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      Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders

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          Abstract

          Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of an array of enzymes with important detoxifying and antioxidant functions. Current findings support the role of high levels of oxidative stress in the pathogenesis of neurological disorders. Given the central role played by Nrf2 in counteracting oxidative damage, a number of studies have targeted the modulation of this transcription factor in order to confer neuroprotection. Nrf2 activity is tightly regulated by oxidative stress and energy-based stimuli. Thus, many dietary interventions based on energy intake regulation, such as dietary energy restriction (DER) or high-fat diet (HFD), modulate Nrf2 with consequences for a variety of cellular processes that affect brain health. DER, by either restricting calorie intake or meal frequency, activates Nrf2 thereby triggering its protective effects, whilst HFD inhibit this pathway, thereby exacerbating oxidative stress. Consequently, DER protocols can be valuable strategies in the management of central nervous system (CNS) disorders. Herein, we review current knowledge of the role of Nrf2 signaling in neurological diseases, namely Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and cerebral ischemia, as well as the potential of energy intake regulation in the management of Nrf2 signaling.

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          The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress.

          A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed.
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            Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

            We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.
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              NRF2 and cancer: the good, the bad and the importance of context.

              Many studies of chemopreventive drugs have suggested that their beneficial effects on suppression of carcinogenesis and many other chronic diseases are mediated through activation of the transcription factor NFE2-related factor 2 (NRF2). More recently, genetic analyses of human tumours have indicated that NRF2 may conversely be oncogenic and cause resistance to chemotherapy. It is therefore controversial whether the activation, or alternatively the inhibition, of NRF2 is a useful strategy for the prevention or treatment of cancer. This Opinion article aims to rationalize these conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                04 February 2019
                2019
                : 10
                : 33
                Affiliations
                [1] 1Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo , São Paulo, Brazil
                [2] 2Laboratory of Neuroendocrinopharmacology and Immunomodulation, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo , São Paulo, Brazil
                Author notes

                Edited by: Javier Egea, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Spain

                Reviewed by: Giustino Orlando, Università degli Studi “G. d’Annunzio” Chieti - Pescara, Italy; Francesca Peruzzi, LSU Health Sciences Center New Orleans, United States

                These authors have contributed equally to this work

                This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2019.00033
                6369171
                30778297
                003dae60-df71-4cdc-b846-a21448b802bd
                Copyright © 2019 Vasconcelos, dos Santos, Scavone and Munhoz.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 October 2018
                : 14 January 2019
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 261, Pages: 18, Words: 0
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                nrf2,dietary energy restriction,high-fat diet,aging,alzheimer’s disease,parkinson’s disease,multiple sclerosis,cerebral ischemia

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