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      Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy

      a , b , b , a , *

      Redox Biology

      Elsevier

      Nrf2, NF-κB, Diabetic neuropathy

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          Abstract

          The Nuclear factor-2 erythroid related factor-2 (Nrf2) is a redox regulated transcription factor involved in the regulation of antioxidant defence systems. It drives the production of endogenous antioxidant defences and detoxifying enzymes. Nuclear factor-kappa light chain enhancer of B cells (NF-κB) is a transcription factor, involved in proinflammatory cytokine production, in addition to its immunological function. Both Nrf2 and NF-κB regulation are co-ordinated in order to maintain redox homeostasis in healthy cells. However, during pathological conditions this regulation is perturbed offering an opportunity for therapeutic intervention. Diabetic neuropathy is a condition, in which change in expression pattern of Nrf2 and NF-κB has been reported. This review aims to focus on the role of the Nrf2 and NF-κB in diabetic neuropathy and summarizes the therapeutic outcomes of various pharmacological modulators targeted at the Nrf2–NF-κB axis in diabetic neuropathy.

          Highlights

          • Hyperglycaemia-induced changes in NF-κB and Nrf2 activity of Nrf2–NF-κB axis contributes to the pathophysiology of diabetic neuropathy.

          • Crosstalk between the Nrf2 and NF-κB pathways can induce neuronal damage via oxidative stress and neuroinflammation.

          • Simultaneous targeting of Nrf2 and NF-κB may be beneficial in diabetic neuropathy.

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          Most cited references 23

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          Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.

          Oxidative stress has been implicated in the etiology of neurodegenerative disease, cancer and aging. Indeed, accumulation of reactive oxygen and nitrogen species generated by inflammatory cells that created oxidative stress is thought to be one of the major factor by which chronic inflammation contributes to neoplastic transformation as well as many other diseases. We have recently reported that mice lacking nuclear factor-erythroid 2-related factor 2 (Nrf2) are more susceptible to dextran sulfate sodium (DSS)-induced colitis and colorectal carcinogenesis. Nrf2 is a basic leucine zipper redox-sensitive transcriptional factor that plays a center role in ARE (antioxidant response element)-mediated induction of phase II detoxifying and antioxidant enzymes. We found that increased susceptibility of Nrf2 deficient mice to DSS-induced colitis and colorectal cancer was associated with decreased expression of antioxidant/phase II detoxifying enzymes in parallel with upregulation of pro-inflammatory cytokines/biomarkers. These findings suggest that Nrf2 may play an important role in defense against oxidative stress possibly by activation of cellular antioxidant machinery as well as suppression of pro-inflammatory signaling pathways. In addition, in vivo and in vitro data generated from our laboratory suggest that many dietary compounds can differentially regulate Nrf2-mediated antioxidant/anti-inflammatory signaling pathways as the first line defense or induce apoptosis once the cells have been damaged. In this review, we will summarize our thoughts on the potential cross-talks between Nrf2 and NFkappaB pathways. Although the mechanisms involved in the cross-talk between these signaling pathways are still illusive, targeting Nrf2-antioxidative stress signaling is an ideal strategy to prevent or treat oxidative stress-related diseases.
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            When NRF2 talks, who's listening?

            Activation of the KEAP1-NRF2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl-reactive, small-molecule pharmacologic agents, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor to antioxidant response elements in the promoter regions of target genes. However, it is becoming evident that some of the protective effects may be mediated indirectly through cross talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses. This review highlights recent observations on the molecular interactions and their functional consequences between NRF2 and the arylhydrocarbon receptor (AhR), NF-κB, p53, and Notch1 signaling pathways.
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              Diabetic neuropathy: mechanisms to management.

              Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscore the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                1 August 2013
                1 August 2013
                2013
                : 1
                : 1
                : 394-397
                Affiliations
                [a ]Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Hyderabad, Bala Nagar, India
                [b ]Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India
                Author notes
                [* ]Corresponding author. Tel.: +91 40 23073741; fax: +91 40 23073751. ashutosh@ 123456niper.ac.in ashutoshniper@ 123456gmail.com
                Article
                REDOX56
                10.1016/j.redox.2013.07.005
                3757712
                24024177
                © 2013 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

                Categories
                Graphical Review

                diabetic neuropathy, nf-κb, nrf2

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