Modulation of redox signaling pathways

The conceptual framework to plan experiments for studying polyphenols as potential antioxidants with impact on human health has been provided essentially by the concept of oxidative stress. In fact, there is strong evidence from epidemiological studies suggesting that an improved antioxidant status is associated with a reduced risk of diseases, such 

Furthermore, the concept of imbalance between oxidants and antioxidants inherent to oxidative stress led to the implementation of antioxidant therapies and interventions to rebalance the disrupted equilibrium. However, the results of these studies are ambiguous and conflicting and, noteworthy, many molecules with strong antioxidant activity in vitro (such as resveratrol, among many others) revealed effects in vivo not related with antioxidant activity. For instance, resveratrol beyond direct antioxidant activities, and at very low concentrations likely found in vivo, modulates several metabolic pathways in a way that may have a positive impact on human health (Das Das, 2007), in particular the activation of NAD -dependent deacetylases sirtuins (e.g., SlRTl), thus preventing metabolic dysfunctioning (Milne et al, 2007 Elliott Jirousek, 2008). 

The several lines of reasoning mentioned earlier indicate that the notion of a systemic antioxidant seems hardly supported in the light of the updated notion of oxidative stress.  

alternate molecular pathways for the biological functions of polyphenols and its metabolites beyond direct antioxidant capacity with impact on both health and disease 

In view of their reduction potential, flavonoids have also been shown to interact with enzymes either unspecifically or specifically and modify their activity through reduction of metals in the active center. Of particular interest, because of their role in inflammatory conditions, is the reductive inactivation of lipoxygenases, cyclo-oxygenases, myeloperoxidase, and xanthine oxidase. In view of prooxidant activity of the enzymes, their inhibition by polyphenols may be regarded as an indirect antioxidation action. The list of enzymatic activities inhibited by flavonoids and other polyphenols also include phospholipase A2, protein kinases, metalloproteinases, drug metabolism enzymes, and telomerase, as reviewed elsewhere (Frade et al, 2005). 

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