Japanese Knotweed for Cardiovascular Health

The cardiovascular research on resveratrol — and by extension Japanese knotweed extract — is the largest body of clinical-trial evidence for any application of this herb. Resveratrol acts on the vascular endothelium (the inner lining of every blood vessel) where it raises nitric oxide bioavailability through endothelial nitric oxide synthase (eNOS) upregulation, reduces oxidized LDL formation, inhibits platelet aggregation, and modestly lowers blood pressure. Wong RHX et al. (2011) demonstrated dose-dependent improvement in flow-mediated dilation; Liu Y et al. meta-analyzed several trials and confirmed small but real systolic BP reductions. The story began with Serge Renaud's 1992 Lancet paper on the "French Paradox" — why the French had low coronary disease rates despite high saturated fat intake — and the answer pointed to red wine polyphenols, of which resveratrol was the most pharmacologically active. The catch is that you would need to drink absurd quantities of wine to match the doses used in trials, which is why knotweed extract is the practical delivery vehicle.

The French Paradox — Where the Field Began
eNOS Upregulation and Nitric Oxide Bioavailability
The Wong 2011 Flow-Mediated Dilation Trial
Blood Pressure Effects (The Meta-Analysis Picture)
Oxidized LDL and Atherosclerosis Prevention
Platelet Aggregation and Antiplatelet Effects
Vascular Inflammation (CRP, IL-6, TNF-α)
Heart Failure and Cardiac Remodeling
Diabetic Vascular Disease
Realistic Effect-Size Estimates
Cautions Specific to Cardiovascular Patients
Key Research Papers
Connections

The French Paradox — Where the Field Began

The modern resveratrol-and-cardiovascular-health story begins with a single epidemiological observation made famous by Serge Renaud, a French epidemiologist working at INSERM (the French equivalent of the NIH). Renaud noticed that French populations had unusually low rates of coronary heart disease compared to other developed countries with similar dietary patterns. The French diet was high in saturated fat (butter, cheese, foie gras, charcuterie), high in cholesterol, and rich in red meat — all factors that would predict high rates of atherosclerosis. Yet coronary mortality in France was roughly half of what would be expected.

Renaud's 1992 Lancet paper ("Wine, alcohol, platelets, and the French paradox for coronary heart disease") proposed that regular moderate red wine consumption explained much of the discrepancy. The hypothesized mechanism involved wine polyphenols — particularly the stilbene resveratrol — reducing platelet aggregation and protecting against atherosclerosis. This paper was the founding document of the "French Paradox" field, and it triggered an enormous research effort that ultimately identified resveratrol as the most pharmacologically active component of red wine.

Several important caveats apply to the French Paradox framing:

The mortality difference is partly an artifact of how coronary deaths are recorded in different countries (France tends to record fewer borderline cases as cardiac deaths)
Mediterranean dietary patterns more broadly (high vegetable, high olive oil, moderate fish, low refined carbohydrate) probably contribute as much as wine specifically
Alcohol per se has a U-shaped relationship with cardiovascular mortality — light-to-moderate drinking is associated with lower mortality than abstinence in many cohort studies, but this is contested in more recent Mendelian randomization studies
The wine-specific component is hard to disentangle from the lifestyle pattern that wine drinking accompanies (regular meals with family, modest portions, no binge drinking)

The most important practical point: the resveratrol content of even a generous wine intake (2 glasses per day) provides only 1 to 4 mg of resveratrol — far below the 100 to 500 mg doses used in clinical trials. If resveratrol is the active ingredient, you cannot get a clinically relevant dose from drinking wine. You need a knotweed extract or purified resveratrol supplement.

The French Paradox launched the field but should not, on its own, be used to justify wine consumption for cardiovascular health. Whatever benefit the French may derive from their dietary pattern, the alcohol carries its own risks (cancer, liver disease, accidents, addiction) that probably outweigh any resveratrol benefit. The practical recommendation is to get the resveratrol from supplements (knotweed extract) and to derive cardiovascular benefit from the Mediterranean diet pattern as a whole.

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eNOS Upregulation and Nitric Oxide Bioavailability

The single most important cardiovascular mechanism of resveratrol is upregulation of endothelial nitric oxide synthase (eNOS), the enzyme that produces nitric oxide (NO) from L-arginine in vascular endothelial cells. Nitric oxide is the central signaling molecule for vascular relaxation: it diffuses from endothelial cells into adjacent smooth muscle, activates soluble guanylyl cyclase, raises cGMP, and triggers smooth muscle relaxation that dilates the vessel.

Impaired NO bioavailability is a hallmark of vascular dysfunction and an early step in atherosclerosis. Endothelial dysfunction — measured clinically as reduced flow-mediated dilation (FMD) — precedes plaque formation and predicts cardiovascular events independent of standard risk factors. Restoring NO bioavailability is therefore a primary therapeutic target for vascular health.

Resveratrol increases eNOS expression and activity through several mechanisms:

SIRT1-mediated eNOS deacetylation — SIRT1 deacetylates eNOS at lysines 496 and 506, increasing its enzymatic activity
Increased eNOS gene expression — resveratrol activates the eNOS promoter, raising baseline enzyme levels
Phosphorylation at serine 1177 — resveratrol activates AMPK and PI3K/Akt pathways that phosphorylate eNOS at the activating serine 1177 site
Reduced eNOS uncoupling — under conditions of oxidative stress, eNOS can "uncouple" from its tetrahydrobiopterin cofactor and start producing superoxide instead of NO. Resveratrol's antioxidant effects (Nrf2 pathway) reduce this uncoupling.
Reduced ADMA — asymmetric dimethylarginine (ADMA) is an endogenous eNOS inhibitor; resveratrol may modulate ADMA levels indirectly through dimethylarginine dimethylaminohydrolase (DDAH) activity

The net effect is that vascular endothelium exposed to resveratrol produces more nitric oxide, with downstream improvements in vasodilation, blood pressure, and platelet inhibition. This is the molecular basis for most of the cardiovascular trial findings discussed below.

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The Wong 2011 Flow-Mediated Dilation Trial

The pivotal modern human trial of resveratrol for vascular function was Wong RHX, Howe PRC, Buckley JD et al. (2011) — "Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure," published in Nutrition, Metabolism & Cardiovascular Diseases. The trial was a randomized, double-blind, placebo-controlled crossover study in 19 overweight/obese adults with mildly elevated blood pressure (mean baseline 134/85 mmHg).

Subjects received single doses of 30 mg, 90 mg, or 270 mg of trans-resveratrol (or placebo) on separate days, with flow-mediated dilation measured one hour after dosing. Flow-mediated dilation is the gold standard non-invasive measurement of endothelial function: the brachial artery is occluded with a cuff for 5 minutes, the cuff is released, and the percentage increase in arterial diameter during the resulting reactive hyperemia is measured by ultrasound.

Results:

FMD improved in a dose-dependent manner
The 270 mg dose produced the largest effect: 1.7% absolute increase in FMD (from baseline of approximately 5% to approximately 6.7%)
The 90 mg dose produced a 0.8% absolute increase
The 30 mg dose produced a small, non-significant increase
Effect was already maximal at 1 hour, consistent with rapid pharmacokinetic onset
No adverse effects observed

The Wong 2011 trial is important because (a) it established that resveratrol produces measurable acute improvement in endothelial function in the target patient population (overweight, hypertensive adults), (b) it identified an effective dose range (270 mg or higher), and (c) it confirmed the mechanism is rapid and consistent with the eNOS-NO pathway rather than requiring weeks of treatment for the effect to develop.

Subsequent chronic-dosing trials by the same group and others (Wong RHX et al. 2013, 2016) demonstrated sustained FMD improvement with continued daily dosing over weeks to months. The effect appears robust across multiple labs and patient populations, although the absolute magnitude (1 to 3% FMD improvement) is modest. For context, the FMD improvement from a Mediterranean diet over 3 months is typically 2 to 3%, similar to the resveratrol effect.

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Blood Pressure Effects (The Meta-Analysis Picture)

Several meta-analyses have pooled the available randomized trials of resveratrol supplementation and blood pressure. The most informative pooled estimates:

Systolic blood pressure — reduction of approximately 2 to 5 mmHg, with the larger effects seen in hypertensive subjects, higher doses (>150 mg/day), and longer treatment durations (>3 months)
Diastolic blood pressure — smaller or no consistent effect
24-hour ambulatory blood pressure — modest reductions in mean 24-hour systolic and especially in daytime systolic
Dose-response — flat above approximately 300 mg/day, suggesting saturation of the relevant binding sites at modest doses

The 2 to 5 mmHg systolic reduction is clinically meaningful in the same way that the corresponding reduction from the DASH diet or moderate sodium restriction is meaningful — small at the individual level but substantial at the population level. A 2 mmHg systolic reduction across a population reduces stroke mortality by approximately 6% and coronary mortality by approximately 4%, per the Lewington meta-analysis of blood-pressure-outcome relationships.

For clinical context, this places resveratrol in the same effect-size category as several other "modest" antihypertensive interventions: moderate sodium restriction (3 to 5 mmHg), DASH diet (5 to 6 mmHg in stage 1 hypertensives), 30 minutes daily moderate exercise (3 to 5 mmHg), and 5% body weight loss (3 to 5 mmHg). Resveratrol is not a replacement for first-line antihypertensive medications (which produce 8 to 15 mmHg reductions per drug) but is a reasonable adjunctive intervention for patients who want to layer multiple modest-effect strategies.

The clinical importance of resveratrol for blood pressure is greatest in:

Stage 1 hypertension (130-139/80-89 mmHg) where the patient and clinician want to avoid pharmaceutical therapy
Patients with metabolic syndrome (where the multi-target mechanism addresses several of the underlying drivers)
Patients on first-line antihypertensives who still have above-goal BP and need adjunctive options
Patients with white-coat hypertension where pharmaceutical therapy is not warranted but lifestyle augmentation is desired

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Oxidized LDL and Atherosclerosis Prevention

Atherosclerotic plaque formation is driven by oxidized LDL (oxLDL) accumulation in the arterial wall. Native LDL particles are not particularly atherogenic; the problem starts when LDL crosses the endothelium into the subendothelial space and undergoes oxidative modification by reactive oxygen species. Oxidized LDL is taken up by macrophages through scavenger receptors (CD36, SR-A) in an unregulated manner, producing the foam cells that are the cellular hallmark of early atherosclerotic plaque.

Resveratrol inhibits LDL oxidation through several mechanisms:

Direct scavenging of reactive oxygen species (hydroxyl radical, peroxyl radical, superoxide)
Chelation of transition metal ions (iron, copper) that catalyze LDL oxidation
Increased expression of paraoxonase 1 (PON1), the HDL-associated enzyme that hydrolyzes oxidized phospholipids
Nrf2-mediated upregulation of glutathione synthesis, providing more endogenous antioxidant capacity in vascular tissue
Reduced expression of scavenger receptors on macrophages, reducing oxLDL uptake even when oxLDL is present

In animal models of atherosclerosis (ApoE-knockout mice on Western-style diet, LDL-receptor-knockout rabbits), resveratrol supplementation reduces atherosclerotic lesion size, foam cell density, and lesion-associated inflammation by 30 to 50% compared to untreated controls. The effect is reproducible across multiple labs and animal models.

The corresponding human data is necessarily indirect because measuring atherosclerotic plaque progression requires either invasive imaging (intravascular ultrasound, optical coherence tomography) or sensitive non-invasive measures (coronary artery calcium scoring, carotid intima-media thickness). The available human trials measuring carotid intima-media thickness as a surrogate for atherosclerosis progression have shown small but favorable trends with resveratrol supplementation. The Tomé-Carneiro 2013 trial in stable CAD patients showed reduced inflammatory and pro-atherogenic markers over 1 year, supporting the mechanistic prediction even though plaque imaging endpoints were not measured.

For more on the underlying atherosclerotic process and the role of multiple antioxidant interventions, see our Atherosclerosis page.

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Platelet Aggregation and Antiplatelet Effects

One of the original mechanisms proposed for the French Paradox was wine polyphenols' effect on platelet aggregation. Resveratrol has measurable antiplatelet activity through inhibition of cyclooxygenase (COX) enzymes, particularly COX-1, the form expressed in platelets. COX-1 produces thromboxane A2, a potent platelet aggregator and vasoconstrictor. Inhibition of COX-1 in platelets reduces thromboxane production and slows platelet aggregation — the same fundamental mechanism by which aspirin works.

Resveratrol's antiplatelet effect is weaker than aspirin's on a per-molecule basis and reversible (aspirin acetylates COX-1 irreversibly, lasting the platelet's 7-10 day lifespan; resveratrol's inhibition reverses as the molecule is cleared). The net clinical effect is more like that of a fish oil dose — measurable platelet aggregation reduction at typical supplement doses, contributing to but not dominating the overall antiplatelet status.

The clinical implications:

For prevention — the antiplatelet effect may contribute to cardiovascular event reduction in long-term resveratrol use, although the effect-size estimates from existing trials do not allow precise quantification
For patients on therapeutic anticoagulation — resveratrol compounds the bleeding risk of warfarin, DOACs (dabigatran, rivaroxaban, apixaban, edoxaban), and antiplatelet drugs (aspirin, clopidogrel, ticagrelor, prasugrel). Patients on these drugs should use resveratrol only under medical supervision.
Pre-surgery — discontinue resveratrol 1 to 2 weeks before any planned surgery or invasive procedure to allow platelet function to normalize
Spontaneous bleeding — case reports of increased bleeding tendency at high doses (1 g/day or above), particularly when combined with other antiplatelet substances (fish oil, garlic, ginkgo, vitamin E)

For most patients not on anticoagulant therapy, the antiplatelet effect of resveratrol at typical doses (100 to 500 mg/day) is mild and not clinically problematic. The Buhner Lyme protocol doses (gram-range whole-root knotweed equivalent) require more caution.

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Vascular Inflammation (CRP, IL-6, TNF-α)

Atherosclerosis is increasingly understood as an inflammatory disease as much as a lipid disease. Multiple clinical trials of anti-inflammatory therapy in cardiovascular disease (most prominently the CANTOS trial of canakinumab, an IL-1β-neutralizing antibody) have shown that reducing vascular inflammation reduces cardiovascular events independent of lipid changes. The major inflammatory biomarkers studied are high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and fibrinogen.

Resveratrol's anti-inflammatory effects, mediated through NF-κB inhibition and SIRT1-mediated p65 deacetylation (see our Anti-Inflammatory deep-dive), translate to measurable reductions in these biomarkers in clinical trials:

hs-CRP — typical reduction of 10 to 20% with sustained dosing
IL-6 — reductions of 10 to 25% in trials with elevated baseline
TNF-α — reductions of 15 to 25% in trials with elevated baseline
Fibrinogen — modest reductions, particularly in metabolic syndrome populations

The Tomé-Carneiro 2013 trial in stable coronary artery disease patients is particularly informative: 12 months of grape-source resveratrol (8 mg/day, lower than most supplement doses) reduced hs-CRP, TNF-α, plasminogen activator inhibitor-1, and inflammatory cytokine production by peripheral blood mononuclear cells. The effects were modest but consistent and reached statistical significance for multiple markers.

For patients with elevated baseline inflammatory markers (hs-CRP >2 mg/L), resveratrol is a reasonable consideration. The effect size is in the range of what statins, fish oil, and Mediterranean dietary pattern produce on inflammatory markers, supporting the broader picture of resveratrol as a member of the modest-effect-size, well-tolerated, layered-intervention category for cardiovascular risk reduction.

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Heart Failure and Cardiac Remodeling

The mechanisms of cardiac remodeling in heart failure include cardiomyocyte hypertrophy, fibrosis, mitochondrial dysfunction, calcium handling abnormalities, and chronic inflammation. Resveratrol acts on several of these pathways:

SIRT1-mediated cardiomyocyte protection — preclinical data show reduced cardiomyocyte apoptosis and improved survival under stress conditions
Improved calcium handling — resveratrol increases SERCA2a (sarcoplasmic reticulum Ca-ATPase) expression and activity, improving diastolic calcium reuptake
Mitochondrial biogenesis — PGC-1α activation increases cardiomyocyte mitochondrial mass, supporting the cell's energetic demands
Reduced cardiac fibrosis — resveratrol inhibits TGF-β-driven fibroblast activation and collagen deposition
Improved endothelial function — the eNOS-NO axis discussed above benefits the coronary microcirculation

Small clinical trials of resveratrol in stable heart failure patients have shown modest improvements in left ventricular ejection fraction, exercise tolerance (6-minute walk distance), and quality-of-life scores. The trials are too small and the heterogeneity too high to support a recommendation for routine use, but the data suggest that resveratrol is at least safe in this population (despite the antiplatelet effect, no excess bleeding signal in heart-failure trials) and may offer modest functional benefit.

For patients with heart failure with preserved ejection fraction (HFpEF), where the underlying pathology is diastolic dysfunction and microvascular endothelial dysfunction, the mechanistic match between resveratrol's actions and the disease pathology is particularly good. There are ongoing trials specifically evaluating resveratrol in HFpEF; results are not yet definitive.

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Diabetic Vascular Disease

Diabetic vascular disease — both macrovascular (coronary, cerebral, peripheral atherosclerosis) and microvascular (retinopathy, nephropathy, neuropathy) — is one of the largest application areas for resveratrol research. The underlying pathology involves hyperglycemia-induced oxidative stress, advanced glycation end-product (AGE) formation, eNOS uncoupling, microvascular inflammation, and accelerated atherosclerosis. Resveratrol's mechanisms hit several of these targets:

Reduced hyperglycemia-induced oxidative stress through Nrf2 activation
Reduced AGE formation and AGE-receptor (RAGE) signaling
Restored eNOS coupling and NO production in diabetic vasculature
Reduced inflammatory cytokine production by perivascular adipose tissue
Modest improvements in insulin sensitivity and glycemic control (HbA1c reductions of 0.2 to 0.5 percentage points in pooled trials)

Several trials specifically in type 2 diabetics have shown improvements in vascular function alongside the glycemic effects. The Brasnyo 2011 trial (10 mg/day for 4 weeks) showed improved insulin sensitivity and reduced oxidative stress markers. The Movahed 2013 trial (1 g/day for 45 days) showed HbA1c reduction of 0.4 percentage points alongside reduced systolic BP. Several smaller trials have shown improvements in carotid intima-media thickness over 6 to 12 months of resveratrol supplementation in diabetic populations.

The effect sizes are modest but meaningful. For diabetics already at high cardiovascular risk, layering resveratrol onto a base of metformin, statin, antihypertensive, and lifestyle intervention is reasonable. For more on diabetic cardiovascular management, see our Type 2 Diabetes page.

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Realistic Effect-Size Estimates

For a patient considering Japanese knotweed (or resveratrol) for cardiovascular health, the most useful framing is comparing the expected effect size to other interventions. The pooled clinical-trial evidence supports the following realistic estimates for typical patient populations on typical doses (100 to 500 mg trans-resveratrol/day or equivalent knotweed extract for 3 to 12 months):

Systolic blood pressure: 2 to 5 mmHg reduction
Flow-mediated dilation: 1 to 3% absolute improvement
LDL cholesterol: 5 to 10 mg/dL reduction
HbA1c (in diabetics): 0.2 to 0.4 percentage point reduction
hs-CRP: 10 to 20% reduction
IL-6: 10 to 25% reduction
Triglycerides: 10 to 20 mg/dL reduction (in elevated baseline)

For comparison, the same magnitude of cardiovascular biomarker improvement comes from:

Mediterranean dietary pattern adopted for 3 to 6 months
30 minutes of moderate aerobic exercise 5 days per week
5 to 10% body weight loss in overweight individuals
Moderate sodium restriction (1500 mg/day vs 3500 mg/day baseline)
Daily fish oil 2 to 4 g/day EPA+DHA
Daily green tea 3 to 4 cups

Resveratrol from knotweed extract is therefore best framed as one component of a multi-faceted lifestyle and supplementation strategy, with effect sizes that are real, well-tolerated, but not transformative. It does not substitute for diet, exercise, sleep, and stress management. It does not substitute for first-line pharmaceutical therapy when that is indicated (statins for established CAD, antihypertensives for stage 2 hypertension, metformin for diabetes). It can layer onto these foundations to provide additional modest benefit.

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Cautions Specific to Cardiovascular Patients

Therapeutic anticoagulation — patients on warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban should use resveratrol only under medical supervision due to compounded bleeding risk. INR monitoring should be more frequent in the first months after starting resveratrol with warfarin.
Antiplatelet therapy — patients on dual antiplatelet therapy (aspirin + clopidogrel/prasugrel/ticagrelor) after coronary stenting are at the highest bleeding risk; resveratrol should be avoided or used at minimal doses during the period of dual antiplatelet therapy.
Pre-surgery — discontinue resveratrol 1 to 2 weeks before any planned surgery, dental procedure, or invasive procedure where bleeding control matters.
Statin interaction — resveratrol inhibits CYP3A4, which metabolizes simvastatin, atorvastatin, and lovastatin. The clinical magnitude of this interaction is uncertain but theoretically could raise statin levels and increase myopathy risk. Pravastatin and rosuvastatin are minimally CYP3A4-metabolized and may be preferred in patients combining statins with resveratrol.
Calcium channel blocker interaction — CYP3A4 also metabolizes amlodipine, diltiazem, verapamil, and felodipine. Theoretical interaction; clinical magnitude unclear.
Lyme carditis — if Japanese knotweed is being used for chronic Lyme symptoms in a patient with cardiac involvement (high-grade AV block, myocarditis), use only under cardiology supervision. The herb may improve some aspects of the cardiac inflammation but is not a substitute for conventional Lyme carditis management.
Atrial fibrillation — no specific contraindication, but patients on therapeutic anticoagulation for AFib should follow the warfarin/DOAC cautions above.
Aortic stenosis — no specific contraindication but no specific benefit established either; surgical aortic valve replacement remains the indicated therapy for severe symptomatic disease.

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Key Research Papers

Renaud S, de Lorgeril M (1992). Wine, alcohol, platelets, and the French paradox for coronary heart disease. The Lancet 339:1523-1526. — PubMed
Wong RHX, Howe PRC, Buckley JD et al. (2011). Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 21:851-856. — PubMed
Wong RHX, Berry NM, Coates AM et al. (2013). Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults. J Hypertens. — PubMed
Liu Y, Ma W, Zhang P et al. (2015). Effect of resveratrol on blood pressure: a meta-analysis of randomized controlled trials. Clin Nutr 34:27-34. — PubMed
Tomé-Carneiro J, Gonzálvez M, Larrosa M et al. (2013). One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol 110:356-363. — PubMed
Bonnefont-Rousselot D (2016). Resveratrol and cardiovascular diseases. Nutrients 8:250. — PubMed
Cho S, Namkoong K, Shin M et al. (2017). Cardiovascular protective effects and clinical applications of resveratrol. J Med Food. — PubMed
Magyar K, Gál R, Riba P et al. (2012). Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. — PubMed
Csiszar A, Labinskyy N, Pinto JT et al. (2009). Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. — PubMed
Mattison JA, Wang M, Bernier M et al. (2014). Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. — PubMed
Liu K, Zhou R, Wang B et al. (2014). Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis. Am J Clin Nutr. — PubMed
Movahed A, Nabipour I, Lieben Louis X et al. (2013). Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid Based Complement Alternat Med. — PubMed

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