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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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          Most cited references 96

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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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              Neurotrophin-regulated signalling pathways.

               L F Reichardt (2006)
              Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-gamma1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-kappaB (NF-kappaB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.
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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
                PONE-D-17-25411
                10.1371/journal.pone.0191207
                5770048
                29338033
                © 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
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                Dopaminergics
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                Neuroscience
                Neurochemistry
                Neurochemicals
                Dopaminergics
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                Developmental Biology
                Cell Differentiation
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                Biochemistry
                Oxidative Damage
                Reactive Oxygen Species
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                Innate Immune System
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                Biology and Life Sciences
                Developmental Biology
                Molecular Development
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                Physical Sciences
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                Chemical Compounds
                Carbon Monoxide
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
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