Nrf2 as a Master Redox Switch in Turning on the Cellular Signaling Involved in the Induction of Cytoprotective Genes by Some Chemopreventive Phytochemicals
ABSTRACT 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.
- SourceAvailable from: Seung-Hwan Kwon
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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). "
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; DOI:10.1016/j.neuroscience.2015.07.030 · 3.33 Impact Factor
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- "Under conditions of oxidative stress, electrophilic substances modify Keap1, inactivate the E3 ligase complex, and allow Nrf2 to accumulate by preventing its degradation by the proteasome (Fig. 2). Nrf2 not bound to the Keap1-E3 ligase complex is phosphorylated (Surh et al., 2008; Zhang et al., 2013) Fig. 1. 'Three birds with one stone' model of Tian et al., 2012. The ubiquitin ligase complex, Keap1-Cul3-Rbx1, ubiquitinates Nrf2, IkB kinase, and Bcl-2 prior to degradation in the proteasome. "
ABSTRACT: Both melatonin and proteasome inhibitors upregulate antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GP), hemoxygenase 1 (HO-1), and NADPH:quinone oxidoreductase (NQO1). Recent evidence suggests that the antioxidant action of both melatonin and proteasome inhibitors involves the Keap1-ARE (Keap1 antioxidant response element) pathway via the upregulation of Nrf2. Melatonin and proteasome inhibitors suppress the degradation of Nrf2 and also enhance its nuclear translocation. In the nucleus Nrf2, together with a cofactor, stimulates the transcription of antioxidant enzymes and detoxifying enzymes. The ligase (E3) complex (Keap1-Cul3-Rbx1) responsible for ubiquitinating Nrf2, prior to proteasomal degradation, also ubiquitinates IkB kinase and the antiapoptotic factor Bcl-2, and possibly additional proteins. In various systems, NF-κB, which is inhibited by IkBα, is downregulated by proteasome inhibitors as well as by melatonin. Similarly in leukemic cells, Bcl-2 is down-regulated by the proteasome inhibitor, bortezomib, and also by melatonin. Thus melatonin administration modulates the activity of three separate substrates of the Keap1-Cul3-Rbx1 ubiquitin ligase. These facts could be accounted for by the hypothesis that melatonin interacts with the ubiquitin ligase complex or, more likely, by the hypothesis that melatonin acts as a proteasome inhibitor. A recent study documented that melatonin acts as a proteasome inhibitor in cancer cells as well as inhibiting chymotrypsin-like activity in cell-free systems of these cells. Further studies, however, are needed to clarify the interaction of melatonin and the ubiquitin-proteasome system as they relate to oxidative stress. Copyright © 2014. Published by Elsevier Ireland Ltd.Molecular and Cellular Endocrinology 12/2014; 401(C). DOI:10.1016/j.mce.2014.12.013 · 4.24 Impact Factor
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- "nase ) , and PKC ( protein kinase C ) . NRF - 2 is activated by these kinases , and thus it is transported from the cytoplasm to the nucleus . In the nucleus Nrf - 2 is connected to anti - oxidant response elements ( ARE ) and elements that promote antioxidant and detoxification genes such as SOD , GPX , and GTS ( glutathione - S - transferase ) ( Surh et al . , 2008 ) . According to study results , the absence of NRF - 2 in the body leads to a defect in the detoxification process of chemical compounds and increases tumor formation induced by chemical agents ( Ramos - Gomez et al . , 2003 ; Kwak et al . , 2004 ) . However , NRF - 2 plays an important role in the induction of defense factors , such a"
ABSTRACT: Oxidative stress is caused by an imbalance in the redox status of the body. In such a state, increase of free radicals in the body can lead to tissue damage. One of the most important species of free radicals is reactive oxygen species (ROS) produced by various metabolic pathways, including aerobic metabolism in the mitochondrial respiratory chain. It plays a critical role in the initiation and progression of various types of cancers. ROS affects different signaling pathways, including growth factors and mitogenic pathways, and controls many cellular processes, including cell proliferation, and thus stimulates the uncontrolled growth of cells which encourages the development of tumors and begins the process of carcinogenesis. Increased oxidative stress caused by reactive species can reduce the body’s antioxidant defense against angiogenesis and metastasis in cancer cells. These processes are main factors in the development of cancer. Bimolecular reactions cause free radicals in which create such compounds as malondialdehyde (MDA) and hydroxyguanosine. These substances can be used as indicators of cancer. In this review, free radicals as oxidizing agents, antioxidants as the immune system, and the role of oxidative stress in cancer, particularly breast cancer, have been investigated in the hope that better identification of the factors involved in the occurrence and spread of cancer will improve the identification of treatment goals.Asian Pacific journal of cancer prevention: APJCP 07/2014; 15(12):4745-4751. DOI:10.7314/APJCP.2014.15.12.4745 · 2.51 Impact Factor