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      Quantitative Proteomics Reveals the Beneficial Effects of Low Glucose on Neuronal Cell Survival in an in vitro Ischemic Penumbral Model

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          Abstract

          Understanding proteomic changes in the ischemic penumbra are crucial to rescue those salvageable cells and reduce the damage of an ischemic stroke. Since the penumbra region is dynamic with heterogeneous cells/tissues, tissue sampling from animal models of stroke for the molecular study is a challenge. In this study, cultured hippocampal HT22 cells under hypoxia treatment for 17.5 h with 0.69 mM low glucose (H+LG) could mimic ischemic penumbral cells since they had much higher cell viability and viable cell number compared to hypoxia without glucose (H−G) treatment. To validate established cell-based ischemic penumbral model and understand the beneficial effects of low glucose (LG), quantitative proteomics analysis was performed on H+LG, H−G, and normoxia with normal 22 mM glucose (N+G) treated cells. We identified 427 differentially abundant proteins (DAPs) between H−G and N+G and further identified 105 DAPs between H+LG and H−G. Analysis of 105 DAPs revealed that LG promotes cell survival by activating HIF1α to enhance glycolysis; preventing the dysregulations of extracellular matrix remodeling, cell cycle and division, and antioxidant and detoxification; as well as attenuating inflammatory reaction response, protein synthesis and neurotransmission activity. Our results demonstrated that this established cell-based system could mimic penumbral conditions and can be used for molecular studies.

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          Most cited references 97

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          Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.

          Multicellular organisms initiate adaptive responses when oxygen (O(2)) availability decreases, but the underlying mechanism of O(2) sensing remains elusive. We find that functionality of complex III of the mitochondrial electron transport chain (ETC) is required for the hypoxic stabilization of HIF-1 alpha and HIF-2 alpha and that an increase in reactive oxygen species (ROS) links this complex to HIF-alpha stabilization. Using RNAi to suppress expression of the Rieske iron-sulfur protein of complex III, hypoxia-induced HIF-1 alpha stabilization is attenuated, and ROS production, measured using a novel ROS-sensitive FRET probe, is decreased. These results demonstrate that mitochondria function as O(2) sensors and signal hypoxic HIF-1 alpha and HIF-2 alpha stabilization by releasing ROS to the cytosol.
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            Global Burden of Stroke.

            On the basis of the GBD (Global Burden of Disease) 2013 Study, this article provides an overview of the global, regional, and country-specific burden of stroke by sex and age groups, including trends in stroke burden from 1990 to 2013, and outlines recommended measures to reduce stroke burden. It shows that although stroke incidence, prevalence, mortality, and disability-adjusted life-years rates tend to decline from 1990 to 2013, the overall stroke burden in terms of absolute number of people affected by, or who remained disabled from, stroke has increased across the globe in both men and women of all ages. This provides a strong argument that "business as usual" for primary stroke prevention is not sufficiently effective. Although prevention of stroke is a complex medical and political issue, there is strong evidence that substantial prevention of stroke is feasible in practice. The need to scale-up the primary prevention actions is urgent.
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              Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.

              The adult brain is extremely vulnerable to various insults. The recent discovery of neural progenitors in adult mammals, however, raises the possibility of repairing damaged tissue by recruiting their latent regenerative potential. Here we show that activation of endogenous progenitors leads to massive regeneration of hippocampal pyramidal neurons after ischemic brain injury. Endogenous progenitors proliferate in response to ischemia and subsequently migrate into the hippocampus to regenerate new neurons. Intraventricular infusion of growth factors markedly augments these responses, thereby increasing the number of newborn neurons. Our studies suggest that regenerated neurons are integrated into the existing brain circuitry and contribute to ameliorating neurological deficits. These results expand the possibility of novel neuronal cell regeneration therapies for stroke and other neurological diseases.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                01 September 2020
                2020
                : 14
                Affiliations
                1Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University , Durham, NC, United States
                2Department of Dermatology, General Hospital of Ningxia Medical University , Yinchuan, China
                3Carilion Clinic, Virginia Tech Carilion School of Medicine , Roanoke, VA, United States
                Author notes

                Edited by: Josephine Herz, Essen University Hospital, Germany

                Reviewed by: Danuta Jantas, Polish Academy of Sciences, Poland; Huoming Zhang, King Abdullah University of Science and Technology, Saudi Arabia

                *Correspondence: Jiahua Xie jxie@ 123456nccu.edu

                Specialty section: This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2020.00272
                7491318
                Copyright © 2020 Li, Kittur, Hung, Li, Ge, Sane and Xie.

                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.

                Page count
                Figures: 11, Tables: 1, Equations: 0, References: 121, Pages: 19, Words: 12858
                Categories
                Cellular Neuroscience
                Original Research

                Neurosciences

                proteomic analysis, neuronal cells, low glucose, hypoxia, ischemic penumbra

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