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      Hydroxychloroquine Protects against Cardiac Ischaemia/Reperfusion Injury In Vivo via Enhancement of ERK1/2 Phosphorylation

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          Abstract

          An increasing number of investigations including human studies demonstrate that pharmacological ischaemic preconditioning is a viable way to protect the heart from myocardial ischaemia/reperfusion (I/R) injury. This study investigated the role of hydroxychloroquine (HCQ) in the heart during I/R injury. In vitro and in vivo models of myocardial I/R injury were used to assess the effects of HCQ. It was found that HCQ was protective in neonatal rat cardiomyocytes through inhibition of apoptosis, measured by TUNEL and cleaved caspase-3. This protection in vitro was mediated through enhancement of ERK1/2 phosphorylation mediated by HCQ in a dose-dependent fashion. A decrease in infarct size was observed in an in vivo model of myocardial I/R injury in HCQ treated animals and furthermore this protection was blocked in the presence of the ERK1/2 inhibitor U0126. For the first time, we have shown that HCQ promotes a preconditioning like protection in an in vivo simulated rat myocardial I/R injury model. Moreover, it was shown that HCQ is protective via enhanced phosphorylation of the pro-survival kinase ERK1/2.

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          Most cited references 22

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          Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death.

          To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting proteins. Both yeast two-hybrid screening and lambda expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. Bad selectively dimerized with Bcl-xL as well as Bcl-2, but not with Bax, Bcl-xs, Mcl-1, A1, or itself. Bad binds more strongly to Bcl-xL than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-xL, but not that of Bcl-2. When Bad dimerized with Bcl-xL, Bax was displaced and apoptosis was restored. When approximately half of Bax was heterodimerized, death was inhibited. The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of Bad influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death.
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            The role of antimalarial agents in the treatment of SLE and lupus nephritis.

            Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that affects various organs. Lupus nephritis is one of the most common, and most important, serious manifestations of SLE. Antimalarial agents are part of the immunomodulatory regimen used to treat patients with SLE; however, their role in the treatment of patients with lupus nephritis in particular is less well recognized, especially by nephrologists. Not all antimalarial agents have been used in the treatment of lupus; this Review will focus on studies using chloroquine and hydroxychloroquine. In addition, this Review will briefly describe the history of antimalarial drug use in patients with SLE, the theorized mechanisms of action of the agents chloroquine and hydroxychloroquine, their efficacy in patients with SLE and those with lupus nephritis, their use in pregnancy, and potential adverse effects. The Review will also cover the latest recommendations regarding monitoring for hydroxychloroquine-associated or chloroquine-associated retinopathy. Overall, antimalarial drugs have numerous beneficial effects in patients with SLE and lupus nephritis, and have a good safety profile.
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              MAP kinase pathways.

               Enesha Cobb (1998)
              MAP kinases help to mediate diverse processes ranging from transcription of protooncogenes to programmed cell death. More than a dozen mammalian MAP kinase family members have been discovered and include, among others, the well studied ERKs and several stress-sensitive enzymes. MAP kinases lie within protein kinase cascades. Each cascade consists of no fewer than three enzymes that are activated in series. Cascades convey information to effectors, coordinates incoming information from other signaling pathways, amplify signals, and allow for a variety of response patterns. Subcellular localization of enzymes in the cascades is an important aspect of their mechanisms of action and contributes to cell-type and ligand-specific responses. Recent findings on these properties of MAP kinase cascades are the major focus of this review.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 December 2015
                2015
                : 10
                : 12
                Affiliations
                [1 ]Centre for Rheumatology, Division of Medicine University College London, Rayne Institute, London, United Kingdom
                [2 ]Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, United Kingdom
                [3 ]Biochemistry Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health & Great Ormond Street Hospital, University College London, London, United Kingdom
                [4 ]UCL Centre for Advanced Biomedical Imaging, Division of Medicine, London, United Kingdom
                [5 ]Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Paris, France
                [6 ]Université René Descartes; Centre de référence maladies auto-immunes et systémiques rares, Service de Médecine Interne, Pôle médecine, Hôpital Cochin, AP-HP, Paris, France
                [7 ]Medical and Molecular Biology Unit, University College London, London, United Kingdom
                Indiana University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LB YI AS. Performed the experiments: LB VT BB. Analyzed the data: LB DS BB. Contributed reagents/materials/analysis tools: DS MFL BB NC. Wrote the paper: LB JM VT CP BB NC DS MFL AS YI.

                [¤]

                Current address: School of Medicine, European University, Nicosia, Cyprus

                Article
                PONE-D-15-28587
                10.1371/journal.pone.0143771
                4670100
                26636577
                © 2015 Bourke et al

                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

                Page count
                Figures: 5, Tables: 0, Pages: 14
                Product
                Funding
                LB is supported by the Grand Challenge PhD Studentship Programme, UCL. YI is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and Arthritis Research UK Grant 20164. CP is supported by Arthritis Research UK Programme Grant 19423.
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