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      Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development

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          Abstract

          CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immune-mediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death of oligodendrocytes and neurons as well as oxidative stress-induced tissue damage. In particular, the complex influence of oxidative stress on inflammation and vice versa makes therapeutic interference complex. All approved MS therapeutics work by modulating the autoimmune response. However, despite substantial developments in the treatment of the relapsing-remitting form of MS, approved therapies for the progressive forms of MS as well as for MS-associated concomitants are limited and much needed. Here, we summarize the contribution of inflammation and oxidative stress to MS pathology and discuss consequences for MS therapy development.

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          Most cited references136

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          The free radical theory of aging matures.

          The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.
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            Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution

            SUMMARY Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer’s disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs.
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              High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease

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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
                2020
                12 May 2020
                : 2020
                : 7191080
                Affiliations
                1Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, 9747 AG Groningen, Netherlands
                2Department of Biology, Drexel University, Philadelphia, PA 19104, USA
                3Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 11521 Athens, Greece
                4Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany
                Author notes

                Academic Editor: Víctor M. Mendoza-Núñez

                Author information
                https://orcid.org/0000-0003-1148-4541
                https://orcid.org/0000-0002-2028-7761
                https://orcid.org/0000-0003-2078-5565
                https://orcid.org/0000-0002-5931-2880
                https://orcid.org/0000-0003-4178-0384
                https://orcid.org/0000-0001-7927-604X
                Article
                10.1155/2020/7191080
                7240663
                32454942
                227fc47b-8c23-4f3e-8030-10a47b74c83d
                Copyright © 2020 Valentina Pegoretti 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
                : 20 November 2019
                : 14 February 2020
                : 4 March 2020
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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