Figure 2.

The Nrf2/ARE pathway and cAMP second messenger system together are the key regulators of cellular antioxidant defence. These pathways can be modulated by stilbenes. Stilbenes can activate nuclear localization of Nrf2 and activation of Nrf2 target genes associated with antioxidant defence and autophagy. Autophagy related protein p62 and Nrf2 form a regulatory loop where p62 enables the release of Nrf2 from cytoplasmic Keap1 complex. When cells are not stressed, the excess of cytoplasmic Nrf2 is eliminated by proteasomal degradation. In addition, stilbenes are capable of activating cAMP response element-binding protein (CREB) target genes and the AMPK pathway by PDE inhibition mediated increase of cellular cAMP levels.