NO signaling in ARE-mediated gene expression
ABSTRACT Nitric oxide (NO) and peroxynitrite, which serve as cell signal molecules, activate the antioxidant response element (ARE) for the induction of phase II antioxidant enzymes as an adaptive response. The reactive nitrogen species plays an essential role in Nrf2 activation and Nrf2 binding to the ARE present in the target genes. In this chapter, we describe the system by which the NO signaling pathway regulates ARE-mediated gene expression, which includes immunochemical assessment and gel shift analysis of Nrf2 activation.
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ABSTRACT: Covering: 2000 to 2013Oxidative stress is the central component of chronic diseases. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway is vital in the up-regulation of cytoprotective genes and enzymes in response to oxidative stress and treatment with certain dietary phytochemicals. Herein, we classify bioactive compounds derived from natural products that are Nrf2/ARE pathway activators and recapitulate the molecular mechanisms for inducing Nrf2 to provide favorable effects in experimental models of chronic diseases. Moreover, pharmacological inhibition of Nrf2 signalling has emerged as promising strategy against multi-drug resistance thereby improving the treatment efficacy. We have also enlisted natural product-derived inhibitors of Nrf2/ARE pathway.Natural Product Reports 11/2013; DOI:10.1039/c3np70065h · 10.72 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder with increased oxidative stress as central component. Till date, treatments related to PD are based on restoring dopamine either by targeting neurotransmitter and/or at receptor levels. These therapeutic approaches try to repair damage but do not address the underlying processes such as oxidative stress and neuroinflammation that contribute to cell death. The central nervous system maintains a robust antioxidant defense mechanism consisting of several cytoprotective genes and enzymes whose expression is controlled by antioxidant response element (ARE) which further depends on activation of nuclear factor erythroid 2-related factor 2 (Nrf2). In response to oxidative or electrophilic stress transcription factor Nrf2 binds to ARE and rescues the cells from oxidative stress and neuroinflammation. Recently, Nrf2 has been utilized as a drug target and some agents are currently under clinical trial. Owing to the potential role of Nrf2 in counteracting oxidative stress and neuroinflammation seen in PD, here we have focused on the molecular mechanism of the Nrf2/ARE antioxidant defense pathway in PD. Further, we also summarize published reports on the potential inducers of Nrf2 that demonstrate neuroprotective effects in experimental models of PD with possible future strategies to increase the transcriptional level of Nrf2 as a therapeutic strategy to provide neuroprotection of damaged dopaminergic neurons in PD.CNS & neurological disorders drug targets 12/2012; DOI:10.2174/1871527311211080012 · 3.57 Impact Factor
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ABSTRACT: Cancer chemoprevention is a process of using either natural or synthetic compounds to reduce the risk of developing cancer. Observations that NF-E2-related factor 2 (Nrf2)-deficient mice lack response to some chemopreventive agents point to the important role of Nrf2 in chemoprevention. Nrf2 is a member of basic-leucine zipper transcription factor family and has been shown to regulate gene expression by binding to a response element, antioxidant responsive element. It is generally believed that activation of Nrf2 signaling is an adaptive response to the environmental and endogenous stresses. Under homeostatic conditions, Nrf2 is suppressed by association with Kelch-like ECH-associated protein 1 (Keap1), but is stimulated upon exposure to oxidative or electrophilic stress. Once activated, Nrf2 translocates into nuclei and upregulates a group of genes that act in concert to combat oxidative stress. Nrf2 is also shown to have protective function against inflammation, a pathological process that could contribute to carcinogenesis. In this review, we will discuss the current progress in the study of Nrf2 signaling, in particular, the mechanisms of Nrf2 activation by chemopreventive agents. We will also discuss some of the potential caveats of Nrf2 in cancer treatment and future opportunity and challenges on regulation of Nrf2-mediated antioxidant and antiinflammatory signaling in the context of cancer prevention. Free full－text is available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966483/ The author(s), in consideration of the acceptance of the above work for publication, does hereby assign and transfer to Mary Ann Liebert, Inc.,all of the rights and interest in and to the copyright of the -titled work in its current form and in any subsequently revised form for publication and/or electronic dissemination.Antioxidants & Redox Signaling 12/2010; 13(11):1679-98. DOI:10.1089/ars.2010.3276 · 8.20 Impact Factor