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      Inhibition of HSP90 Promotes Neural Stem Cell Survival from Oxidative Stress through Attenuating NF- κB/p65 Activation

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          Abstract

          Stem cell survival after transplantation determines the efficiency of stem cell treatment, which develops as a novel potential therapy for several central nervous system (CNS) diseases in recent decades. The engrafted stem cells face the damage of oxidative stress, inflammation, and immune response at the lesion point in host. Among the damaging pathologies, oxidative stress directs stem cells to apoptosis and even death through several signalling pathways and DNA damage. However, the in-detail mechanism of stem cell survival from oxidative stress has not been revealed clearly. Here, in this study, we used hydrogen peroxide (H 2O 2) to induce the oxidative damage on neural stem cells (NSCs). The damage was in consequence demonstrated involving the activation of heat shock protein 90 (HSP90) and NF- κB/p65 signalling pathways. Further application of the pharmacological inhibitors, respectively, targeting at each signalling indicated an upper-stream role of HSP90 upon NF- κB/p65 on NSCs survival. Preinhibition of HSP90 with the specific inhibitor displayed a significant protection on NSCs against oxidative stress. In conclusion, inhibition of HSP90 would attenuate NF- κB/p65 activation by oxidative induction and promote NSCs survival from oxidative damage. The HSP90/NF- κB mechanism provides a new evidence on rescuing NSCs from oxidative stress and also promotes the stem cell application on CNS pathologies.

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          Most cited references 21

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          Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

          Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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            Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system

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              Ginsenoside Rg1 protects against hydrogen peroxide-induced cell death in PC12 cells via inhibiting NF-κB activation.

               Jun-Feng Kou,  Bo Yu,  Qian Liu (2010)
              Oxidative stress is a major cause in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral ischemia. Ginsenoside Rg1, a natural product extracted from Panax ginseng C.A. Meyer, has been reported to exert notable neuroprotective activities, which partly ascribed to its antioxidative activity. However, its molecular mechanism against oxidative stress induced by exogenous hydrogen peroxide (H(2)O(2)) remained unclear. In this study, we investigated its effect on H(2)O(2)-induced cell death and explored possible signaling pathway in PC12 cells. We proved that pretreatment with Rg1 at concentrations of 0.1-10 μM remarkably reduced the cytotoxicity induced by 400 μM of H(2)O(2) in PC12 cells by MTT and Hoechst and PI double staining assay. Of note, we demonstrated the activation of NF-κB signaling pathway induced by H(2)O(2) thoroughly in PC12 cells, and Rg1 suppressed phosphorylation and nuclear translocation of NF-κB/p65, phosphorylation and degradation of inhibitor protein of κB (IκB) as well as the phosphorylation of IκB-kinase complex (IKK) by western blotting or indirect immunofluorescence assay. Besides, Rg1 also inhibited the activation of Akt and the extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, the protection of Rg1 on H(2)O(2)-injured PC12 cells was attenuated by pretreatment with two NF-κB pathway inhibitors (JSH-23 or BOT-64). In conclusion, our results suggest that Rg1 could rescue the cell injury by H(2)O(2) via down-regulation NF-κB signaling pathway as well as Akt and ERK1/2 activation, which put new evidence on the neuroprotective mechanism of Rg1 against the oxidative stress and the regulatory role of H(2)O(2) in NF-κB pathway in PC12 cells. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi Publishing Corporation
                1942-0900
                1942-0994
                2016
                12 October 2016
                : 2016
                Affiliations
                1Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China
                2School of Dentistry, Cardiff Institute of Tissue Engineering and Repair, Cardiff University, Heath Park, Cardiff CF14 4XY, UK
                3State Key Laboratory of Military Stomatology & National Clinical Research Centre for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Operative Dentistry & Endodontics, School of Stomatology, Fourth Military Medical University, No. 145 Western Changle Road, Xi'an, Shaanxi 710032, China
                4Department of Chemistry & Chemical Biology, MSC03 2060, University of New Mexico, Clark Hall B58, Albuquerque, NM 87131-0001, USA
                5College of Chemistry and Materials Science, Jiangsu Key Laboratory of Biofunctional Materials, Nanjing Normal University, Nanjing 210023, China
                Author notes

                Academic Editor: Javier Egea

                Article
                10.1155/2016/3507290
                5080492
                27818721
                Copyright © 2016 Qian Liu 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.

                Funding
                Funded by: Natural Science Foundation of Jiangsu Province
                Award ID: BK20160607
                Funded by: National Natural Science Foundation of China
                Award ID: 81530038
                Funded by: European Research Council StG
                Award ID: 243261
                Funded by: Wellcome Trust
                Award ID: WT082887
                Funded by: Royal Society URF Award
                Award ID: UF051616
                Funded by: Jiangsu Provincial Special Program of Medical Science
                Award ID: BL2013025
                Funded by: China Postdoctoral Science Foundation
                Award ID: 201150M1571
                Categories
                Research Article

                Molecular medicine

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