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      “Only a Life Lived for Others Is Worth Living”: Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions

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          Strategies of antioxidant defense.

           H Sies (1993)
          Cellular protection against the deleterious effects of reactive oxidants generated in aerobic metabolism, called oxidative stress, is organized at multiple levels. Defense strategies include three levels of protection; prevention, interception, and repair. Regulation of the antioxidant capacity includes the maintenance of adequate levels of antioxidant and the localization of antioxidant compounds and enzymes. Short-term and long-term adaptation and cell specialisation in these functions are new areas of interest. Control over the activity of prooxidant enzymes, such as NADPH oxidase and NO synthases, is crucial. Synthetic antioxidants mimic biological strategies.
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            ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

            Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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              Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

              Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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                Author and article information

                Journal
                Antioxidants & Redox Signaling
                Antioxidants & Redox Signaling
                Mary Ann Liebert Inc
                1523-0864
                1557-7716
                November 2018
                November 2018
                : 29
                : 13
                : 1333-1358
                Affiliations
                [1 ]Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [2 ]Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [3 ]Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [4 ]Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [5 ]Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [6 ]Exposure Assessment Branch/NIOSH/CDC, West Virginia University, Morgantown, West Virginia.
                [7 ]Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia.
                [8 ]Department of Medicine, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [9 ]Department of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [10 ]Asthma Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [11 ]Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [12 ]Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [13 ]The Wistar Institute, Philadelphia, Pennsylvania.
                [14 ]Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania.
                [15 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
                Article
                10.1089/ars.2017.7124
                © 2018
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