Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, South Korea.
Planta Medica (Impact Factor: 2.15). 11/2008; 74(13):1526-39. DOI: 10.1055/s-0028-1088302
Source: PubMed


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.

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    • "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). "
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    ABSTRACT: Sulfuretin, one of the major flavonoid glycosides found in the stem bark of Albizzia julibrissin and heartwood of Rhus verniciflua, is a known anti-oxidant. We previously demonstrated that sulfuretin inhibits neuronal death via reactive oxygen species (ROS)-dependent mechanisms in cultured cells, although other relevant mechanisms of action of this compound remain largely uncharacterized. As part of our ongoing exploration of the pharmacological actions of sulfuretin, we studied the neuroprotective effects of sulfuretin against amyloid beta (Aβ)-induced neurotoxicity in neuronal cells and investigated the possible mechanisms involved. Specifically, we found in the present study that sulfuretin significantly attenuates the decrease in cell viability, release of lactate dehydrogenase (LDH), and accumulation of ROS associated with Aβ25-35-induced neurotoxicity in neuronal cells. Furthermore, sulfuretin stimulated the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream target of phosphatidylinositol 3-kinases (PI3K)/Akt. We demonstrated that sulfuretin induces the expression of heme oxygenase-1 (HO-1), an anti-oxidant response gene. Notably, we found that the neuroprotective effects of sulfuretin were diminished by an Nrf2 small interfering RNA (siRNA), the HO-1 inhibitor zinc protoporphyrin IX (ZnPP), as well as the PI3K/Akt inhibitor LY294002. Taken together, these results indicated that sulfuretin protects neuronal cells from Aβ25-35-induced neurotoxicity through activation of Nrf/HO-1 and PI3K/Akt signaling pathways. Our results also indicate that sulfuretin-induced induction of Nrf2-dependent HO-1 expression via the PI3K/Akt signaling pathway has preventive and/or therapeutic potential for the management of Alzheimer's disease (AD). Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 304. DOI:10.1016/j.neuroscience.2015.07.030 · 3.36 Impact Factor
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    • "[1] [2]). 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 [2] [3] [4] [5] [6] [7]. In the inactive form, Nrf2 heterodimerizes in the cytoplasm with the repressor Kelchlike ECH-associated protein 1 (Keap1). "
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    ABSTRACT: Glutathione S-transferase π (GSTP), a phase II gene downstream of the Nrf2-ARE/EpRE transcription pathway, plays a key role in both the signaling and detoxification response to Se-organic compounds with thiol peroxidase activity. We here investigated the role of GSTP on the Nrf2 activation response of cells challenged with a new class of diselenides derived from the basic structure of (PhSe)2. These diselenides, and particularly DSBA, behave as mild thiol peroxidases leading to a moderate generation of H2O2 and NOx, and signaling of stress-activated and survival-promoting MAPKs, which ultimately control the mitochondrial pathway of apoptosis. Used in murine embryonic fibroblasts (MEFs) and HepG2 human hepatocarcinoma cells to produce sub-maximal conditions of stress, the diselenide compounds stimulated Nrf2 nuclear translocation and the transcription of the same Nrf2 gene as well as of GSTP and other phase II genes. This resulted in a higher degree of protection against H2O2 cytotoxicity (hormetic effect). Diselenide toxicity increased in GSTP knockout MEFs by a higher generation of NOx and SAPK-JNK activation. A lowered hormetic potential of these cells was observed in association with an abnormal expression and nuclear translocation of Nrf2 protein. Immunoprecipitation and affinity purification experiments revealed the existence of a Nrf2/GSTP complex in MEFs and HepG2 cells. Covalent oligomers of GSTP subunits were observed in DSBA treated cells. In conclusion, GSTP gene expression influences the Nrf2-dependent response to hormetic diselenides. Mechanistic interpretation for this GSTP-dependent effect may include a direct and redox-sensitive interaction of GSTP with Nrf2 protein. Copyright © 2015 Elsevier B.V. All rights reserved.
    Free Radical Biology and Medicine 07/2015; DOI:10.1016/j.freeradbiomed.2015.06.039 · 5.74 Impact Factor
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    • "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). "
    Life extension: Lessons from Drosophila, 05/2015: chapter Phytochemicals with lifespan extension effect in Drosophila: pages 229-244; Springer., ISBN: 978-3-319-18325-1
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