Alcohol consumption leads to higher HDL-cholesterol levels, but the same effect was observed in animal models with alcohol-free red wine [13].

Red wine phenolic extract decrease plasma cholesterol, triglyceride and Apo B levels in hamsters [14]. In cell lines resveratrol inhibits lipid peroxidation and improves the efflux by which HDL removes the excess of cholesterol from macrophages. Such a process is fundamental for reverse cholesterol transport which, on its turn, is on the basis for protection against atherosclerosis [15].

Polyphenols inhibits LDL oxidation in a more powerful manner than vitamin E as demonstrated by Frankel [16]. Moreover red wine consumption reduces plasma levels of Lp(a) [17] that, as it is known, is able to reduce the fibrinolytic activity. Red wine constituents also inhibit foamcell synthesis [18].

Recently, in a double-blind, placebo-controlled trial post-infarction patients treated with resveratrol for three months showed a significant reduction of LDL cholesterol. [19]

An inverse relationship between alcohol consumption and both fibrinogen and antithrombin has been demonstrated [20]; other authors observed a direct association between alcohol consumption and protein S [18], ultimately stimulating the surface-localized endothelial cell fibrinolysis.

The same group showed is that differently from what observed with beer and spirits to which could be due ischaemic events 24 - 48 hours after consumption, wine does not exert rebound effects [9].

Three glasses a day of red wine can significantly inhibit platelet aggregation, more than what observed with grapejuice or resveratrol-enriched grape juice, thus underlining the role of alcoholic components [21]. Resveratrol, catechin and quercetin are powerful inhibitors of platelet aggregation by different mechanisms among which decreesed thromboxane synthesis with consequent reduced activation of cycloand lipo-oxygenase must be mentioned [22]. Many papers strengthened this particular action of wine thus leading to consider it an “aspirin-like” compound [23]. However, results in normal subjects are controversial and someone did not observed ex vivo the same response. This might depend on different factors such bioavailability, intestinal clearance or drinking amount [24].

Protection against cardiovascular diseases is exerted by wine polyphenols that play an important influence on endothelium. In animal models and cultured cells different authors showed a vasodilating effect elicited by wine [25]. On human endothelium wine’s effects are rather controversial. In human umbilical vein endothelial cells (HUVEC) treated with a red wine polyphenolic extract Leikert [26] observed a significant nitric oxide (NO) increase via a raised eNOS protein expression. In the same cell line, resveratrol upregulated eNOS by stimulating promoter and transcription factors [27]. From these starting points, many studies on human volunteers proved a significant flowmediated dilation (FMD) after consuming a high fat meal associated with red wine [28,29]. After the observation of an increased FMD even with a dealcoholized red wine, some authors hypothesized the so called “Japanese Paradox” [30] with the creation of a tasty and healthy dealcoholized wine. Unfortunately, such investigations do not take account the important social role of the alcoholic beverages, expecially wine.

If we consider that polyphenols are detectable in the plasma of non supplemented humans at concentrations comparable to those required to induce 50% of maximal endothelium-dependent vasorelaxation, it can be hypothesized that in vivo effective concentrations can be reached [31].

In more than 300 men and 200 women who underwent coronary angiography, Liu et al. [32] showed that alcohol consumption was related to a lower risk of severe coronary stenosis in men, while in patients with angiographically documented coronary artery disease, Teragawa et al. [33] found that alcohol, if consumed at least once a week, positively influenced endothelial function.

Recently, Magyar showed that post infarction patients, treated with resveratrol show a significant improvement of endothelial function measured with FMD [19].

As we mentioned in our previous papers on this topic [3-6], all these data, rather controversial, lead us to think that beneficial effects could be due both to polyphenols and alcohol.

Many typical mediterranean foods, like onions, are a great source of polyphenols [34]. In fact, Mediterranean diet has been shown to reduce endothelial damage and to influence the endothelial ability to repair itself [35].

Hypertensives, according to WHO estimation [36], are about 600 millions and the number of prehypertensives is increasing. Hypertension is a common background in stroke [36] and a key factor in the progression of kidney disease [37]. A direct relationship between alcohol consumption and arterial hypertension is well documented [38] and this kind of association is also confirmed for a daily wine consumption greater than 3 glasses [39]. Some polyphenols, expecially quercetin (which is largely present in white wines) showed instead anti-hypertensive properties. In animal model of experimental hypertension, quercetin reduced blood pressure, cardiac and renal hypertrophy and blunted the hypertension-induced vascular remodeling in a dose-dependent manner [40]. In another model of salt-hypertensive rats, chronic oral administration of quercetin showed the same effects of verapamil on systolic blood pressure [41].

In the Predimed Study [42], a clinical, multicentric randomized, controlled trial total polyphenol urinary excretion, as biomarker of the total polyphenol intake, was measured in more than 500 subjects. This parameter was strictly inversely related to the prevalence of both systolic and diastolic hypertension. Polyphenols probably reduce arterial pressure also thanks to their ability to inhibit angiotensin converting enzyme, as demonstrated by ActisGoretta [43].

In light of all these considerations, it’s easy to understand how the deep, complex interactions between dietary factors, wine and their pathophysiological targets could be responsible of a reduced cardiovascular risk.

The relationship between wine consumption and kidney disease is very interesting if we consider that chronic kidney disease is associated with accelerated atherosclerotic damage and more frequent cardiovascular events. Oxidative stress and endothelial dysfunction, which are interrelated [44], are involved in the pathophysiology of many renal diseases [45] In rat models of diabetic nephropathy, quercetin showed to be able in reducing the disease progression [46]. In human patients with the same chronic kidney disease a similar result was obtained with a polyphenol-enriched diet [47].

Another wine constituent, the phytoalexin resveratrol, showed inhibitory effects on proteinuria, hypoalbuminemia and hyperlipidemia in nephritic rats [48]. Its nephroprotective effects were usually ascribed to its ability in modulate nitric oxide production and endothelial function. In fact it enhances production and activity of endothelial nitric oxide synthase (eNOS) [27]. More recently Mannari and coworkers [49] hypothesized that nephroprotection could be also due to the sirtuin regulation by NO modulation. Sirtuins are a protein family which is involved in several different biological processes, from glucose homeostasis to aging and cancer. Sirtuin-1 is the most investigated member of this family. It is a NAD(+) dependent deacetylase that regulates body stress responses by adjusting cell adaptations [50]. It is widely expressed in various tissues (liver, pancreas, muscles, adipose tissue, brain). Resveratrol activates sirtuin-1 via an allosteric interaction thus eliciting its effects.

The association between wine consumption and diabetes mellitus has been largely examined. From the epidemiological point of view, Conigrave and coworkers [51] showed an inverse linear relationship between daily alcohol intake and diabetes; the corrected relative risk gave to white wine the major protective role. More recently, in the EPIC-InterAct Study [52] carried out in eight European Countries, a moderate alcohol consumption has been associated with a lower risk of developing diabetes in female population. The same result was not observed in males probably due to the different body fat distribution.

In animal models of metabolic syndrome (Zucker rats), Rivera [53] showed that a daily administration of resveratrol carried out for 4 weeks lead to a reduction of plasma glucose levels, triglycerides, total cholesterol, free fatty acids, insulin and leptin and a significant decrease of liver fat content. These effects were ascribed to the increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase in the liver of these animals. Furthermore a significant improve in inflammatory conditions and an increased expression of eNOS in the visceral adipose tissue of the Zucker rats were noted.

In diabetic subjects, Ceriello and coworkers [54] some years ago showed as a standard meal is associated with a decrease of plasma total radical antioxidant power (TRAP); while if red wine is introduced in the same meal, the decrease of TRAP was not observed, thus underlining the antioxidant role of wine.

The antioxidant properties of wine polyphenols play a role in prevention of long term diabetic complications such as neuropathy, nephropathy and retinopathy. In fact polyphenols prevent the accumulation of oxidative/nitrative stress products in different body tissues as observed in animal models [55].

It has been demonstrated, in various cell culture and animal models, that wine polyphenols protect neuronal cells by attenuating oxidative stress and cell damage. Regular wine consumption has been associated with a reduced incidence of neurodegenerative diseases. Among the polyphenols, resveratrol has been related with a lower reduction of Beta-amyloid via sirtuin-1 actions [50]. Resveratrol also acts on glial inflammation which is strictly involved in brain damage. In fact it has been demonstrated to be implicated in several cell mechanisms that lead to a reduced production of glial inflammatory mediators [56].

However, as suggested by Albarracin [57] and coworkers, it remains unclear how these compounds reach the brain, what concentrations are necessary, and what biologically active forms are needed to have beneficial effects. Therefore, further research is needed about this topic.

The role of wine is controversial. A direct relationship between alcohol consumption and colo-rectal cancer has been reported and a similar association was observed for what regards liver, pharynx and larynx cancer [58-61]. A weaker association was observed between alcohol consumption and pancreas and neck cancer. No sure data are available for other many cancers whilst for what concerns the renal cancer a protective role of alcohol has been demonstrated [62].

Polyphenols, instead exert a protective role against cancer risk. Supposed mechanisms for this protections are: reduced expression of pro-oxidant enzymes which are involved in carcinogenesis; inhibition of transcription factor activation; apoptosis; impairment of cancer angiogenesis [63].

Recently resveratrol has been shown to involved in pain control, a crucial topic for cancer patients. In fact, it regulates nociceptive signaling via inhibition of cyclin-dependent kinase 5 (cdk5). Resveratrol blocks the TNF α- mediated increase in p35 promoter activity thus reducing cdk5, which is actually considered a key target molecule for analgesia [64].

Besides wine, many dietary constituents were associated with cancer prevention: olive oil, fish, fruit and vegetables. Considering that all these foods are present in the Mediterranean diet, we have to look at this dietary habit as the healthiest one for prevention.