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Intermittent, low dose carbon monoxide exposure enhances survival and dopaminergic differentiation of human neural stem cells

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      Abstract

      Exploratory studies using human fetal tissue have suggested that intrastriatal transplantation of dopaminergic neurons may become a future treatment for patients with Parkinson’s disease. However, the use of human fetal tissue is compromised by ethical, regulatory and practical concerns. Human stem cells constitute an alternative source of cells for transplantation in Parkinson’s disease, but efficient protocols for controlled dopaminergic differentiation need to be developed. Short-term, low-level carbon monoxide (CO) exposure has been shown to affect signaling in several tissues, resulting in both protection and generation of reactive oxygen species. The present study investigated the effect of CO produced by a novel CO-releasing molecule on dopaminergic differentiation of human neural stem cells. Short-term exposure to 25 ppm CO at days 0 and 4 significantly increased the relative content of β-tubulin III-immunoreactive immature neurons and tyrosine hydroxylase expressing catecholaminergic neurons, as assessed 6 days after differentiation. Also the number of microtubule associated protein 2-positive mature neurons had increased significantly. Moreover, the content of apoptotic cells (Caspase3) was reduced, whereas the expression of a cell proliferation marker (Ki67) was left unchanged. Increased expression of hypoxia inducible factor-1α and production of reactive oxygen species (ROS) in cultures exposed to CO may suggest a mechanism involving mitochondrial alterations and generation of ROS. In conclusion, the present procedure using controlled, short-term CO exposure allows efficient dopaminergic differentiation of human neural stem cells at low cost and may as such be useful for derivation of cells for experimental studies and future development of donor cells for transplantation in Parkinson’s disease.

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      Epidemiology of Parkinson's disease.

      The causes of Parkinson's disease (PD), the second most common neurodegenerative disorder, are still largely unknown. Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes. Numerous epidemiological studies have been done to identify such non-genetic risk factors, but most were small and methodologically limited. Larger, well-designed prospective cohort studies have only recently reached a stage at which they have enough incident patients and person-years of follow-up to investigate possible risk factors and their interactions. In this article, we review what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies.
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        Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.

        Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.
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          Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications.

          The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.
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            Author and article information

            Affiliations
            [1 ] Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
            [2 ] Instituto de Biologia Experimental e Tecnológica (IBET), Oeiras, Portugal
            [3 ] Instituto de Tecnologia Química e Biológica (ITQB), Oeiras, Portugal
            [4 ] CEDOC, NOVA Medical School/Faculdade de Ciência Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
            [5 ] Department of Pathology, Odense University Hospital, Denmark & Department of Clinical Research, University of Southern Denmark, Odense, Denmark
            [6 ] Center for Insoluble Protein Structures (inSPIN), Department of Chemistry, Aarhus University, Aarhus, Denmark
            [7 ] Department of Molecular Biology and Center of Molecular Biology Severo Ochoa, University Autonoma Madrid-C.S.I.C Campus Cantoblanco, Madrid, Spain
            [8 ] Department of Neurology, Zealand University Hospital, Roskilde, Denmark
            Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, POLAND
            Author notes

            Competing Interests: The authors have declared that no competing interests exist.

            Contributors
            Role: Conceptualization, Role: Data curation, Role: Formal analysis, Role: Investigation, Role: Methodology, Role: Visualization, Role: Writing – original draft
            Role: Conceptualization, Role: Data curation, Role: Formal analysis, Role: Investigation, Role: Methodology, Role: Writing – original draft
            Role: Conceptualization, Role: Data curation, Role: Formal analysis, Role: Investigation, Role: Writing – original draft
            Role: Data curation, Role: Formal analysis, Role: Methodology, Role: Validation
            Role: Formal analysis, Role: Methodology, Role: Writing – review & editing
            Role: Data curation, Role: Investigation
            Role: Conceptualization, Role: Methodology, Role: Resources
            Role: Methodology, Role: Resources
            Role: Formal analysis, Role: Methodology, Role: Writing – review & editing
            Role: Investigation, Role: Methodology, Role: Resources
            Role: Conceptualization, Role: Investigation, Role: Methodology, Role: Resources
            Role: Conceptualization, Role: Methodology, Role: Resources, Role: Writing – review & editing
            Role: Conceptualization, Role: Data curation, Role: Formal analysis, Role: Methodology, Role: Visualization, Role: Writing – original draft
            ORCID: http://orcid.org/0000-0002-9571-1336, Role: Conceptualization, Role: Data curation, Role: Funding acquisition, Role: Investigation, Role: Methodology, Role: Project administration, Role: Resources, Role: Supervision, Role: Writing – review & editing
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, CA USA )
            1932-6203
            16 January 2018
            2018
            : 13
            : 1
            29338033 5770048 10.1371/journal.pone.0191207 PONE-D-17-25411
            © 2018 Dreyer-Andersen et al

            This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

            Counts
            Figures: 7, Tables: 0, Pages: 24
            Product
            Funding
            Funded by: The Lundbeck Foundation
            Award Recipient : ORCID: http://orcid.org/0000-0002-9571-1336
            Funded by: The Danish Parkinson Association
            Award Recipient : ORCID: http://orcid.org/0000-0002-9571-1336
            Funded by: IMK Almene Fond
            Award Recipient : ORCID: http://orcid.org/0000-0002-9571-1336
            Funded by: The Danish National Research Foundation
            Award ID: DNRF118
            Award Recipient :
            This research was supported by the Lundbeck Foundation (MM, NDA), the Danish Parkinson Association (MM), IMK Almene Fond (MM), and the Danish National Research Foundation (TS, SF; grant no. DNRF118). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology and Life Sciences
            Cell Biology
            Cellular Types
            Animal Cells
            Neurons
            Biology and Life Sciences
            Neuroscience
            Cellular Neuroscience
            Neurons
            Biology and Life Sciences
            Developmental Biology
            Cell Differentiation
            Neuronal Differentiation
            Biology and Life Sciences
            Biochemistry
            Neurochemistry
            Neurochemicals
            Dopaminergics
            Biology and Life Sciences
            Neuroscience
            Neurochemistry
            Neurochemicals
            Dopaminergics
            Biology and Life Sciences
            Developmental Biology
            Cell Differentiation
            Biology and Life Sciences
            Biochemistry
            Oxidative Damage
            Reactive Oxygen Species
            Biology and Life Sciences
            Physiology
            Immune Physiology
            Cytokines
            Medicine and Health Sciences
            Physiology
            Immune Physiology
            Cytokines
            Biology and Life Sciences
            Immunology
            Immune System
            Innate Immune System
            Cytokines
            Medicine and Health Sciences
            Immunology
            Immune System
            Innate Immune System
            Cytokines
            Biology and Life Sciences
            Developmental Biology
            Molecular Development
            Cytokines
            Physical Sciences
            Chemistry
            Chemical Compounds
            Carbon Monoxide
            Biology and Life Sciences
            Cell Biology
            Cell Processes
            Cell Death
            Apoptosis
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