Vitis vinifera / Wijnstok

History

Grape leaves have been seen in fossils dating back to prehistoric times. Grapes were domesticated in western Asia before 5000 BC and have been mentioned in biblical writings and depicted in tomb paintings dating back to 2375 BC. Circa 1635, Jesuit fathers brought Spanish grapes to Mexico, establishing vineyards in what is now Socorro, New Mexico, the area of the earliest planting of grapes in the United States. 1 In 1652, Nicholas Culpeper recommended grapes as a mouthwash. 2 In the 1850s, California became involved in grape culture. 1 In 1927, physician A.M. Liebstein mentioned grapes as being beneficial for dyspeptic and febrile conditions, liver and kidney ailments, tuberculosis, hemorrhoids, varicose veins, osteomyelitis, gangrene, and cancer. The Grape Cure (1928, Johanna Brandt) claimed that grapes had cured the author's abdominal cancer. 3 Modern scientific studies demonstrate a variety of beneficial effects from grapes.

Chemistry

Grapes are ≈ 80% water and contain 70 calories/100 g. The sugar (carbohydrate) content is ≈ 16%. 1 Commercial grape juice is lower in sucrose than other fruit juices. 4 Other sugars, amino acids, and organic acids in grape juice and wines have been detected. 5 The amino acid arginine has been separated from grape juice. 6 Grapes contain tartaric and carboxylic acids, including malic, citric, lactic, succinic, and shikimic acids. 2 , 7 Vitamins A, B 1 , B 2 , and C also are present in grapes, as are minerals including chromium and potassium. 1 , 2 Anthocyanins are found in grapes with red pigments, 2 as well as in other pigmented fruits such as the blackberry, strawberry, and blueberry. 8 A review discussing anthocyanins in grapes, juices, and wines is available. 9 Flavonoids including quercetin, catechins, myricetin, and kaempferol are the more important constituents in purple grape juice and red wine.10 Catechin concentrations are substantial in red wine (27 to 96 mg/L) but low to negligible in white wine and commercially available grape juices tested in another report. 11 Other constituents found in grapes include tannins, inositol, choline, and pectin. 2 Glutathione and thiol-containing compounds have been found in the juice. 12 Isomers of resveratrol in grape juice and wine also are present, 13 as are antioxidants. 14

Grape Juice, Purple Uses and Pharmacology

In general, grapes are nourishing and mildly laxative, offering support in the GI tract and liver. Red grape leaves are known to be astringent and anti-inflammatory. Red leaves and grapes are used in the treatment of varicose veins, hemorrhoids, and capillary fragility. 2 Grape juice is high in chromium, a mineral that is part of the glucose tolerance factor, which works with insulin to promote utilization of sugar. 1

Cardiovascular function

Attention has focused on purple grape juice and its beneficial effects in heart health. Certain flavonoids in purple grape juice and red wines may be responsible for keeping heart-damaging blood clots from forming. Aspirin is used for this purpose as well, but its effects against platelet aggregation are negated by adrenaline, which is released under stressful situations. Flavonoids are not affected by adrenaline, and thus are still available to prevent clot formation.15

Pure grape juice's ability to slow onset of oxidation, reduce platelet activity, and increase nitric oxide production collectively may contribute to healthy cardiovascular function. 16

Animal data

Research reveals no animal data in regards to the use of purple grape juice for cardiovascular activity.

Clinical data

An older report demonstrates anti-platelet aggregation and thrombin production to be reduced by grape juice and red wine. However, the study suggests that the ethanol contained in the wine is the dominant anti-aggregatory component because of its greater ability to prevent platelet aggregation as compared with grape juice. 17 In a randomized, crossover study involving 10 patients, purple grape juice consumption for 1 week reduced the whole blood platelet aggregation response by 77% vs orange and grapefruit juices, confirming purple grape juice's effects in decreasing risk of coronary thrombosis and MI because of increased polyphenolic concentration present (≈ 3 times more than the other juices). 17 Another report in 15 coronary artery disease (CAD) patients concluded that short-term ingestion of purple grape juice improved endothelium-dependent vasodilation and prevented LDL oxidation, reducing negative cardiovascular outcomes. This was shown to be caused by flavonoid components present. 10 Compared with controls, 14 patients with CAD, consuming 7 to 10 mL/kg/day of purple grape juice for 14 days, demonstrated increased lag time measurements, which determine cholesterol oxidation time. (The longer the lag time, the slower the onset of oxidation.) It was concluded that this delay in oxidation of LDL cholesterol is beneficial because it is usually a key contributor to the development of atherosclerosis.Other uses

Grape juice possesses marked antiviral properties in vitro against such viruses as poliovirus and herpes simplex virus. Tannins may be responsible for these effects. Studies also have demonstrated grape juice as being antibacterial, drastically reducing tooth decay in animals. The caffeic acid constituent prevents cancer in animals. Raisins are linked to lower rates of cancer deaths in elderly patients. 3

Dosage

There is no clinical evidence to support specific dosage recommendations for purple grape juice.

Pregnancy/Lactation

Generally recognized as safe or used as food. Avoid dosages above those found in food because safety and efficacy are unproven.

Interactions

None well documented.

Adverse Reactions

Research reveals little or no information regarding adverse reactions with the use of purple grape juice.

Toxicology

Research reveals little or no information regarding toxicology with the use of purple grape juice.

Bibliography

1. Ensminger A, et al. Foods & Nutrition Encyclopedia, 2nd ed. (Vol.1). Boca Raton, FL: CRC Press;1994:1093-99.

2. Chevallier A. The Encyclopedia of Medicinal Plants . New York, NY: DK Publishing;1996:281.

3. Carper J. The Food Pharmacy . New York, NY: Bantam Books;1988:211-12.

4. Yoon J, et al. Chemometric aspects of sugar profiles in fruit juices using HPLC and GC. Bull Korean Chem Soc 1997;18(7):695-702.

5. Linget C, et al. Online dialysis with HPLC for the automated preparation and analysis of amino acids, sugars, and organic acids in grape juice and wines. Analusius 1998;26(1):35-39.

6. Austin K, et al. Spectrophotometric assay for arginine in grape juice and must. Am J Enol Vitic 2000;51(3):227-232.

7. Fuleki T, et al. Carboxylic acid composition of authentic varietal and commercial grape juice. J AOAC Int 1993;76(3):591-600.

8. Koswig S, et al. HPLC method for determination of anthocyanins in colored juices and other pigmented foods. Fluess Obst 1995;62(4):125,128-30.

9. Mazza G. Anthocyanins in grapes and grape products. Crit Rev Food Sci Nutr 1995;35(4):341-71.

10. Stein J, et al. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation 1999;100(10):1050-55.

11. Arts I, et al. Catechin contents of foods commonly consumed in the Netherlands. Part 2. Tea, wine, fruit juices, and chocolate milk. J Agric Food Chem 2000;48(5):1752-57.

12. Park S, et al. Automated HPLC analysis of glutathione and thiol-containing compounds in grape juice and wine using pre-column derivatization with fluorescence detection. Food Chem 2000;68(4):475-80.

13. Soleas G, et al. A derivatized gas chromatographic-mass spectrometric method for the analysis of both isomers of resveratrol in juice and wine. Am J Enol Vitic 1995;46(3):346-52.

14. Wang H, et al. Total antioxidant capacity of fruits. J Agric Food Chem 1996;44(3):701-05.

15. http://www.lifeplusvitamins.com/heart.htm . .

17. Pace-Asciak C, et al. Wines and grape juices as modulators of platelet aggregation in healthy human subjects. Clin Chim Acta 1996;246(1,2):163-82.

18. Keevil J, et al. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr 2000;130(1):53-56.

Andere links naar Vitis

http://botanical.com/botanical/mgmh/v/vine--09.html

http://www.plantaardigheden.nl/bloesemremedies/planten/32Wijnstok.htm

http://www.ema.europa.eu/docs/en_GB/document_library/Herbal_-_Community_herbal_monograph/2010/01/WC500034672.pdf

http://www.florahealth.com/flora/home/Canada/HealthInformation/Encyclopedias/GrapeLeaf.htm

Biological activity of procyanidins from Vitis vinifera LE Bombardelli, P Morazzoni, M Carini, G Aldini… - BioFactors, 1997 - IOS Press

... Page 3. E. Bombardelli et al. / Biological activity of procyanidins from Vitis vinifera L. 431 ...References [1] Oxidative stress, in: Lipoproteins and Cardiovascular Dysfunction, C. Rice-Evans and KR Bruckdorfer, eds, Portland Press Research Monograph, London, UK, 1995. ...

Vitis vinifera in de gemmotherapie

De Wijnstok is sinds lang gekend om zijn vrucht en alle bijproducten die eruit voortvloeien. Minder gekend is het gebruik van zijn blaadjes, zijn sap (als oogwater) en zijn knoppen. Zijn werking in gemmotherapie ligt bij chronische ontstekingen op alle niveaus.

• • Op niveau van de huid vormt de Wijnstokknop een remedie voor bepaalde huidaandoeningen, roos, wratten en collagenose. De meeste symptomen hebben een inwendige oorsprong, dikwijls intestinaal.

  • Op gebied van het spijsverteringsstelsel werkt deze knop bij intestinale ontstekingen, zoals granulomateuze rectocolitis, colitis, Crohn ileïtis.

  • Als anti-inflammatoire ageert de Wijnstokknop op het veneuze vaatstelsel: bij aambeien, pijnlijke flebitis, baarmoederbloedingen, bij de menopauze, pijnlijke overvloedige maandstonden (hypermenorrhea), adenitis ( lymfeklieren ontsteking).

  • Het is vooral op de gewrichten dat de anti-inflammatoire eigenschappen van de Wijnstokknop vooral toepassing vinden, en meeste bij chronische aandoeningen zoals acute gewrichtsreuma, verschillende artrosepijnen, coxartrose, gonartrose, vooral deze van de kleine gewrichten.

Vitis vinifera

La vigne rouge est reconnue pour ses capacités à traiter le syndrome des jambes lourdes et d'autres troubles circulatoires ou veineux, tels que les varices et les hémorroïdes. Elle est aussi très efficace pour traiter les migraines et les règles douloureuses.

Vigne rougeNom scientifique : Vitis vinifera

Noms communs : vigne rouge, vigne à vin, vigne vinifère, vigne des teinturiers

Nom anglais: grape vine

Formes et préparations : gélules, décoctions, infusions, baumes, lotions, teinture mère

Propriétés médicinales de la vigne rouge

UTILISATION INTERNE

Traitement des problèmes de circulation sanguine (syndrome des jambes lourdes, varices, hémorroïdes) et des règles douloureuses ou irrégulières.

UTILISATION EXTERNE

En baume et en lotion, la vigne rouge est recommandée pour lutter contre les varices et les jambes lourdes. En décoction et en infusion, elle régule l' insuffisance veineuse et les règles abondantes.

INDICATIONS THÉRAPEUTIQUES USUELLES

Anti-inflammatoire et antioedémateuse : jambes lourdes, fragilité capillaire (petits vaisseaux situés sous la peau), hémorroïdes, varices ; action antioxydante ; propriétés diurétiques.

AUTRES INDICATIONS THÉRAPEUTIQUES DÉMONTRÉES

La vigne rouge renforce l'organisme dans les cas de troubles digestifs ou hépatiques. Elle permet l'évacuation des mucosités bronchiques et offre ses propriétés apaisantes à la peau.

La vigne rouge est un arbrisseau sarmenteux à tiges grimpantes. Cultivée en Europe depuis l'Antiquité, essentiellement pour ses fruits, elle a été, par la suite, introduite dans le monde entier. Ses feuilles sont palmées et son fruit, le raisin, est utilisé pour produire le vin. Une variété de vigne rouge, la Vitis vinifera sylvestris , est une espèce rare et protégée, dont la récolte est strictement interdite en France.

PARTIES UTILISÉES

Les phytothérapeutes utilisent les feuilles, les fruits (le raisin) ainsi que la sève et les pépins des raisins.

PRINCIPES ACTIFS

La vigne rouge contient des polyphénols (notamment du resvératrol) et des flavonoïdes (oligo-proanthocyanidines et quercétine). Ce sont ces éléments qui lui confèrent ses propriétés antioxydantes et vasoconstrictrices.

Utilisation et posologie de la vigne rouge

DOSAGE

Pour traiter l'insuffisance veineuse et les varices : prendre quotidiennement, en décoction ou en infusion, de 30 à 50 g d'extrait de feuilles de vigne ou de 15 à 30 g d'extrait de pépins.

Précautions d'emploi de la vigne rouge

La vigne rouge contenant des tanins astringents (agissant notamment au niveau de l'utérus), est déconseillée, à fortes doses, aux femmes enceintes et aux jeunes enfants.

CONTRE-INDICATIONS

Pas de contre-indications connues.

INTERACTIONS AVEC DES PLANTES MÉDICINALES OU DES COMPLÉMENTS

En association avec d'autres plantes (l'hamamélis, notamment), son action sur la circulation sanguine en général et sur les varices en particulier est renforcée (baume avec de l'aubépine, du cyprès et du chardon-Marie ).

INTERACTIONS AVEC DES MÉDICAMENTS

Il est déconseillé de consommer des doses trop importantes de vigne rouge lors de la prise d'anticoagulants, car elle pourrait réduire leur efficacité.

Phytother Res. 2009 Sep;23(9):1197-204. doi: 10.1002/ptr.2761.

Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds.

Nassiri-Asl M1, Hosseinzadeh H.

Vitis vinifera, known as the grapevine, is native to southern Europe and Western Asia. Grape seed and skin contain several active components including flavonoids, polyphenols, anthocyanins, proanthocyanidins, procyanidines, and the stilbene derivative resveratrol. Grape seed extract in particular has been reported to possess a broad spectrum of pharmacological and therapeutic effects such as antioxidative, anti-inflammatory, and antimicrobial activities, as well as having cardioprotective, hepatoprotective, and neuroprotective effects. Thus, the present review attempts to give a short overview on the pharmacological, toxicological, and clinical studies of grape and its active components.

Nutr Res. 2008 Nov;28(11):729-37. doi: 10.1016/j.nutres.2008.08.007.

Cardioprotective actions of grape polyphenols.

Leifert WR1, Abeywardena MY.

The aim of this review is to discuss the accumulating evidence that suggests that grape extracts and purified grape polyphenols possess a diverse array of biological actions and may be beneficial in the prevention of some inflammatory-mediated diseases including cardiovascular disease. The active components from grape extracts, which include the grape seed, grape skin, and grape juice, that have been identified thus far include polyphenols such as resveratrol, phenolic acids, anthocyanins, and flavonoids. All possess potent antioxidant properties and have been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. These compounds also possess a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic, antiarrhythmic, and vasorelaxation actions. Although not exclusive, antioxidant properties of grape polyphenols are likely to be central to their mechanism(s) of action, which also include cellular signaling mechanisms and interactions at the genomic level. This review discusses some of the evidence favoring the consumption of grape extracts rich in polyphenols in the prevention of cardiovascular disease. Consumption of grape and grape extracts and/or grape products such as red wine may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease.

World J Mens Health. 2015 Aug;33(2):109-16. doi: 10.5534/wjmh.2015.33.2.109. Epub 2015 Aug 19.

The Effect of Vitis vinifera L. Juice on Serum Levels of Inhibin B, Sperm Count in Adult Male Rats.

Afzalzadeh MR1, Ahangarpour A2, Amirzargar A3, Varnamkhasti MK1, Ganjalidarani H1.

Vitis vinifera is a species of Vitis that is native to the Mediterranean region, central Europe, and southwestern Asia, and has been used as a drug in traditional medicine. Traditional medicinal plants have been used for medical purposes with increasing effectiveness. It is important to identify drugs that inhibit spermatogenesis. Therefore, the present study aimed to investigate the effect of grape juice (GJ) on serum levels of inhibin B and sperm count in normal male rats.

MATERIALS AND METHODS:

Thirty-five adult male rats were randomly divided into five groups, each containing seven rats. Rats in the control group received 1 mL of normal saline over the course of the study. The experimental groups received GJ (100, 200, 400, and 1,600 mg/kg, orally, for 35 days consecutively). At the end of the treatment period, fertility indices were measured, including body weight difference, sex organ weight, sperm motility and count, epididymal sperm reserve, daily sperm production (DSP), and serum inhibin B levels.

RESULTS:

We found that GJ reduces body weight difference, was associated with decreased sperm motility and count in all treatment groups (p≤0.05 and p≤0.001, respectively). Moreover, DSP was significantly decreased in all treatment groups compared to the control group (p≤0.05), except in the group receiving 100 mg/kg of GJ. Inhibin B levels were significantly decreased in all treatment groups (p≤0.05).

CONCLUSIONS:

The results of our study suggest that GJ in all doses, but especially in higher doses, may decrease fertility in male rats.

Grapes and Cardiovascular Disease1–3

Mustali M. Dohadwala and Joseph A. Vita *

+ Author Affiliations

Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118

Epidemiological studies suggest that consumption of wine, grape products, and other foods containing polyphenols is associated with decreased risk for cardiovascular disease. The benefits of wine consumption appear to be greater than other alcoholic beverages. Experimental studies indicate that grape polyphenols could reduce atherosclerosis by a number of mechanisms, including inhibition of oxidation of LDL and other favorable effects on cellular redox state, improvement of endothelial function, lowering blood pressure, inhibition of platelet aggregation, reducing inflammation, and activating novel proteins that prevent cell senescence, e.g. Sirtuin 1. Translational studies in humans support these beneficial effects. More clinical studies are needed to confirm these effects and formulate dietary guidelines. The available data, however, strongly support the recommendation that a diet rich in fruits and vegetables, including grapes, can decrease the risk for cardiovascular disease.

The medicinal value of the grapevine and its fruit, Vitis vinifera, has been recognized for over 6000 y (1). In ancient Egypt, sap from grapevines was made into an ointment to treat skin and eye conditions. The fruit was crushed into wine elixirs or ripened to serve as therapeutics for a multitude of conditions, including nausea, constipation, cholera, smallpox, liver disease, and cancers. In the past century, disease states such as hypertension, coronary heart disease, and stroke have become markedly more prevalent. Despite aggressive management of cardiovascular risk factors and improved outcomes, the societal burden from cardiovascular disease remains high, and in the past few decades there has been increased interest in lifestyle and dietary approaches to reducing cardiovascular risk. Recent evidence suggests there are cardioprotective benefits from diets rich in natural fruits and vegetables, such as grapes. This review will outline the epidemiological evidence supporting the cardiovascular benefits of grape consumption. We will then consider experimental and translational studies that elucidate potential mechanisms of benefit.

Epidemiology

The “French Paradox.”

In 1979, St. Leger et al. (2) drew attention to the protective effects of wine against ischemic heart disease. Epidemiologic data collected by the WHO revealed a discord in cardiovascular mortality in a cohort of subjects from Toulouse, France, compared with other cohorts from 17 Western countries, including the United States and the United Kingdom (3–5). Interestingly, the French cohort had lower risk despite higher consumption of saturated fat (3). This counterintuitive finding, which was coined the “French Paradox,” stimulated further analysis leading to the suggestion that increased consumption of wine in France and other Mediterranean countries might be the explanation.

More recent epidemiological studies provide further support for a beneficial effect of wine. Initially, reduced risk was attributed to its ethanol content (3,6–8). Other studies, however, indicated that wine might confer benefits above and beyond those of other alcoholic beverages, suggesting that nonalcoholic factors in wine may also play a protective role (9–11). For example, wine consumption was found to be cardioprotective, whereas beer intake was not, in a meta-analysis of 13 studies and 209,418 participants (9). Despite these data, it remains possible that ethanol and/or other aspects of the Mediterranean diet or lifestyle might better explain the French paradox.

Grape polyphenols and cardiovascular risk.

Grapes contain a wide variety of polyphenol compounds, including flavonoids, phenolic acids, and resveratrol. There is extensive epidemiological evidence suggesting that dietary intake of these compounds reduces cardiovascular mortality (12–17). Numerous studies in vitro as well as in animals and humans demonstrate beneficial effects of grape polyphenols on traditional cardiovascular risk factors (Table 1). Population-based studies have observed markedly lower cardiovascular disease mortality in cohorts with higher consumption of relevant flavonoids, including flavonols, flavones, and flavan-3-ols (13–15,18–20). In a study of 34,489 postmenopausal American women, dietary intake of foods containing flavanones and anthocyanidins was associated with decreased cardiovascular and all-cause mortality (21). In that study, consumption of red wine was specifically associated with decreased risk of coronary heart disease.

Further evidence that polyphenol content in wine accounts for cardiovascular benefits may be derived from studies comparing different types of wine. The highest concentrations of grape polyphenols are found in the skin, stems, and seeds. The longer contact with these components during the production of red wine increases polyphenolic content up to 10-fold compared with white wine (22). Investigators suggest that this difference in phytochemical content explains the reported additional health benefit of red wine over white wine or grape juice (23). In support of this possibility, numerous human studies suggest that red wine has greater antioxidant effects and more favorable effects on lipid metabolism than white wine (24). It must be acknowledged, however, that several observational studies from North American cohorts did not reveal differential effects of red and white wines (10,25).

Negative studies of polyphenol consumption and cardiovascular disease.

Despite the large body of evidence supporting a link between polyphenol consumption and reduced cardiovascular risk, some concerns are worth noting. A number of well-done observational studies have shown no relationship between polyphenol consumption and cardiovascular outcomes (26,27). These apparently discrepant results might be explained by a variety of factors. Dietary questionnaires are an imperfect method to assess polyphenol intake and the available studies have focused on only a few specific compounds. In addition, the overall levels and ranges of polyphenol intake within the studied cohorts and the confounding effects of socioeconomic class, other dietary factors, and concomitant risk factors might explain the lack of consistent findings (28). Despite these lingering questions, the accumulated data from multiple studies prompted the AHA to recommend a diet rich in fruits and vegetables, including grapes, as an approach to prevent cardiovascular disease (29).

Mechanistic studies

Antioxidant properties.

Grape polyphenols have important antioxidant properties. According to the oxidative hypothesis, oxidative modification of LDL is a primary initiating event in atherosclerosis [reviewed by Diaz et al. (30)]. As a corollary, this hypothesis suggests that antioxidant treatment to limit LDL oxidation should prevent atherosclerosis and its complications. These concepts stimulated many studies that examined the antiatherosclerotic effects of antioxidant vitamins in animal models and surrogate endpoints in humans and ultimately prompted investigators to conduct large-scale clinical trials of antioxidant treatment for cardiovascular disease (31). Despite the failure of randomized trials with antioxidant vitamins, such as vitamin E, vitamin C, and β carotene, there remains strong evidence that an imbalance between production of reactive oxygen species and antioxidant defense mechanisms contributes to the pathogenesis of atherosclerosis (32). We now understand that redox signaling is important for normal cellular physiology and the response to environmental stress, possibly explaining why high-dose antioxidant supplementation does not show benefits. It remains clear, however, that “oxidative stress” has pathophysiological effects on enzyme function, cell signaling, and gene expression that contribute to disease development. Interventions that affect cellular redox status have the potential to reduce risk.

In this context, many studies investigating beneficial mechanisms of grape polyphenols have focused on their antioxidant properties. Flavonoids and other polyphenols found in grapes have the capacity to scavenge reactive oxygen species (33). When fed to animals and humans, such compounds have been shown to increase the radical scavenging capacity of plasma (34). In addition to scavenging radicals, polyphenols alter cellular redox status by other mechanisms, including chelating metals that promote lipid peroxidation and modulating the activity of antioxidant enzymes.

Given the oxidative hypothesis of atherosclerosis, a potentially important property of grape-derived polyphenols is the ability to inhibit LDL oxidation. In the key initial step in atherogenesis, oxidized LDL (oxLDL) is taken up by macrophages in an unregulated manner to form foam cells. OxLDL also promotes atherosclerosis by altering endothelial function, stimulating platelet activation, and inducing a proinflammatory state in the vascular wall (30). In vitro studies have demonstrated that grape-derived flavonoids and resveratrol limit ex vivo LDL oxidation (35). Red wine has been found to be more potent than white wine or pure ethanol in this regard (36).

There is evidence that these effects are relevant to atherogenesis in animals. Hayek et al. (37) observed that hypercholesterolemic mice consuming wine polyphenols for 6 wk had markedly less atherosclerosis than control animals. These treatments were associated with protection against LDL oxidation. Vinson et al. (38) demonstrated reduced aortic atherosclerosis in hamsters supplemented with polyphenol-rich beverages. Zern et al. (39) observed a reduction in cholesterol accumulation in the aortas of ovariectomized guinea pigs fed a lyophilized grape preparation. Interestingly, Stocker et al. (40) observed reduced atherosclerosis but no decrease in LDL oxidation within the arterial wall following treatment with dealcoholized red wine in mice, suggesting that mechanisms other than LDL protection may also be important.

To translate these mechanistic findings to humans, Stein et al. (41) demonstrated a reduction in the susceptibility of LDL to copper-mediated oxidation following consumption of purple grape juice for 2 wk in patients with coronary artery disease. Red wine consumption in healthy subjects also reduced urinary levels of prostoglandin F2-α, a marker of systemic lipid peroxidation (42). A similar effect on urinary isoprostane concentrations were observed in pre- and postmenopausal women following treatment with lyophilized grape powder for 4 wk (43). At the present time, no study, to our knowledge, has shown a relation between polyphenol consumption and reduced atherosclerosis in humans. It remains to be determined whether inhibition of LDL oxidation is a clinically relevant mechanism in humans.

Endothelial function.

The vascular endothelium plays a central role in the regulation of vascular tone, thrombosis, local inflammation, and cell proliferation by producing paracrine factors that act on the arterial wall and blood cells (44). Endothelium-derived nitric oxide (NO) is a vasodilator and inhibits platelets, leukocyte adhesion to the endothelial surface, and proliferation of vascular smooth muscle cells. When healthy, the endothelium promotes a vasodilator, antithrombotic, and antiinflammatory state. However, cardiovascular disease risk factors alter endothelial phenotype in a manner that promotes atherogenesis, lesion progression, and plaque vulnerability.

In humans, endothelial dysfunction is associated with traditional risk factors and established atherosclerosis (45). Furthermore, endothelial dysfunction predicts progression of atherosclerosis and incidence of cardiovascular events (46,47). Furthermore, endothelial dysfunction is reversed by a number of interventions proven to reduce cardiovascular risk, such as lipid-lowering therapy, angiotensin-converting inhibitors, smoking cessation, and weight loss (44). Failure of the endothelium to respond to such therapy identifies patients at higher risk (48).

In vitro studies have demonstrated favorable effects of grape products on endothelial function. In cultured endothelial cells, wine, grape juice, grape seed extract, and specific polyphenols increase the activity of the endothelial isoform of NO synthase and stimulate NO production (49,50). In the short term, polyphenols stimulate endothelial NO synthase phosphorylation via phsophatidylinositol-3-hydroxy kinase and Akt (51). Longer term exposure to red wine extracts or resveratrol stimulates an increase in enzyme expression and activity (49,50). The effects of resveratrol on endothelial function may be mediated through an effect on Sirtuin-1, which regulates the expression of genes related to cell survival and the stress response (6,52). Furthermore, activation of Sirtuin-1 decreases the activity of p53, a regulator of apoptosis and the cell cycle, and activates AMP-dependent protein kinase, a regulator of cellular energy status (53).

Human studies support a benefit of grape beverages on endothelial function (54). Stein et al. (41) observed that consumption of purple grape juice for 2 or 4 wk improved endothelium-dependent brachial artery flow-mediated dilation in patients with coronary artery disease. Dealcoholized wine also improved brachial artery flow-mediated dilation in healthy subjects (55). Interestingly, red wine consumption prevents the acute impairment of endothelial function that occurs following cigarette smoking (56) or consumption of a high-fat meal (57).

In addition to the effects on NO, grapes have important effects on other molecular aspects of vascular function. For example, flavonoid-containing beverages increase endothelial production of prostacyclin and suppress production of endothelin-1, a potent endothelium-derived vasoconstrictor (58,59). In regard to regulation of fibrinolysis, catechins and resveratrol increase protein levels and activity of tissue plasminogen activator, an effect that is likely to be cardioprotective (60). Finally, there is increasing evidence that polyphenols affect endothelial regulation of inflammation. Red wine constituents reduce adhesion of monocytes to the endothelial surface and block cytokine-induced expression of endothelial adhesion molecules (61). Thus, grape polyphenols induce multiple favorable changes in endothelial cell phenotype that could reduce cardiovascular risk.

Antiplatelet effects.

Platelets play a critical role in all phases of atherosclerosis. Antiplatelet drugs, particularly aspirin, have proven beneficial effects on cardiovascular risk. Because polyphenols have been shown to have platelet inhibitory effects, there is great interest in the possibility that grape consumption might provide similar protection. In vitro studies have shown that grape-derived polyphenols inhibit platelet activity and elucidated a number of potential mechanisms. Flavonoids inhibit cyclooxygenase and reduce production of thromboxane A2. Red wine polyphenols also decrease platelet production of hydrogen peroxide and inhibit activation of phospholipase C and protein kinase C (62). Dilute grape juice inhibits platelet aggregation and this effect is associated with decreased production of superoxide anion and increased platelet NO production (34).

Feeding grape juice to animals also has important antiplatelet effects. Demrow et al. (63) used a coronary artery platelet aggregation model (Folts model) that mimics acute coronary syndromes to demonstrate platelet inhibition following oral administration of red wine to dogs. Similar effects were observed in monkeys (64) and these effects have been shown to depend on NO production (65).

Human studies have also demonstrated antiplatelet effects of grape-derived beverages. Freedman et al. (34) demonstrated that grape juice consumption for 14 d decreased platelet aggregation and superoxide production and increased NO production in healthy volunteers. In that study, grape juice also inhibited protein kinase C and spared cellular antioxidants. Red wine has more potent antiplatelet effects than white wine (66) and these effects are not seen with other beverages, such as orange juice and grapefruit juice, which contain other antioxidants (67).

Antiinflammatory and other mechanisms.

The importance of inflammation for all stages of atherosclerosis is increasingly recognized and there are data suggesting that grape polyphenols have antiinflammatory effects. For example, red wine and polyphenols inhibit activation of nuclear factor-κB and production of proinflammatory factors in endothelial cells and inflammatory cells (61,68). Incubation of monocytes with catechin decreased their adhesion to endothelial cells (69). Relevant polyphenols also inhibit activation of nuclear factor-κB in T lymphocyte cell lines (70). Resveratrol has also been shown to have antiinflammatory effects, including inhibition of adhesion molecule expression (6,71). In humans, treatment with lyophilized grape powder for 4 wk was associated with a reduction in tissue necrosis factor-α, but not C-reactive protein or interleukin-6 (43). Wine and gin consumption for 4 wk also reduced systemic markers of inflammation in healthy men and the effect was more marked following wine consumption (72). Thus, antiinflammatory effects might be a contributing mechanism for the benefits of grape polyphenols against cardiovascular disease.

Clinical implications

As reviewed in the preceding sections, there is strong epidemiological evidence linking reduced cardiovascular risk with consumption of grapes and other polyphenol-rich foods. Experimental and translational studies suggest several important mechanisms that might account for such an effect. An important remaining question is how to incorporate these data into specific recommendations for dietary intake for the general public. A detailed discussion of these issues is beyond the scope of this review, but a number of factors complicate the formulation of such recommendations at the population level. For example, obtaining an accurate estimate of current intake is confounded by structural diversity, wide distribution in foods, and variations in content of polyphenols (73). Polyphenol bioactivity is further clouded by variable bioavailability due in part to differences in food matrix and human gut absorption (74,75). Ultimately, such efforts are limited, because it remains uncertain which components of polyphenol-rich foods actually confer benefit.

In addition to developing better dietary recommendations, emerging studies showing cardiovascular benefits of polyphenol-rich foods have also prompted interest by the pharmaceutical industry. It is possible that purified formulations of specific grape constituents, e.g. resveratrol, might be efficacious as drugs for cardiovascular disease treatment or prevention. Indeed, such promise has led to identifying synthetic polyphenol analogs that might have greater potency and therapeutic potential. Such compounds will require large-scale trials before they can be approved for clinical use. In the meantime, the available evidence supports a diet rich in fruits and vegetables, including grapes, as an appropriate strategy to reduce the risk of cardiovascular disease.

LITERATURE CITED

1.↵ Ziskind B, Halioua B. Occupational medicine in ancient Egypt. Med Hypotheses. 2007;69:942–5. CrossRefMedline

2.↵ St Leger AS, Cochrane AL, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet. 1979;1:1017–20. Medline

3.↵ Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992;339:1523–6. CrossRefMedline

4. Keil U, Kuulasmaa K. WHO MONICA Project: risk factors. Int J Epidemiol. 1989;18:S46–55. CrossRefMedline

5.↵ Colling M, Weggemann S, Doring A, Keil U, Wolfram G. [Nutrition survey of adults using a 7-day protocol–a pilot study in the Augsburg MONICA project]. Offentl Gesundheitswes. 1989;51:94–7. Medline

6.↵ Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5:493–506. CrossRefMedline

7. Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med. 1993;329:1829–34. CrossRefMedline

8.↵ Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits. BMJ. 1996;312:731–6. Abstract/FREE Full Text

9.↵ Di Castelnuovo A, Rotondo S, Iacoviello L, Donati MB, de Gaetano G. Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002;105:2836–44. Abstract/FREE Full Text

10.↵ Klatsky AL, Friedman GD, Armstrong MA, Kipp H. Wine, liquor, beer, and mortality. Am J Epidemiol. 2003;158:585–95. Abstract/FREE Full Text

11.↵ Gronbaek M, Becker U, Johansen D, Gottschau A, Schnohr P, Hein HO, Jensen G, Sorensen TI. Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer. Ann Intern Med. 2000;133:411–9. CrossRefMedline

12.↵ Hertog MGL, Kromhout D, Aravanis C, Blackburn H, Buzino R, Fidanza F. Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study. Arch Intern Med. 1995;155:381–6. CrossRefMedline

13.↵ Arts IC, Hollman PC, Feskens EJ, Bueno De Mesquita HB, Kromhout D. Catechin intake and associated dietary and lifestyle factors in a representative sample of Dutch men and women. Eur J Clin Nutr. 2001;55:76–81. CrossRefMedline

14. Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC. Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am J Clin Nutr. 2002;75:880–6. Abstract/FREE Full Text

15.↵ Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312:478–81. Abstract/FREE Full Text

16. Ness AR, Powles JW. Fruit and vegetables, and cardiovascular disease: a review. Int J Epidemiol. 1997;26:1–13. Abstract/FREE Full Text

17.↵ Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, Griel AE, Etherton TD. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med. 2002;113 Suppl 9B:S71–88. CrossRef

18.↵ Hertog MGL, Feskens EJM, Hollman PCH, Martijn B, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993;342:1007–11. CrossRefMedline

19. Yochum L, Kushi LH, Meyer K, Folsom AR. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol. 1999;149:943–9. Abstract/FREE Full Text

20.↵ Hirvonen T, Pietinen P, Virtanen M, Ovaskainen ML, Hakkinen S, Albanes D, Virtamo J. Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology. 2001;12:62–7. CrossRefMedline

21.↵ Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA, Jacobs DR Jr. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007;85:895–909. Abstract/FREE Full Text

22.↵ Sparwel J, Vantler M, Caglayan E, Kappert K, Fries JW, Dietrich H, Bohm M, Erdmann E, Rosenkranz S. Differential effects of red and white wines on inhibition of the platelet-derived growth factor receptor: impact of the mash fermentation. Cardiovasc Res. 2009;81:758–70. Abstract/FREE Full Text

23.↵ Opie LH, Lecour S. The red wine hypothesis: from concepts to protective signaling molecules. Eur Heart J. 2007;28:1683–93. Abstract/FREE Full Text

24.↵ van Velden DP, Mansvelt EP, Troup GJ. Red wines good, white wines bad? Redox Rep. 2002;7:315–6. CrossRefMedline

25.↵ Stampfer MJ, Kang JH, Chen J, Cherry R, Grodstein F. Effects of moderate alcohol consumption on cognitive function in women. N Engl J Med. 2005;352:245–53. CrossRefMedline

26.↵ Sesso HD, Gaziano JM, Liu S, Buring JE. Flavonoid intake and the risk of cardiovascular disease in women. Am J Clin Nutr. 2003;77:1400–8. Abstract/FREE Full Text

27.↵ Lin J, Rexrode KM, Hu F, Albert CM, Chae CU, Rimm EB, Stampfer MJ, Manson JE. Dietary intakes of flavonols and flavones and coronary heart disease in US women. Am J Epidemiol. 2007;165:1305–13. Abstract/FREE Full Text

28.↵ Vita JA. Tea consumption and cardiovascular disease: effects on endothelial function. J Nutr. 2003;133:S3293–7.

29.↵ Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, Franklin B, Kris-Etherton P, Harris WS, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114:82–96. Abstract/FREE Full Text

30.↵ Diaz MN, Frei B, Vita JA, Keaney JF Jr. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337:408–17. CrossRefMedline

31.↵ Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154–60. CrossRefMedline

32.↵ Stocker R, Keaney JF Jr. The role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84:1381–478. Abstract/FREE Full Text

33.↵ Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med. 1996;20:933–56. CrossRefMedline

34.↵ Freedman JE, Parker C III, Li L, Perlman JA, Frei B, Ivanov V, Deak LR, Iafrati MD, Folts JD. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. 2001;103:2792–8. Abstract/FREE Full Text

35.↵ Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of LDL oxidation by resveratrol. Lancet. 1993;341:1103–4. CrossRefMedline

36.↵ Rifici VA, Schneider SH, Khachadurian AK. Lipoprotein oxidation mediated by J774 murine macrophages is inhibited by individual red wine polyphenols but not by ethanol. J Nutr. 2002;132:2532–7. Abstract/FREE Full Text

37.↵ Hayek T, Furman B, Vaya JR, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M. Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol. 1997;17:2744–52. Abstract/FREE Full Text

38.↵ Vinson JA, Teufel K, Wu N. Red wine, dealcoholized red wine, and especially grape juice, inhibit atherosclerosis in a hamster model. Atherosclerosis. 2001;156:67–72. CrossRefMedline

39.↵ Zern TL, West KL, Fernandez ML. Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs. J Nutr. 2003;133:2268–72. Abstract/FREE Full Text

40.↵ Stocker R, O'Halloran RA. Dealcoholized red wine decreases atherosclerosis in apolipoprotein E gene-deficient mice independently of inhibition of lipid peroxidation in the artery wall. Am J Clin Nutr. 2004;79:123–30. Abstract/FREE Full Text

41.↵ Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation. 1999;100:1050–5. Abstract/FREE Full Text

42.↵ Pignatelli P, Ghiselli A, Buchetti B, Carnevale R, Natella F, Germano G, Fimognari F, Di Santo S, Lenti L, et al. Polyphenols synergistically inhibit oxidative stress in subjects given red and white wine. Atherosclerosis. 2006;188:77–83. CrossRefMedline

43.↵ Zern TL, Wood RJ, Greene C, West KL, Liu Y, Aggarwal D, Shachter NS, Fernandez ML. Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. J Nutr. 2005;135:1911–7. Abstract/FREE Full Text

44.↵ Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42:1149–60. CrossRefMedline

45.↵ Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman B, Fan S, Osypiuk E, et al. Clinical correlates and heritability of endothelial function in the community: the Framingham Heart Study. Circulation. 2004;109:613–9. Abstract/FREE Full Text

46.↵ Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653–8. Abstract/FREE Full Text

47.↵ Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ, Marmot MG, Deanfield JE. Endothelial function predicts progression of carotid intima-media thickness. Circulation. 2009;119:1005–12.

48.↵ Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002;40:505–10. CrossRefMedline

49.↵ Leikert JF, Rathel TR, Wohlfart P, Cheynier V, Vollmar AM, Dirsch VM. Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation. 2002;106:1614–7. Abstract/FREE Full Text

50.↵ Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, Forstermann U. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002;106:1652–8. Abstract/FREE Full Text

51.↵ Lorenz M, Wessler S, Follmann E, Michaelis W, Dusterhoft T, Baumann G, Stangl K, Stangl V. A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. J Biol Chem. 2004;279:6190–5. Abstract/FREE Full Text

52.↵ Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, DeRicco J, Kasuno K, Irani K. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 2007;104:14855–60. Abstract/FREE Full Text

53.↵ Suchankova G, Nelson LE, Gerhart-Hines Z, Kelly M, Gauthier MS, Saha AK, Ido Y, Puigserver P, Ruderman NB. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun. 2009;378:836–41. Epub 2008 Dec 9. CrossRefMedline

54.↵ Flesch M, Schwarz A, Bohm M. Effects of red and white wine on endothelium-dependent vasorelaxation of rat aorta and human coronary arteries. Am J Physiol. 1998;275:H1183–90. Medline

55.↵ Agewall S, Wright S, Doughty RN, Whalley GA, Duxbury M, Sharpe N. Does a glass of red wine improve endothelial function? Eur Heart J. 2000;21:74–8. Abstract/FREE Full Text

56.↵ Papamichael C, Karatzis E, Karatzi K, Aznaouridis K, Papaioannou T, Protogerou A, Stamatelopoulos K, Zampelas A, Lekakis J, et al. Red wine's antioxidants counteract acute endothelial dysfunction caused by cigarette smoking in healthy nonsmokers. Am Heart J. 2004;147:E5. Medline

57.↵ Cuevas AM, Guasch V, Castillo O, Irribarra V, Mizon C, San Martin A, Strobel P, Perez D, Germain AM, et al. A high-fat diet induces and red wine counteracts endothelial dysfunction in human volunteers. Lipids. 2000;35:143–8. CrossRefMedline

58.↵ Gryglewski RJ, Korbut R, Robak J, Swies J. On the mechanism of antithrombotic action of flavonoids. Biochem Pharmacol. 1987;36:317–22. CrossRefMedline

59.↵ Corder R, Douthwaite JA, Lees DM, Khan NQ, Viseu Dos Santos AC, Wood EG, Carrier MJ. Endothelin-1 synthesis reduced by red wine. Nature. 2001;414:863–4. CrossRefMedline

60.↵ Abou-Agag LH, Aikens ML, Tabengwa EM, Benza RL, Shows SR, Grenett HE, Booyse FM. Polyphyenolics increase t-PA and u-PA gene transcription in cultured human endothelial cells. Alcohol Clin Exp Res. 2001;25:155–62. CrossRefMedline

61.↵ Carluccio MA, Siculella L, Ancora MA, Massaro M, Scoditti E, Storelli C, Visioli F, Distante A, De Caterina R. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc Biol. 2003;23:622–9. Abstract/FREE Full Text

62.↵ Pignatelli P, Pulcinelli FM, Celestini A, Lenti L, Ghiselli A, Gazzaniga PP, Violi F. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Am J Clin Nutr. 2000;72:1150–5. Abstract/FREE Full Text

63.↵ Demrow HS, Slane PR, Folts JD. Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation. 1995;91:1182–8. Abstract/FREE Full Text

64.↵ Osman HE, Maalej N, Shanmuganayagam D, Folts JD. Grape juice but not orange or grapefruit juice inhibits platelet activity in dogs and monkeys. J Nutr. 1998;128:2307–12. Abstract/FREE Full Text

65.↵ Wollny T, Aiello L, Di Tommaso D, Bellavia V, Rotilio D, Donati MB, de Gaetano G, Iacoviello L. Modulation of haemostatic function and prevention of experimental thrombosis by red wine in rats: a role for increased nitric oxide production. Br J Pharmacol. 1999;127:747–55. CrossRefMedline

66.↵ Gresele P, Pignatelli P, Guglielmini G, Carnevale R, Mezzasoma AM, Ghiselli A, Momi S, Violi F. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. 2008;138:1602–8. Abstract/FREE Full Text

67.↵ Keevil JG, Osman HE, Reed JD, Folts JD. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr. 2000;130:53–6. Abstract/FREE Full Text

68.↵ Blanco-Colio LM, Valderrama M, Alvarez-Sala LA, Bustos C, Ortego M, Hernandez-Presa MA, Cancelas P, Gomez-Gerique J, Millan J, et al. Red wine intake prevents nuclear factor-kappaB activation in peripheral blood mononuclear cells of healthy volunteers during postprandial lipemia. Circulation. 2000;102:1020–6. Abstract/FREE Full Text

69.↵ Koga T, Meydani M. Effect of plasma metabolites of (+)-catechin and quercetin on monocyte adhesion to human aortic endothelial cells. Am J Clin Nutr. 2001;73:941–8. Abstract/FREE Full Text

70.↵ Mackenzie GG, Carrasquedo F, Delfino JM, Keen CL, Fraga CG, Oteiza PI. Epicatechin, catechin, and dimeric procyanidins inhibit PMA-induced NF-kappaB activation at multiple steps in Jurkat T cells. FASEB J. 2004;18:167–9. Abstract/FREE Full Text

71.↵ Ferrero ME, Bertelli AE, Fulgenzi A, Pellegatta F, Corsi MM, Bonfrate M, Ferrara F, De Caterina R, Giovannini L, et al. Activity in vitro of resveratrol on granulocyte and monocyte adhesion to endothelium. Am J Clin Nutr. 1998;68:1208–14. Abstract

72.↵ Estruch R, Sacanella E, Badia E, Antunez E, Nicolas JM, Fernandez-Sola J, Rotilio D, de Gaetano G, Rubin E, et al. Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers. Atherosclerosis. 2004;175:117–23. CrossRefMedline

73.↵ Erdman JW Jr, Balentine D, Arab L, Beecher G, Dwyer JT, Folts J, Harnly J, Hollman P, Keen CL, et al. Flavonoids and heart health: proceedings of the ILSI North America Flavonoids workshop, May 31-June 1, 2005, Washington, DC. J Nutr. 2007;137:S718–37.

74.↵ Rice-Evans CA, Miller NJ. Antioxidant activities of flavonoids as bioactive components of food. Biochem Soc Trans. 1996;24:790–5. FREE Full Text

75.↵ Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr. 2000;130:S2073–85.

76.↵ Diebolt M, Bucher B, Andriantsitohaina R. Wine polyphenols decrease blood pressure, improve NO vasodilatation, and induce gene expression. Hypertension. 2001;38:159–65. Abstract/FREE Full Text

77.↵ Actis-Goretta L, Ottaviani JI, Fraga CG. Inhibition of angiotensin converting enzyme activity by flavanol-rich foods. J Agric Food Chem. 2006;54:229–34. CrossRefMedline

78.↵ Mizutani K, Ikeda K, Kawai Y, Yamori Y. Extract of wine phenolics improves aortic biomechanical properties in stroke-prone spontaneously hypertensive rats (SHRSP). J Nutr Sci Vitaminol (Tokyo). 1999;45:95–106. Medline

79.↵ Bernatova I, Pechanova O, Babal P, Kysela S, Stvrtina S, Andriantsitohaina R. Wine polyphenols improve cardiovascular remodeling and vascular function in NO-deficient hypertension. Am J Physiol Heart Circ Physiol. 2002;282:H942–8. Abstract/FREE Full Text

80.↵ Sarr M, Chataigneau M, Martins S, Schott C, El Bedoui J, Oak MH, Muller B, Chataigneau T, Schini-Kerth VB. Red wine polyphenols prevent angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase. Cardiovasc Res. 2006;71:794–802. Abstract/FREE Full Text

81.↵ Park YK, Kim JS, Kang MH. Concord grape juice supplementation reduces blood pressure in Korean hypertensive men: double-blind, placebo controlled intervention trial. Biofactors. 2004;22:145–7. CrossRefMedline

82.↵ Peng N, Clark JT, Prasain J, Kim H, White CR, Wyss JM. Antihypertensive and cognitive effects of grape polyphenols in estrogen-depleted, female, spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2005;289:R771–5. Abstract/FREE Full Text

83.↵ Pinent M, Blay M, Blade MC, Salvado MJ, Arola L, Ardevol A. Grape seed-derived procyanidins have an antihyperglycemic effect in streptozotocin-induced diabetic rats and insulinomimetic activity in insulin-sensitive cell lines. Endocrinology. 2004;145:4985–90. CrossRefMedline

84.↵ Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, Zhai Q. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab. 2007;6:307–19. CrossRefMedline

85.↵ Auger C, Rouanet JM, Vanderlinde R, Bornet A, Decorde K, Lequeux N, Cristol JP, Teissedre PL. Polyphenols-enriched Chardonnay white wine and sparkling Pinot Noir red wine identically prevent early atherosclerosis in hamsters. J Agric Food Chem. 2005;53:9823–9. CrossRefMedline

86.↵ Auger C, Caporiccio B, Landrault N, Teissedre PL, Laurent C, Cros G, Besancon P, Rouanet JM. Red wine phenolic compounds reduce plasma lipids and apolipoprotein B and prevent early aortic atherosclerosis in hypercholesterolemic golden Syrian hamsters (Mesocricetus auratus). J Nutr. 2002;132:1207–13. Abstract/FREE Full Text

87.↵ Davalos A, Fernandez-Hernando C, Cerrato F, Martinez-Botas J, Gomez-Coronado D, Gomez-Cordoves C, Lasuncion MA. Red grape juice polyphenols alter cholesterol homeostasis and increase LDL-receptor activity in human cells in vitro. J Nutr. 2006;136:1766–73. Abstract/FREE Full Text

88.↵ Pal S, Ho N, Santos C, Dubois P, Mamo J, Croft K, Allister E. Red wine polyphenolics increase LDL receptor expression and activity and suppress the secretion of ApoB100 from human HepG2 cells. J Nutr. 2003;133:700–6. Abstract/FREE Full Text

89.↵ Castilla P, Echarri R, Davalos A, Cerrato F, Ortega H, Teruel JL, Lucas MF, Gomez-Coronado D, Ortuno J, et al. Concentrated red grape juice exerts antioxidant, hypolipidemic, and antiinflammatory effects in both hemodialysis patients and healthy subjects. Am J Clin Nutr. 2006;84:252–62. Abstract/FREE Full Text

90.↵ Abu-Amsha Caccetta R, Burke V, Mori TA, Beilin LJ, Puddey IB, Croft KD. Red wine polyphenols, in the absence of alcohol, reduce lipid peroxidative stress in smoking subjects. Free Radic Biol Med. 2001;30:636–42. CrossRefMedline

91.↵ Vigna GB, Costantini F, Aldini G, Carini M, Catapano A, Schena F, Tangerini A, Zanca R, Bombardelli E, et al. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism. 2003;52:1250–7. CrossRefMedline

92.↵ Pezzuto JM, Venkatasubramanian V, Hamad M, Morris KR. Unraveling the relationship between grapes and health. J Nutr. 2009;139:1783–7.

93. Zunino SJ. Type 2 diabetes and glycemic response to grapes or grape products. J Nutr. 2009;139:1794–800.

94. Percival SS. Grape consumption supports immunity in animals and humans. J Nutr. 2009;139:1801–5.

95. Kaur M, Agarwal C, Agarwal R. Anticancer and cancer chemopreventive potential of grape seed extract and other grape-based products. J Nutr. 2009;139:1806–12. CrossRef

96. Joseph JA, Shukitt-Hale B, Willis LM. Grape juice, berries, and walnuts affect brain aging and behavior. J Nutr. 2009;139:1813–7.

97. Wu CD. Grape products and oral health. J Nutr. 2009;139:1818–23.

98.↵ Forester SC, Waterhouse AL. Metabolites are key to understanding health effects of wine polyphenolics. J Nutr. 2009;139:1824–31.