4.1.1. Flavan-3-ols

Flavanols are relevant molecules in grapes and wine for their contribution to color stabilization and their astringent and bitter properties [142]. They are generally referred to as catechins and in their structure, the double bond on the C ring is absent and, accordingly, two chiral carbons are found (C2 and C3, see Figure 2) [143]. The monomeric catechins can exist in the form of four stereoisomers, depending on the hydroxylation on the C4 of the C ring. The *trans* isomer is called catechin, the *cis* one is called epicatechin. When catechins and epicatechins polymerize, they form condensed tannins also known as proanthocyanidins [144]. The organoleptic and pharmacological properties of tannins are strictly related to their structure and polymerization degree. Molecules with a higher polymerization degree have stronger radical scavenger activity and moreover, they are more bioavailable thanks to increased resistance to acid hydrolysis in the stomach [145]. Indeed, grape seed proanthocyanidins have been found to promote health-benefit via inhibition of protein damage linked to their antioxidant capacities and enzyme inhibition [146]. Grape seed proanthocyanidins extract is able to activate AMPK in C2C12 myotubes, consequently switching on Nrf1, SIRT1, and PGC-1α. This mechanism is behind the increase in slow myosin heavy chain, decrease in fast myosin chains, increased activity of succinic dehydrogenase and malate dehydrogenase, and decreased activity of lactate dehydrogenase all of these leading to increased resistance to fatigue [91]. (-)-Epigallocatechin-3-gallate (EGCG) wields an antioxidant activity through a combination of mechanisms. On one side it acts as a radical scavenger or by chelating metal ions that favor the formation of radicals [85], on the other, it enhances the activity of endogenous antioxidant enzymes as well as inhibits the activity of pro-oxidant enzymes and pro- inflammatory TLR4 pathways [57,86,87]. EGCG

has a role in mitigating the oxidative stress-based inflammation in T2D and obesity by regulating the NFkB, Adenosine Monophosphate Activated Protein Kinase (AMPK), and Mitogen-Activated Protein Kinases (MAPK) signaling pathways, thus decreasing IR and increasing muscle lipid oxidation [88,89]. EGCG has a beneficial effect on the aging process by promoting autophagy through activation of Beclin 1 and apoptosis by induction of caspase proteins [90], see Table 2.
