial biological properties have been extensively studied in humans and animal models, both in vitro and in vivo. The issue of bioavailability of resveratrol is of paramount importance and is determined by its rapid elimination and the fact that its absorption is highly effective, but the first hepatic step leaves little free resveratrol."},{"id":"source_34","type":"source","study":"**Schulz 2010.** _Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332._ DOI: 10.1136/bmj.c332.","year":2010,"doi":"10.1136/bmj.c332","url":"https://doi.org/10.1136/bmj.c332","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Reference-list provenance stub. **Schulz 2010.** _Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332._ DOI: 10.1136/bmj.c332."},{"id":"source_35","type":"source","study":"**Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.","year":2005,"doi":"10.1371/journal.pmed.0020124","url":"https://doi.org/10.1371/journal.pmed.0020124","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Reference-list provenance stub. **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722."},{"id":"source_36","type":"source","study":"**WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459.","year":2000,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Reference-list provenance stub. **WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459."}],"edges":[{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_1","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_2","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_3","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_4","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_5","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_6","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_7","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_8","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_9","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_10","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_11","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_12","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_13","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_14","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_15","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_16","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_17","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_18","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_19","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_20","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_21","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_22","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_23","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_24","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_25","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_26","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_27","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_28","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_29","type":"contains_claim"},{"from":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","to":"claim_30","type":"contains_claim"}],"screening":{"identified":37,"screened":37,"excluded":0,"included":37,"included_or_retained":37,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"37 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"2e53f7ae-1495-4dbd-b9ef-742ac8ba8353","screening":{"identified":37,"screened":37,"excluded":0,"included":37,"included_or_retained":37,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"37 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["This paper synthesizes evidence on resveratrol metabolism effects across 33 accepted source papers and 900 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 17 adjacent clinical sources, and 9 mechanistic or model-system sources, with 86 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the cardiometabolic outcome class, null signals in the contextual adjacent evidence, skeletal, fracture, and bone, dosing and pharmacokinetics outcome classes, and negative signals in the contextual adjacent evidence outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.","The conclusion is that resveratrol metabolism effects remains a bounded geroscience case: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","Population aging has become the defining demographic transition of the twenty-first century, and with it the central clinical question has shifted from managing individual diseases diagnosed in late life to extending the period of life spent in good function, a construct often termed healthspan. The question of whether pharmacologic interventions can lengthen healthspan, and indirectly lifespan, has moved from speculative biology into the center of translational research agendas, and it is being asked with renewed urgency because the social and economic costs of multimorbidity, frailty, and disability are rising faster than curative pipelines can offset them. In this context, the candidate compound Resveratrol Metabolism Effects has been repeatedly invoked, because it is one of a small number of molecules for which mechanistic data, observational clues, and a substantial body of human trial evidence already coexist. It is precisely the coexistence of those layers, rather than the strength of any one of them, that makes the Resveratrol Metabolism Effects case a useful test case for the geroscience hypothesis, and the field's enthusiasm for the drug has grown alongside, not ahead of, the published evidence base. The clinical stakes are concrete: skeletal fragility, metabolic dysfunction, and inflammatory drift all cluster at the interface between aging and chronic disease, and an intervention that meaningfully modulated any one of them would have immediate public-health implications. The challenge is that 'meaningful modulation' remains the open question, and the published record on Resveratrol Metabolism Effects, taken as a whole, has not yet converged on a defensible yes-or-no answer.","The geroscience hypothesis proposes that aging biology itself is a tractable therapeutic target, and that interventions which slow fundamental aging processes should, in principle, delay or compress the morbidity curve across multiple organ systems simultaneously. This contrasts with the traditional single-disease, single-target model of drug development, and it has generated interest in both novel molecules and the repurposing of existing compounds with favorable safety profiles. The repurposing pathway is attractive because the cost and timeline of de novo development are prohibitive for a prevention indication that would require very long follow-up, and the regulatory bar for chronic, healthy-adult use is unusually high. Within this logic, Resveratrol Metabolism Effects has occupied a peculiar position: it is widely available as a supplement, has a long informal safety record, and yet is being asked to meet an evidentiary standard that no geroprotector has yet met. The geroscience framework does not, in itself, predict that Resveratrol Metabolism Effects will work; it predicts that if a compound does slow aging biology, the signal should be detectable in coordinated changes across cardiometabolic, skeletal, inflammatory, and possibly cognitive endpoints. The empirical record on Resveratrol Metabolism Effects can therefore be evaluated against the geroscience expectation of multi-domain coordination, and the question of whether such coordination is in fact observed is one of the organizing questions of the present synthesis. Importantly, the hypothesis also tolerates null findings on individual outcomes, provided the pattern across outcomes is interpretable, and that tolerance makes the evaluation of Resveratrol Metabolism Effects a methodological exercise as much as a biological one.","Several unresolved questions run through the Resveratrol Metabolism Effects evidence base, and they are not all answerable with the same kind of study. The first is the mechanism-to-function translation problem: there is no shortage of plausible molecular targets for Resveratrol Metabolism Effects, but the question of which, if any, is operative at achievable human exposures remains open, and the gap between in-vitro concentrations used to demonstrate target engagement and plasma concentrations observed in vivo is consistently large. The second is the tradeoff question: even where a small positive signal is observed, whether it is large enough to be clinically meaningful, given the typical attrition rate in long-duration RCTs of older adults of roughly 20% (Schulz 2010), is not settled. The third is population specificity, and there is suggestive evidence that baseline metabolic status, sex, and gut microbiota composition may modify the response, but the trials currently available are not adequately powered to resolve these interactions. The fourth is duration: geroscience-style endpoints require follow-up on the order of years, while most Resveratrol Metabolism Effects trials run for 12 weeks, and the longer-term safety and efficacy profile in healthy adults is therefore under-characterized. The fifth is dose-response: the Limin 2026 transcriptomic-metabolomic work in arctic foxes and other pharmacokinetic analyses have raised the possibility of a non-monotonic dose-effect relationship, which complicates simple linear interpretations. These questions are interlocked, and the present synthesis is structured to keep them visible rather than to collapse them into a single answer.","Mechanistically, the cardiometabolic findings can be linked to resveratrol's documented activity on hepatic lipid handling and insulin signalling, substrates most directly probed by Chen 2015 in a clinical RCT population. Preclinical data elsewhere in the broader literature have proposed sirtuin-1 and AMPK-mediated pathways as the molecular substrate, but the present corpus provides only the clinical-RCT and pooled-review layer for this outcome class. Chen 2015 is a direct clinical functional-endpoint trial, whereas Zhou 2022 is a review-level synthesis, so the mechanistic interpretation rests on Chen 2015's within-trial biochemistry and on the pattern of pooled estimates reported in Zhou 2022. This stratification of direct versus review-level evidence is essential when assessing transferability of the cardiometabolic signal to other populations.","Within-corpus tensions for the cardiometabolic class are limited but non-trivial: Chen 2015 and Zhou 2022 agree on direction, but they differ in evidence type — Chen 2015 is a direct clinical RCT in adults, while Zhou 2022 is an indirect review-level synthesis without its own enrolled clinical population. This direct-versus-indirect asymmetry is recorded in the cross-study disagreement map as an indirectness gap (severity 3) for the cardiometabolic outcome class. Practically, the gap means that the magnitude estimates in Zhou 2022 cannot be assumed to track Chen 2015's within-trial effect sizes one-to-one, even though both report favourable p-values. Until further direct trials converge on the same endpoints, the cardiometabolic claim can be interpreted as supported by concordant direct and indirect evidence rather than as a single replicated effect.","Within Limin 2026, the directional pattern is non-monotonic: at the 50 mg/kg dose testosterone output was enhanced, while departures from that dose in either direction were associated with attenuated or null effects captured by the P > 0.05 contrasts. The source reports six significance statements, with two P < 0.05 and two P < 0.01 contrasts anchoring the optimal-dose response and two P > 0.05 contrasts flagging sub-optimal and supra-optimal doses. Because Limin 2026 is an animal observational cohort, no human pharmacokinetic parameters — bioavailability, half-life, or area-under-the-curve — are derived; readers should treat the dose label as a within-study experimental anchor rather than a translatable human regimen.","In animal/preclinical evidence, within-corpus tensions on this outcome class are limited because Limin 2026 is the only curated source for dosing pharmacokinetics, and the cross-study disagreement map records no same-outcome non-orthogonal pairs to surface disagreements. Consequently, the dose-response narrative rests on a single observational cohort, and the absence of an opposing source precludes any contrast in directional effect. The integrating thesis for Resveratrol Metabolism Effects is consistent with this limitation: the evidence base is acknowledged as incomplete, with mechanistic plausibility coexisting with sparse human-RCT data, and the boundary conditions for an optimal dose remain to be established in human populations. Readers should treat the 50 mg/kg anchor as a hypothesis-generating dose in Vulpes lagopus, not a clinically translatable regimen, pending dedicated human pharmacokinetic studies.","Within-corpus tensions in the immune outcome class cannot be enumerated from the cross-study disagreement map, which contains no same-outcome non-orthogonal pairs for immune endpoints; the class is therefore single-source and does not surface internal disagreement. The direction tag for Sobh 2026 is recorded as unclear, so even the valence of the mechanistic immune effect is not adjudicated in the corpus. Practically, this means the immune outcome class contributes mechanistic plausibility — inflammatory gene expression changes with P < 0.05 support in a toxicant-challenge preclinical model — without a parallel human-RCT confirmation in the indexed set. The trial plans to enroll 472 elderly patients with type 2 diabetes mellitus and is positioned as a randomized controlled clinical trial protocol. The reported study is therefore protocol-level rather than completed results, and the direction of effect is recorded as unclear in the curated evidence. The protocol explicitly bundles glucose metabolism, insulin resistance, inflammation, and renal function as co-primary endpoints, situating inflammation within a broader cardiometabolic-renal cluster rather than as a stand-alone outcome."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\ntrans -Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe non-monotonic dose-effect of resveratrol on testicular steroidogenesis in male arctic foxes (Vulpes lagopus): Mechanisms revealed by integrated transcriptomic and metabolomic analyses,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEfficacy of Resveratrol Supplementation on Glucose and Lipid Metabolism: A Meta-Analysis and Systematic Review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nResveratrol Alleviates Corticosterone-Induced Hepatic Lipid Metabolism Disorder and Oxidative Stress by Regulating the Nrf2 and AMPK/Sirt1 Signaling Pathways in AA Broilers,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nExamination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDoes Resveratrol Impact Oxidative Stress Markers in Patients with Head and Neck Cancer Receiving Home Enteral Nutrition?,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCombining in vivo and in vitro studies to elucidate the inhibitory effect of resveratrol on vorolanib metabolism,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Effects of resveratrol therapy on glucose metabolism, insulin resistance, inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDecellularized ovarian bioscaffolds and resveratrol-loaded polymeric nanoparticles support in vitro viability and ultrastructural preservation of bovine preantral follicles,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Effects of Resveratrol, Curcumin and Quercetin Supplementation on Bone Metabolism—A Systematic Review\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nResveratrol Alleviates Arsenic-Induced Liver Fibrosis in Rats by Correcting SIRT1-Mediated Disorder of Hepatic Bile Acid Metabolism,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTriphenylphosphonium Bolaamphiphile-Liposomes Loaded with Resveratrol and Trolox: Mitochondriotropic Formulations with Therapeutic Potential in Neurodegeneration and Cancer,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nUntargeted Metabolomics Reveals Acylcarnitines as Major Metabolic Targets of Resveratrol in Breast Cancer Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDevelopment and Validation of RP-HPLC Method for trans -Resveratrol in HPβCD-Loaded Stealth Liposomes: Stability and Release Studies,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol for the Management of Human Health: How Far Have We Come? A Systematic Review of Resveratrol Clinical Trials to Highlight Gaps and Opportunities,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nResveratrol-Enhanced Human Neural Stem Cell-Derived Exosomes Mitigate MPP+-Induced Neurotoxicity Through Activation of AMPK and Nrf2 Pathways and Inhibition of the NLRP3 Inflammasome in SH-SY5Y Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol’s bibliometric and visual analysis from 2014 to 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol ameliorates intrahepatic cholestasis of pregnancy by modulating the gut-liver axis and FXR-mediated bile acid homeostasis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffect of (Poly)phenols on Lipid and Glucose Metabolisms in 3T3-L1 Adipocytes: an Integrated Analysis of Mechanistic Approaches,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMolecular and Analytical Understanding of Resveratrol Interactions for Advanced Biotechnological Applications,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMechanistic Evaluation of Chlorfenapyr-Induced Hepatotoxicity and the Mitigating Actions of Resveratrol-Loaded Chitosan Nanoparticles.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHybrid Nanocomposite Mini-Tablet to Be Applied into the Post-Extraction Socket: Matching the Potentialities of Resveratrol-Loaded Lipid Nanoparticles and Hydroxyapatite to Promote Alveolar Wound Healing,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol Attenuates Trimethylamine- N -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWhat Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEffects of resveratrol on bone health in type 2 diabetic patients. A double-blind randomized-controlled trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol and Cardiovascular Diseases,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMetabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nResveratrol: A miraculous natural compound for diseases treatment,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"**Schulz 2010.** _Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332._ DOI: 10.1136/bmj.c332.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n**Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n**WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. 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