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      Identification of Proteins Differentially Expressed in the Striatum by Melatonin in a Middle Cerebral Artery Occlusion Rat Model—a Proteomic and in silico Approach

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          Abstract

          Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, starting from acute ATP loss to subsequent membrane depolarization, glutamate excitotoxicity, and calcium overload. Melatonin is a potent antioxidant that exerts protective effects in different experimental stroke models. In this study, melatonin effects were demonstrated by a proteomic and in silico approach. The proteomic study identified differentially expressed proteins by 2D gel electrophoresis in the striatum 24 h after middle cerebral artery occlusion. Proteomic analysis revealed several proteins with aberrant expression and was validated by western blot and immunofluorescence analysis. Homology modeling was performed to build 3D structures for γ-enolase, thioredoxin (TRX), and heat shock 60 (HSP60) by the template crystal structures using a protein data bank as a sequence database. The structure refinement of each model was achieved by energy minimization via molecular dynamic simulation, and the generated models were further assessed for stability by Procheck and ProSA. The models were processed for docking analysis using AutoDock Vina, and post-docking analysis was determined by discovery studio. The proteomic study showed decreased expression of γ-enolase, TRX, and protein phosphatase 2A subunit B and increased expression of collapsin response mediator protein 2 and HSP60 in the striatum after ischemic injury. Treatment with melatonin modulated the expression profiles of these proteins. This study demonstrated the neuroprotective role of melatonin in the ischemic striatum using a proteomic and in silico approach. Collectively, melatonin may act in a multimechanistic way by modulating the expression of several proteins in the ischemic striatum.

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          Most cited references 84

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          Free radicals and antioxidants in normal physiological functions and human disease.

          Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.
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            Heart disease and stroke statistics--2015 update: a report from the American Heart Association.

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              SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information

              Protein structure homology modelling has become a routine technique to generate 3D models for proteins when experimental structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modelling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estimation for selection of the most suitable templates and provides estimates of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                10 December 2018
                2018
                : 12
                Affiliations
                1Division of Applied Life Science (BK 21), College of Natural Science, Gyeongsang National University , Jinju, South Korea
                2Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad , Rawalpindi, Pakistan
                3Department of Pharmacy, Faculty of Life Science, Sarhad University of Science and Information Technology , Peshawar, Pakistan
                4Department of Anatomy, College of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University , Jinju, South Korea
                Author notes

                Edited by: Francisco Lopez-Munoz, Universidad Camilo José Cela, Spain

                Reviewed by: Anwen Shao, Second Affiliated Hospital, Zhejiang University School of Medicine, China; Alejandro Romero, Complutense University of Madrid, Spain

                *Correspondence: Myeong Ok Kim, mokim@ 123456gnu.ac.kr ; mokim@ 123456gsnu.ac.kr

                These authors have contributed equally to this work

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2018.00888
                6295458
                Copyright © 2018 Shah, Zeb, Ali, Muhammad, Faheem, Alam, Saeed, Koh, Lee and Kim.

                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.

                Counts
                Figures: 6, Tables: 2, Equations: 0, References: 84, Pages: 15, Words: 0
                Categories
                Neuroscience
                Original Research

                Neurosciences

                melatonin, striatum, ischemic stroke, docking, neuroprotection

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