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      Crosstalk between Oxidative Stress and Ferroptosis/Oxytosis in Ischemic Stroke: Possible Targets and Molecular Mechanisms

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          Abstract

          Oxidative stress is a key cause of ischemic stroke and an initiator of neuronal dysfunction and death, mainly through the overproduction of peroxides and the depletion of antioxidants. Ferroptosis/oxytosis is a unique, oxidative stress-induced cell death pathway characterized by lipid peroxidation and glutathione depletion. Both oxidative stress and ferroptosis/oxytosis have common molecular pathways. This review summarizes the possible targets and the mechanisms underlying the crosstalk between oxidative stress and ferroptosis/oxytosis in ischemic stroke. This knowledge might help to further understand the pathophysiology of ischemic stroke and open new perspectives for the treatment of ischemic stroke.

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          Most cited references147

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Heart Disease and Stroke Statistics—2020 Update

            Circulation
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              Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

              Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2021
                11 May 2021
                : 2021
                : 6643382
                Affiliations
                1Stroke Center & Clinical Trial and Research Center for Stroke, Department of Neurology, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, China
                2China National Comprehensive Stroke Center, No. 1 Xinmin Street, Changchun 130021, China
                3Jilin Provincial Key Laboratory of Cerebrovascular Disease, No. 1 Xinmin Street, Changchun 130021, China
                Author notes

                Academic Editor: Wei Zhao

                Author information
                https://orcid.org/0000-0002-9729-8522
                https://orcid.org/0000-0002-8922-3862
                Article
                10.1155/2021/6643382
                8133868
                34055196
                b9dee608-ee16-4127-b6b3-862d34933c36
                Copyright © 2021 Jia-Xin Ren et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 November 2020
                : 23 April 2021
                Funding
                Funded by: Jilin Provincial Key Laboratory
                Award ID: 20190901005JC
                Funded by: Program for Jilin University Science and Technology Innovative Research Team
                Award ID: 2017TD-12
                Funded by: National Natural Science Foundation of China
                Award ID: 82071291
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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