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      Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

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          Abstract

          Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.

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          Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

          Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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            Neurotoxic reactive astrocytes are induced by activated microglia

            A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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              Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation

              Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T (Treg) cells expressing transcription factor Foxp3 play a key role in limiting inflammatory responses in the intestine 1 . Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory Th17 cells 2-6 , the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we hypothesized that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We found that a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg cell numbers upon provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells as the observed phenomenon was dependent upon intronic enhancer CNS1, essential for extrathymic, but dispensable for thymic Treg cell differentiation 1, 7 . In addition to butyrate, de novo Treg cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of HDAC inhibition, but not acetate, lacking this activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                14 July 2020
                July 2020
                : 9
                : 7
                : 1687
                Affiliations
                [1 ]Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, 28029 Madrid, Spain; mpajares@ 123456iib.uam.es (M.P.); airojo@ 123456iib.uam.es (A.I.R.); lbosca@ 123456iib.uam.es (L.B.)
                [2 ]Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, 28031 Madrid, Spain
                [3 ]Instituto de Investigación Sanitaria La Paz (IdiPaz), 28029 Madrid, Spain
                [4 ]Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, 28029 Madrid, Spain
                [5 ]Department Cellular and Molecular Medicine, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania; gina.manda@ 123456gmail.com
                [6 ]Centro de Investigación Biomédica en Red Sobre Enfermedades Cardiovasculares (CIBERcv), ISCIII, 28029 Madrid, Spain
                Author notes
                [* ]Correspondence: antonio.cuadrado@ 123456uam.es ; Tel.: +34-915854383; Fax: +34-915854401
                Author information
                https://orcid.org/0000-0002-9706-1883
                https://orcid.org/0000-0002-0253-5469
                https://orcid.org/0000-0002-4039-7140
                Article
                cells-09-01687
                10.3390/cells9071687
                7408280
                32674367
                eb797b14-e79e-4b10-a1de-96db97ae82aa
                © 2020 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
                : 17 June 2020
                : 13 July 2020
                Categories
                Review

                parkinson’s disease,neuroinflammation,immune system,therapy,neurodegeneration

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