RSV exerts antioxidant, anti-inflammatory, antifibrotic and cardiometabolic protective properties ^[1][23]. Moreover, it reduces platelet aggregation, enhances vasodilation (and nitric oxide bioavailability), reduces endothelial activation and modulates the metabolism of glucose and lipids.

All these beneficial cardiometabolic RSV-related effects are mediated by different molecular targets, some of which have already been identified (e.g., the activation of sirtuin 1 and AMPK, as well as the inhibition of NfκB) (Table 1) ^[1][23]. ARecently, a further possible mechanism that RSV uses to modulate endothelial function has been identified in the inhibition of the Pin1/Notch1 signaling pathway ^[2][24]. Nevertheless, it is known that RSV acts as an SIRT1 activator, decreasing vascular oxidative stress and preventing endothelial dysfunction ^[3][25]. In an in vitro model, the upregulation of SIRT1 appeared as a key factor for the activity of RSV in providing antiglycative/antioxidative defense and protection against high-glucose damage ^[4][26].

In two different in vitro models (rat aortic rings and human umbilical vein endothelial cells (HUVEC)), RSV was demonstrated to reduce both the acute high-glucose-induced endothelium-dependent relaxation damage induced by acetylcholine in phenylephrine-precontracted vessels, as well as cytotoxicity and oxidative stress, through a mechanism involving ROS scavenging, and was found to likely increase NO bioavailability ^[5][27]. The expression of antioxidant enzymes and endothelial-type nitric oxide synthase (eNOS) and reduction in the expression of inflammatory mediators are modulated by RSV through FoxO/SIRT1 activation and NRF2-dependent transcription ^[6][28]. Indeed, animal studies confirmed the beneficial effects of RSV supplementation on NO (circulating NO metabolites, eNOS expression, eNOS phosphorylation and eNOS uncoupling), generally in parallel to an improvement in blood pressure ^[7][29].

Moreover, RSV supplementation modulates the expression of different genes related to inflammation (INF-γ and TNF-α) and oxidative stress (heme oxygenase-1 and nitric oxide synthase) in the rat heart ^[8][30].

In rats, the administration of RSV (30 mg/kg·bw/daily for 10 weeks) reduced liver steatosis, oxidative stress and inflammation, improving the lipid profile as well as insulin sensitivity. It also reverted alterations in the hepatic mRNA expression levels of genes related to lipid metabolism and insulin signaling ^[9][31]. Moreover, RSV was shown to preserve β-cell function through the inhibition of the activity of phosphodiesterase, which hydrolyzes the phosphodiester bonds of cAMP and cGMP, thereby modulating various cellular signaling pathways ^[10][32]. Recent data also demonstrated that RSV reduces autophagy-mediated β-cell death via the inhibition of the CXCL16/ox-LDL pathway ^[11][33].

Other studies indicated that RSV reduces the apoptosis and modulates the paracrine function of cardiac microvascular endothelial cells under ischemia/reperfusion conditions ^[12][34]. In addition, RSV inhibits ox-LDL-induced endothelial injury (through the downregulation of circ_0091822 to upregulate miR-106b-5p-related TLR4) ^[13][35]. Ex vivo results on adipose tissue revealed that RSV inhibits adipogenesis through the activation of the AMPK-SIRT1-FOXO1 signaling pathway ^[14][15][36,37]. Moreover, RSV reduces the accumulation of triglycerides through the activation of PPARγ and SIRT1 ^[16][17][38,39].

Increasing evidence also highlights an important effect of RSV on the modulation of microbiota composition (type 2 diabetic animals and patients), similar to those induced by anti-diabetic drugs such as metformin, thus resulting in beneficial effects for T2D patients ^[18][40].

RSV supplementation had beneficial effects on some outcomes, such as blood pressure, the lipid profile, glycemic control and insulin resistance in T2D; the waist circumference in metabolic syndrome (MS); and body weight and inflammation markers in nonalcoholic fatty liver disease (NAFLD) ^[19][41]. In fact, it also improves insulin resistance and the glycolysis pathway, likely by modulating SIRT2, as evidenced using polycystic ovary syndrome granulosa cells ^[20][42]. Moreover, a meta-analysis of randomized controlled studies indicated that RSV is able to improve the lipid profile, reducing the TC, TG and LDL-C levels ^[21][11]. A meta-analysis of 25 studies (1171 participants, with 578 in the placebo group and 593 in the intervention group) demonstrated the benefits of RSV intake on lipid and glucose metabolism, with significant decreases in waist circumference, hemoglobin A1c, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol following RSV administration, exhibiting its major clinical value for obese and T2D patients ^[22][43]. Another recent meta-analysis of randomized controlled trials reported that RSV significantly enhances endothelial function, improving the flow-mediated dilation and intercellular adhesion molecule 1 (ICAM-1) levels ^[23][44].

An effect of resveratrol on mitochondrial function has been demonstrated in human muscle samples, which may constitute a beneficial effect in regard to cardiovascular disease (CVD) as well as the vascular and cardiac muscle, mitochondrial dysfunction being a general problem in CVD, in which different damaging processes can cause exhaustion that RSV may postpone ^[24][45].

RSV takes part in such a wide range of biological activities that it remains difficult to define its entire spectrum of actions. Moreover, many aspects need to be further evaluated, including the definition of an RSV threshold above which its effects are ensured, this also being the case for other variables that need to be taken into account (e.g., the durations of supplementation and the effects elicited, the RSV source (always being careful to avoid adverse effects derived from excessive alcohol consumption), age, the absorption and metabolism of RSV and other dietary components, but also individual genetic and gut microbiota characteristics) ^[8][30].

The recent available data essentially focus on the metabolic benefits of RSV in the context of obesity and T2D. In a meta-analysis including 11 randomized controlled trials (388 subjects), RSV significantly reduced fasting glucose, insulin, HbA1C and insulin resistance in T2D patients ^[25][46]. However, no significant effects of RSV on glycemic status were observed in the nondiabetic subjects ^[25][46]. Thus, further studies need to be planned based on the general population in order to evaluate the potential benefits of RSV in humans (e.g., the prevention of weight gain and metabolic dysfunction).

The combination of RSV with other substances may also be more effective in the treatment or prevention of cardiometabolic diseases, this being a strategy that is currently under evaluation based on subjects with metabolic syndrome, T2D or obesity (e.g., hesperetin; δ-Tocotrienol; a combination of curcumin, RSV, zinc, magnesium, selenium and vitamin D) ^{[26][27][28][29]}[47,48,49,50].

Moreover, synthetic nano-systems or biologically derived carriers may incapsulate RSV, enhancing its physicochemical properties and targeted delivery, thus opening up a wide range of applications, including the CM setting ^[30][51].