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). "
Free Radical Biology and Medicine 07/2015; DOI:10.1016/j.freeradbiomed.2015.06.039 · 5.74 Impact Factor
"Moreover, increase in GST-Mu levels could be a result of adaptive responses to oxidatively modified products and also to produce a response against peroxides, since GSTs are known to be effective towards various peroxides within a cell. One possible explanation for the increase in gene expression could be the induction of some transcription factors such as nuclear factor kappa B (NFjB) and nuclear factor erythroid 2-related factor (Nrf2) which are the key mediator of the redox homeostatic gene regulatory network, where under conditions of oxidative and electrophilic stress, their downstream signaling pathways could be activated to enhance the expression of multiple antioxidant and phase II enzymes (Marinho et al., 2014; Surh et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Context: Oxidative stress has been implicated in the progression of pathogenesis in diabetes mellitus and leads variety of deformations in central nervous system. Recent studies have provided several insights on therapeutic uses of resveratrol in diabetic complications.
Objective: The present study reveals if resveratrol ameliorates oxidative stress and molecular changes in the brain frontal cortex of streptozotocin-induced diabetic rats.
Materials and methods: Rats were divided into four groups; control, diabetic, resveratrol treated control, resveratrol treated diabetic. After diabetes induction, resveratrol (20 mg/kg) was given intraperitoneally once daily throughout 4 weeks. In addition to enzymatic activities, gene and protein expressions of brain antioxidant enzymes were utilized by qRT-PCR and Western blot, respectively.
Results: The results indicated a significant elevation in total oxidant species (1.22-fold) and malonedialdehyde (1.38-fold) contents in diabetic rat brain cortex tissues. In addition, significant augmentation in the activities of catalase (1.38-fold) and superoxide dismutase (3-fold) was witnessed with the gene and protein expression levels reflecting a transcriptional regulation. Resveratrol treatment significantly normalized diabetic malonedialdehyde and oxidized glutathione levels and strengthens the action of all antioxidant enzymes. Recovery of the diabetes associated changes reflects the reduction of oxidative conditions by resveratrol and reveals the decrease in the requirement for the activation of antioxidant defense systems in the brain tissues of diabetic rats.
Discussion and conclusion: Potent antioxidant and neuroprotective properties of resveratrol against diabetes-induced oxidative damage were demonstrated and the results would orient the new studies searching for molecular mechanism of diabetes-induced changes in brain tissues.
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