Figure 4: Effect of diabetes on Nrf2 signaling and current mechanism of action of current therapeutics. Sulforaphane and tert-Butylhydroquinone (tBHQ) prevents ubiquitination of Nrf2, thereby reducing proteasomal degradation. The triterpenoid derivative of dihydro-CDDO-trifluorethyl amid (Dh404) has been shown to directly disrupt Keap1 association and reduce Keap1-dependent suppression of Nrf2, thereby increasing Nrf2 stability. Inhibition of GSK-3 by SB216763 increases Nrf2 protein stability by preventing phosphorylation of Ser335 and Ser338 DSGIS338 and β-TrCP mediated ubiquitination. TDZD-8 and Lithium are GSK-3B inhibitors that prevents GSK-3B-Fyn mediated nuclear export of Nrf2 and normalizes basal and inducible levels of Nrf2 in diabetic rat fibroblasts [12]. Class I HDACs deacetylate Nrf2, which reduces DNA binding and increases nuclear export and cytosolic accumulation. Class I HDAC inhibitors reduce deacetylation of Nrf2, thereby promoting DNA binding and Nrf2 activity.