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      Suppression of Oxidative Stress as Potential Therapeutic Approach for Normal Tension Glaucoma

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          Abstract

          Glaucoma is a neurodegenerative disease of the eye, which involves degeneration of retinal ganglion cells (RGCs): the output neurons of the retina to the brain, which with their axons comprise the optic nerve. Recent studies have shown the possible involvement of oxidative stress in the pathogenesis of glaucoma, especially in the subtype of normal tension glaucoma. Basic experiments utilizing rodent and primate models of glaucoma revealed that antioxidants protect RGCs under various pathological conditions including glutamate neurotoxicity and optic nerve injury. These results suggested that existing drugs and food factors may be useful for prevention and hence therapy of glaucoma. In this review, we highlight some therapeutic candidates, particularly those with antioxidant properties, and discuss the therapeutic potential of RGC protection by modulating gene expressions that prevent and ameliorate glaucoma.

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          Most cited references81

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          Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.

          Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli, including growth factors and environmental stresses. A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. Overexpression of ASK1 induced apoptotic cell death, and ASK1 was activated in cells treated with tumor necrosis factor-alpha (TNF-alpha). Moreover, TNF-alpha-induced apoptosis was inhibited by a catalytically inactive form of ASK1. ASK1 may be a key element in the mechanism of stress- and cytokine-induced apoptosis.
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            Induction of autophagy by spermidine promotes longevity.

            Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.
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              Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes

              Neuronal types in the central nervous system differ dramatically in their resilience to injury or insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ~80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC, characterized transcriptomic, physiological, and morphological changes that preceded degeneration, and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo , we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury, and demonstrates that differential gene expression can be used to reveal molecular targets for intervention. High-throughput single cell RNA-seq characterizes 46 types of adult mouse retinal ganglion cells and documents dramatic difference among them in their ability to survive axotomy. Manipulation of genes differentially expressed between resilient and vulnerable types enhances survival and axon regeneration.
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                Author and article information

                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                16 September 2020
                September 2020
                : 9
                : 9
                : 874
                Affiliations
                [1 ]Visual Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; harada-ck@ 123456igakuken.or.jp (C.H.); noro-tk@ 123456igakuken.or.jp (T.N.); guo-xl@ 123456igakuken.or.jp (X.G.); namekata-kz@ 123456igakuken.or.jp (K.N.); harada-tk@ 123456igakuken.or.jp (T.H.)
                [2 ]Department of Ophthalmology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan; tnakano@ 123456jikei.ac.jp
                Author notes
                [* ]Correspondence: kimura-at@ 123456igakuken.or.jp ; Tel.: +81-3-6834-2340
                Article
                antioxidants-09-00874
                10.3390/antiox9090874
                7554707
                32947996
                106668e9-f35b-4b9a-8864-9f459924a8db
                © 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
                : 31 August 2020
                : 14 September 2020
                Categories
                Review

                glaucoma,retinal ganglion cell,optic nerve,oxidative stress,neuroprotection,glutamate transporters,ask1,marmoset,drug repositioning,food factor

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