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      Endothelial Iron Homeostasis Regulates Blood-Brain Barrier Integrity via the HIF2α—Ve-Cadherin Pathway

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          Abstract

          The objective of this study was to investigate the molecular response to damage at the blood-brain barrier (BBB) and to elucidate critical pathways that might lead to effective treatment in central nervous system (CNS) pathologies in which the BBB is compromised. We have used a human, stem-cell derived in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. Chemical injury induced by exposure to an organophosphate resulted in rapid lipid peroxidation, initiating a ferroptosis-like process. Additionally, mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability were induced, leading to apoptotic cell death. Yet, these processes did not directly result in damage to barrier functionality, since blocking them did not reverse the increased permeability. We found that the iron chelator, Desferal© significantly decreased MRF and apoptosis subsequent to barrier insult, while also rescuing barrier integrity by inhibiting the labile iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin specifically on the endothelial cell surface. Moreover, the novel nitroxide JP4-039 significantly rescued both injury-induced endothelium cell toxicity and barrier functionality. Elucidating a regulatory pathway that maintains BBB integrity illuminates a potential therapeutic approach to protect the BBB degradation that is evident in many neurological diseases.

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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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            Ferroptosis: Death by Lipid Peroxidation.

            Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.
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              Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

              The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                28 February 2021
                March 2021
                : 13
                : 3
                : 311
                Affiliations
                [1 ]The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel; Daniel.rand@ 123456sheba.health.gov.il (D.R.); Orly.Ravid@ 123456sheba.health.gov.il (O.R.); Dana.Atrakchi@ 123456sheba.health.gov.il (D.A.); hilaisraelov8@ 123456gmail.com (H.I.); yael.bresler@ 123456sheba.health.gov.il (Y.B.); Chen.Shemesh@ 123456sheba.health.gov.il (C.S.); Liora.Omesi@ 123456sheba.health.gov.il (L.O.); Sigal.LirazZaltsman@ 123456sheba.health.gov.il (S.L.-Z.); michal.beeri@ 123456mssm.edu (M.S.B.)
                [2 ]Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel
                [3 ]Department of Pharmacology, The Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem 97905, Israel
                [4 ]Department of Sports Therapy, Institute for Health and Medical Professions, Ono Academic College, Kiryat Ono 55000, Israel
                [5 ]Blood-Brain Barrier Laboratory (LBHE), Artois University, UR 2465, F-62300 Lens, France; fabien.gosselet@ 123456univ-artois.fr
                [6 ]Department of Chemistry and Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA; taber.maskrey@ 123456pitt.edu (T.S.M.); pwipf@ 123456pitt.edu (P.W.)
                [7 ]Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [8 ]School of Psychology, Interdisciplinary Center (IDC), Herzliya 4610101, Israel
                [9 ]The Nehemia Rubin Excellence in Biomedical Research—The TELEM Program, Sheba Medical Center, Tel-Hashomer 5262000, Israel
                Author notes
                Author information
                https://orcid.org/0000-0002-0481-5026
                https://orcid.org/0000-0001-7693-5863
                Article
                pharmaceutics-13-00311
                10.3390/pharmaceutics13030311
                7997362
                33670876
                d213368a-5c93-49c5-ab41-692e7c04f916
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 26 January 2021
                : 24 February 2021
                Categories
                Article

                blood-brain barrier,iron,dfo,hif2a,ve-cadherin
                blood-brain barrier, iron, dfo, hif2a, ve-cadherin

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