A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.
"Neuroscience 304 (2015) 14–28 it then binds to promoter sequences known as antioxidant response elements (AREs) (Keum, 2012). Nuclear accumulation of Nrf2 results in the upregulation of phase II detoxifying anti-oxidant enzymes such as NAD(P)H, quinone oxidoreductase, heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit, and glutamate-cysteine ligase modifier subunit (Surh et al., 2008). Among the various known cytoprotective enzymes, HO-1 has received considerable attention (Nakaso et al., 2006). "
" ). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a main player in the transcriptional control of this response, with expected implications in disease prevention and anti-aging medicine      . In the inactive form, Nrf2 heterodimerizes in the cytoplasm with the repressor Kelchlike ECH-associated protein 1 (Keap1). "
"These findings indicate that NRF2/Keap1 signaling plays a role in the regulation of longevity as a master mediator of anti-oxidant and detoxification responses (Sykiotis and Bohmann 2008). Numerous phytochemicals such as curcumin, resveratrol, EGCG, sulphoraphane, and acetyl-L-carnitine are known to be potent antioxidants that activate NRF2 via several steps (Jeong et al. 2005, Wu et al. 2006, Surh et al. 2008). Some of these compounds such as sulforaphane, an isothiocyanante found in broccoli, oxidize or modify the cysteine thiol groups of Keap1, thereby stabilizing and activating NRF2 (Hong et al. 2005). "
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