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.
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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 · 1.50 Impact Factor
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ABSTRACT: Aging is a natural biological process that is characterized by a progressive accumulation of macromolecular damage. In the proteome, aging is accompanied by decreased protein homeostasis and function of the major cellular proteolytic systems, leading to the accumulation of unfolded, misfolded or aggregated proteins. In particular, the proteasome is responsible for the removal of normal as well as damaged or misfolded proteins. Extensive work during last several years has clearly demonstrated that proteasome activation by either genetic means or use of compounds significantly retards aging. Importantly, this represents a common feature across evolution thereby suggesting proteasome activation to be an evolutionary conserved mechanism of aging and longevity regulation. This review article reports on the means of function of these proteasome activators and how they regulate aging in different species.Free Radical Biology and Medicine 03/2014; 71. DOI:10.1016/j.freeradbiomed.2014.03.031 · 5.71 Impact Factor
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ABSTRACT: We would like to acknowledge the reviewers for their expert assistance and all authors for their contribution to the issue.Oxidative medicine and cellular longevity 01/2014; 2014:678741. DOI:10.1155/2014/678741 · 3.36 Impact Factor