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Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the “French paradox,” which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed.

The mechanism of protein kinase C (PKC) regulation by alpha-tocopherol has been investigated in smooth-muscle cells. Treatment of rat aortic A7r5 smooth-muscle cells with alpha-tocopherol resulted in a time- and dose-dependent inhibition of PKC. The inhibition was not related to a direct interaction of alpha-tocopherol with the enzyme nor with a diminution of its expression. Western analysis demonstrated the presence of PKCalpha, beta, delta, epsilon, zeta and micro isoforms in these cells. Autophosphorylation and kinase activities of the different isoforms have shown that only PKCalpha was inhibited by alpha-tocopherol. The inhibitory effects were not mimicked by beta-tocopherol, an analogue of alpha-tocopherol with similar antioxidant properties. The inhibition of PKCalpha by alpha-tocopherol has been found to be associated with its dephosphorylation. Moreover the finding of an activation of protein phosphatase type 2A in vitro by alpha-tocopherol suggests that this enzyme might be responsible for the observed dephosphorylation and subsequent deactivation of PKCalpha. It is therefore proposed that PKCalpha inhibition by alpha-tocopherol is linked to the activation of a protein phosphatase, which in turn dephosphorylates PKCalpha and inhibits its activity.

Endoplasmic reticulum (ER) is the major site of protein folding and calcium storage. Beside the role of ER in protein homeostasis, it controls the cholesterol production and lipid-membrane biosynthesis as well as surviving and cell death signaling mechanisms in the cell. It is well-documented that elevated plasma cholesterol induces adverse effects in cardiovascular diseases (CVDs), liver disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatosis hepatitis (NASH), and metabolic diseases which are associated with oxidative and ER stress. Recent animal model and human studies have showed high cholesterol and ER stress as an emerging factors involved in the development of many metabolic diseases. In this review, we will summarize the crucial effects of hypercholesterolemia and ER stress response in the pathogenesis of CVDs, NAFLD/NASH, diabetes and obesity which are major health problems in western countries.

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