DOCSLIB.ORG

The Involvement of the Kynurenine Pathway in Parkinson’S Disease in Vitro Models

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Involvement of the Kynurenine Pathway in Parkinson’S Disease in Vitro Models THE INVOLVEMENT OF THE KYNURENINE PATHWAY IN PARKINSON’S DISEASE IN VITRO MODELS A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy March 2012 The Neuroinflammation group School of Medical Sciences The University of New South Wales i Abstract Parkinson’s disease (PD) is caused by a progressive loss of dopaminergic neurons in the Substantia Nigra (SN) in patients. The kynurenine pathway (KP) of tryptophan (TRP) metabolism is a key regulatory mechanism of the immune response. The KP is activated in several neuroinflammatory diseases and is likely to be involved in PD pathogenesis. Activation of the KP can lead to production of the excitotoxin quinolinic acid (QUIN) or neuroprotective metabolites such as picolinic acid (PIC) or kynurenic acid (KYNA). The first rate-limiting inducible enzyme of the KP is indoleamine 2,3-dioxygenase (IDO). We hypothesise that the KP in human dopaminergic neurons may lead to the production of neuroprotective KP metabolites and that these neurons will be very sensitive to QUIN excitotoxicity produced by microglia. The main findings of this project are: 1) establishment of an in vitro model of human dopaminergic neurons differentiated from human neuroblastoma cell lines, 2) a primary human in vitro model for dopaminergic neurons established by optimisation of an isolation procedure and culture conditions of neurons derived from human foetal SN, 3) full characterisation of KP in these models by HPLC, GC/MS and quantitative RT-PCR, 4) the KP is highly activated in dopaminergic neurons in inflammatory conditions and is shifted toward production of neuroprotective metabolites, 5) QUIN is neurotoxic for dopaminergic neurons, causing neuronal loss and denervation. In conclusion, this study provides new in vitro models for human dopaminergic models and strong evidence for the involvement of KP in PD pathogenesis and that this is associated with inflammation. This study provides important tools to investigate mechanisms of dopaminergic neuronal death and may suggest various neuroprotective strategies for future development based on KP modulation. ii Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). Signed …………………………………………….......... Date …………………………………………….............. Witness …………………………………………………... iii ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. iv Acknowledgements First, I would like to express my gratitude to my supervisor, A/Prof. Gilles Guillemin, for giving me the opportunity to undertake this PhD project. I appreciate your supervision, continuous support, deep expertise, and critical comments throughout my candidature. Your great enthusiasm, humour and positive attitude made my experience rewarding and enjoyable. I would like to believe that my thinking and writing are clearer, all as a result of your guidance. I would like to thank Prof Kay Double, my co-supervisor, for her support and valuable advises. I gratefully thank our collaborators from Spain, Prof Herrero and Prof Barcia for generously sharing your great knowledge on Parkinson’s disease and your recourses. You have provided us with results of valuable experiments, which put a base to this study. Lots of thanks to my colleges at Neuroinflammation unit, you shared with me your knowledge, time and experience. Thank you Dr Edwin Lim, Ms Seray Adams and Ms Priyanka Anand for the help with HPLC and GC/MS experiments. I have made many friends along the way: Ms Gayathri Sundaram, Dr Nady Braidy, Ms Jon-Min Lee, Ms Seray Adams and Ms Gloria Castellano, thank you all for day-to-day consults, valuable comments and good laugh. A special thank you for Ms Sonia Bustamante (BMSF, UNSW)) and Dr Alexandrer Macmillan (BMIF, UNSW) for their great patience and assistance with the experiments. This thesis would not have been possible without everyone’s supports. The PhD journey was very challenging for me and as a result left me with so many people I would love to thank. I would like to thank my colleges from Diabetes Transplant Unit: Dr Catalina Palma, Dr Methichit Chayosumrit, Dr Kerstin Brand and Dr Estella Sanchez. Your friendship, support and encouragement helped me a lot. My deepest gratitude goes to my family including my daughters Dana and Keren, my mum and dad, my grandmother Feiga and many more relatives who have always believed in me and supported me through these times. I would like to thank to my husband, Slav, not only for providing his editing and programming skills but also for the encouragement, great support and love. I recognize that this research would not have been possible without the financial assistance of Parkinson’s NSW. Thank you for your support and the hope that you give to those suffering with this devastating disease. Finally, I would like to consider this study to be the start of a promising future research, rather than only a dissertation. v Publications Zinger A, Barcia C, Hererro MT, Guillemin GJ. “The involvement of Neuroinflammation and Kynurenine Pathway in Parkinson’s disease”, Parkinson’s Disease, 2011. Article ID 716859 Zinger A, Barcia C, Hererro MT, Guillemin GJ. “Characterization of Kynurenine pathway in human dopaminergic neurons” (in preparation). vi Awards Postgraduate Research Student Scholarship Travel Grant International Conference on Alzheimer's and Parkinson's Diseases, 2011 School of Medical Sciences Research Travel Award Australian Neuroscience Society (ANS) 2011 Seed grant Parkinson's NSW Research grant program, 2010. School of Medical Sciences Research Travel Award 5th AH&MR Congress, 2010 UNSW Commercialisation Training Scheme Research Scholarship, 2010-2011. Australian Postgraduate Award, 2008-2011 Rising star dean’s award, 2008-2011 vii List of abbreviations 3HAA 3-Hydroxyanthranilic acid 3HAAO 3-Hydroxyanthranilic acid oxygenase 3HK 3-Hydroxykynurenine 5HT 5-Hydroxytryptamine 5HIIA 5-Hydroxyindoleacetic acid ACMS Aminocarboxymuconate semialdehyde ACMSD Aminocarboxymuconate semialdehyde decarboxylase ACTB Actin beta AC Adenylyl cyclase AFMID Arylformamidase AraC Arabinofuranosyl Cytidine BBB Blood-brain barrier BSA Bovine serum albumin BCA Bicinchoninic acid BDNF Brain-derived neurotrophic factor B2M Beta-2 microglobulin cDNA complementary DNA CNS Central nervous system CSF Cerebrospinal fluid COX Cyclo oxygenase DAPI 4’,6-Diamidino-2-phenylindole Db-cAMP Dibutyryladenosine 3':5' cyclic monophosphate DNA Deoxyribonucleic acid DNase I Deoxyribonuclease I dNTPs Deoxynucleotide triphosphates DAT Dopamine transporter EDTA Ethylenediaminetetraacetic acid 1 FBS Fetal bovine serum GABA γ-Aminobutyric acid GAPDH Glyceraldehyde phosphate dehydrogenase GAD Glutamic acid decarboxylase GCH1 GTP cyclohydroxilase 1 GC/MS Gas chromatography/mass spectrometry GOT2 Glutamic-oxaloacetic transaminase 2 GPi Internal paladial segment GPe External paladial GPR G-protein coupled receptor HAAO 3-Hydroxyanthranilate 3,4-dioxygenase HPRT Hypoxanthine-guanine phosphoribosyltransferase HPLC High performance liquid chromatography IDO Indoleamine, 2-3 dioxygenase IFN- Interferon KAT Kynurenine aminotransferase KMO Kynurenine 3-monooxygenase KP Kynurenine pathway KYN Kynurenine KYNA Kynurenic acid KYNU L-Kynurenine hydrolase LDH Lactate dehydrogenase LB Lewy body LPS Lipopolysaccharide MAO Monoamine oxidase MAP2 Microtubule-associated protein 2 MHC Major histocompatibility complex MPTP 1-Methyl-4-phenyl-1,2,3,6-tetra-pyridine MPP+ 1-Methyl-4-phenylpyridinium 2 mRNA Messenger RNA NADPH Nicotinamide adenine dinucleotide phosphate NAD+ Nicotinamide adenine dinucleotide NGF Neuronal growth factor NeuN Neuronal Nuclei NO Nitric oxide NOS Nitric oxide synthase NMDA N-methyl-D-aspartate NMDAR N-methyl-D-aspartate receptor NSAID Nonsteroidal anti-inflammatory drugs PD Parkinson’s disease PIC Picolinic acid PS Penicillin/streptomycin QPRT Quinolinate phosphoribosyltransferase QUIN Quinolinic acid ROS Reactive oxygen species RNA Ribonucleic acid RNS Repetitive nerve stimulation RT-PCR Reverse transcriptase-polymerase chain reaction SN Substantia nigra SNpc Substantia nigra pars compacta SNpr Substantia nigra pars reticulata SYN Alpha synuclein STN Subthalamic nucleus TDO
Load more

Recommended publications
  • Monoamine Oxydases Et Athérosclérose : Signalisation Mitogène Et Études in Vivo
    UNIVERSITE TOULOUSE III - PAUL SABATIER Sciences THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE TOULOUSE III Discipline : Innovation Pharmacologique Présentée et soutenue par : Christelle Coatrieux le 08 octobre 2007 Monoamine oxydases et athérosclérose : signalisation mitogène et études in vivo Jury Monsieur Luc Rochette Rapporteur Professeur, Université de Bourgogne, Dijon Monsieur Ramaroson Andriantsitohaina Rapporteur Directeur de Recherche, INSERM, Angers Monsieur Philippe Valet Président Professeur, Université Paul Sabatier, Toulouse III Madame Nathalie Augé Examinateur Chargé de Recherche, INSERM Monsieur Angelo Parini Directeur de Thèse Professeur, Université Paul Sabatier, Toulouse III INSERM, U858, équipes 6/10, Institut Louis Bugnard, CHU Rangueil, Toulouse Résumé Les espèces réactives de l’oxygène (EROs) sont impliquées dans l’activation de nombreuses voies de signalisation cellulaires, conduisant à différentes réponses comme la prolifération. Les EROs, à cause du stress oxydant qu’elles génèrent, sont impliquées dans de nombreuses pathologies, notamment l’athérosclérose. Les monoamine oxydases (MAOs) sont deux flavoenzymes responsables de la dégradation des catécholamines et des amines biogènes comme la sérotonine ; elles sont une source importante d’EROs. Il a été montré qu’elles peuvent être impliquées dans la prolifération cellulaire ou l’apoptose du fait du stress oxydant qu’elles génèrent. Ce travail de thèse a montré que la MAO-A, en dégradant son substrat (sérotonine ou tyramine), active une voie de signalisation mitogène particulière : la voie métalloprotéase- 2/sphingolipides (MMP2/sphingolipides), et contribue à la prolifération de cellules musculaire lisses vasculaires induite par ces monoamines. De plus, une étude complémentaire a confirmé l’importance des EROs comme stimulus mitogène (utilisation de peroxyde d’hydrogène exogène), et a décrit plus spécifiquement les étapes en amont de l’activation de MMP2, ainsi que l’activation par la MMP2 de la sphingomyélinase neutre (première enzyme de la cascade des sphingolipides).
    [Show full text]
  • Electronic Supplementary Material (ESI) for Analyst. This Journal Is © the Royal Society of Chemistry 2017
    Electronic Supplementary Material (ESI) for Analyst. This journal is © The Royal Society of Chemistry 2017 Supplemental Table 2. Proteins Increased in Either Blood or Horizon media Table 2A. Proteins Increased in Spores Produced on Horizon Soil Over Spores Produced on Blood Medium quasi.fdr Protein Protein Class/Name KEGG Pathway Names or Function (if ID Pathways found in KEGG) Amino Acid Metabolism bat00250, bat00280, Alanine, aspartate and glutamate metabolism, bat00410, Valine, leucine and isoleucine degradation, bat00640, beta-Alanine metabolism to acetyl CoA, 4.50E-07 BAS0310 4-aminobutyrate aminotransferase bat00650 Propanoate metabolism, Butanoate metabolism bat00270, bat00330, Cysteine and methionine metabolism, Arginine bat00410, and proline metabolism, beta-Alanine 3.84E-10 BAS5060 spermidine synthase bat00480 metabolism, Glutathione metabolism bat00270, bat00330, Cysteine and methionine metabolism, Arginine bat00410, and proline metabolism, beta-Alanine 2.30E-09 BAS5219 spermidine synthase bat00480 metabolism, Glutathione metabolism bat00250, Alanine, aspartate and glutamate metabolism, 6.94E-07 BAS0561 alanine dehydrogenase bat00430 Taurine and hypotaurine metabolism bat00250, Alanine, aspartate and glutamate metabolism, 5.23E-07 BAS4521 alanine dehydrogenase bat00430 Taurine and hypotaurine metabolism 0.005627 BAS5218 agmatinase, putative bat00330 Arginine and proline metabolism 2,3,4,5-tetrahydropyridine-2- carboxylate N-succinyltransferase, 1.40E-10 BAS3891 putative bat00300 Lysine biosynthesis bat00010, bat00020, Glycolysis
    [Show full text]
  • METABOLIC EVOLUTION in GALDIERIA SULPHURARIA By
    METABOLIC EVOLUTION IN GALDIERIA SULPHURARIA By CHAD M. TERNES Bachelor of Science in Botany Oklahoma State University Stillwater, Oklahoma 2009 Submitted to the Faculty of the Graduate College of the Oklahoma State University in partial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY May, 2015 METABOLIC EVOLUTION IN GALDIERIA SUPHURARIA Dissertation Approved: Dr. Gerald Schoenknecht Dissertation Adviser Dr. David Meinke Dr. Andrew Doust Dr. Patricia Canaan ii Name: CHAD M. TERNES Date of Degree: MAY, 2015 Title of Study: METABOLIC EVOLUTION IN GALDIERIA SULPHURARIA Major Field: PLANT SCIENCE Abstract: The thermoacidophilic, unicellular, red alga Galdieria sulphuraria possesses characteristics, including salt and heavy metal tolerance, unsurpassed by any other alga. Like most plastid bearing eukaryotes, G. sulphuraria can grow photoautotrophically. Additionally, it can also grow solely as a heterotroph, which results in the cessation of photosynthetic pigment biosynthesis. The ability to grow heterotrophically is likely correlated with G. sulphuraria ’s broad capacity for carbon metabolism, which rivals that of fungi. Annotation of the metabolic pathways encoded by the genome of G. sulphuraria revealed several pathways that are uncharacteristic for plants and algae, even red algae. Phylogenetic analyses of the enzymes underlying the metabolic pathways suggest multiple instances of horizontal gene transfer, in addition to endosymbiotic gene transfer and conservation through ancestry. Although some metabolic pathways as a whole appear to be retained through ancestry, genes encoding individual enzymes within a pathway were substituted by genes that were acquired horizontally from other domains of life. Thus, metabolic pathways in G. sulphuraria appear to be composed of a ‘metabolic patchwork’, underscored by a mosaic of genes resulting from multiple evolutionary processes.
    [Show full text]
  • Mt-Atp8 Gene in the Conplastic Mouse Strain C57BL/6J-Mtfvb/NJ on the Mitochondrial Function and Consequent Alterations to Metabolic and Immunological Phenotypes
    From the Lübeck Institute of Experimental Dermatology of the University of Lübeck Director: Prof. Dr. Saleh M. Ibrahim Interplay of mtDNA, metabolism and microbiota in the pathogenesis of AIBD Dissertation for Fulfillment of Requirements for the Doctoral Degree of the University of Lübeck from the Department of Natural Sciences Submitted by Paul Schilf from Rostock Lübeck, 2016 First referee: Prof. Dr. Saleh M. Ibrahim Second referee: Prof. Dr. Stephan Anemüller Chairman: Prof. Dr. Rainer Duden Date of oral examination: 30.03.2017 Approved for printing: Lübeck, 06.04.2017 Ich versichere, dass ich die Dissertation ohne fremde Hilfe angefertigt und keine anderen als die angegebenen Hilfsmittel verwendet habe. Weder vorher noch gleichzeitig habe ich andernorts einen Zulassungsantrag gestellt oder diese Dissertation vorgelegt. ABSTRACT Mitochondria are critical in the regulation of cellular metabolism and influence signaling processes and inflammatory responses. Mitochondrial DNA mutations and mitochondrial dysfunction are known to cause a wide range of pathological conditions and are associated with various immune diseases. The findings in this work describe the effect of a mutation in the mitochondrially encoded mt-Atp8 gene in the conplastic mouse strain C57BL/6J-mtFVB/NJ on the mitochondrial function and consequent alterations to metabolic and immunological phenotypes. This work provides insights into the mutation-induced cellular adaptations that influence the inflammatory milieu and shape pathological processes, in particular focusing on autoimmune bullous diseases, which have recently been reported to be associated with mtDNA polymorphisms in the human MT-ATP8 gene. The mt-Atp8 mutation diminishes the assembly of the ATP synthase complex into multimers and decreases mitochondrial respiration, affects generation of reactive oxygen species thus leading to a shift in the metabolic balance and reduction in the energy state of the cell as indicated by the ratio ATP to ADP.
    [Show full text]
  • Table 2. Significant
    Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S.
    [Show full text]
  • Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ Ortal Barel,1 Zamir Shorer,2 Hagit Flusser,2 Rivka Ofir,1 Ginat Narkis,1 Gal Finer,1 Hanah Shalev,2 Ahmad Nasasra,2 Ann Saada,3 and Ohad S. Birk1,4,* A consanguineous Israeli Bedouin kindred presented with an autosomal-recessive nonlethal phenotype of severe psychomotor retarda- tion and extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia, and marked global dementia with defects in verbal and expressive communication skills. Metabolic workup was normal except for mildly elevated blood lactate levels. Brain magnetic resonance imaging (MRI) showed increased density in the putamen, with decreased density and size of the caudate and lentiform nuclei. Reduced activity specifically of mitochondrial complex III and variable decrease in complex I activity were evident in muscle biopsies. Homozygosity of affected individuals to UQCRB and to BCSIL, previously associated with isolated complex III deficiency, was ruled out. Genome-wide linkage analysis identified a homozygosity locus of approximately 9 cM on chromosome 5q31 that was further narrowed down to 2.14 cM, harboring 30 genes (logarithm of the odds [LOD] score 8.82 at q ¼ 0). All 30 genes were sequenced, revealing a single missense (p.Ser45Phe) mutation in UQCRQ (encoding ubiquinol-cytochrome c reductase, complex III subunit VII, 9.5 kDa), one of the ten nuclear
    [Show full text]
  • Control Engineering Perspective on Genome-Scale Metabolic Modeling
    Control Engineering Perspective on Genome-Scale Metabolic Modeling by Andrew Louis Damiani A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama December 12, 2015 Key words: Scheffersomyces stipitis, Flux Balance Analysis, Genome-scale metabolic models, System Identification Framework, Model Validation, Phenotype Phase Plane Analysis Copyright 2015 by Andrew Damiani Approved by Jin Wang, Chair, Associate Professor of Chemical Engineering Q. Peter He, Associate Professor of Chemical Engineering, Tuskegee University Thomas W. Jeffries, Professor of Bacteriology, Emeritus; University of Wisconsin-Madison Allan E. David, Assistant Professor of Chemical Engineering Yoon Y. Lee, Professor of Chemical Engineering Abstract Fossil fuels impart major problems on the global economy and have detrimental effects to the environment, which has caused a world-wide initiative of producing renewable fuels. Lignocellulosic bioethanol for renewable energy has recently gained attention, because it can overcome the limitations that first generation biofuels impose. Nonetheless, in order to have this process commercialized, the biological conversion of pentose sugars, mainly xylose, needs to be improved. Scheffersomyces stipitis has a physiology that makes it a valuable candidate for lignocellulosic bioethanol production, and lately has provided genes for designing recombinant Saccharomyces cerevisiae. In this study, a system biology approach was taken to understand the relationship of the genotype to phenotype, whereby genome-scale metabolic models (GSMMs) are used in conjunction with constraint-based modeling. The major restriction of GSMMs is having an accurate methodology for validation and evaluation. This is due to the size and complexity of the models.
    [Show full text]
  • Targeting the Tryptophan Hydroxylase 2 Gene for Functional Analysis in Mice and Serotonergic Differentiation of Embryonic Stem Cells
    TARGETING THE TRYPTOPHAN HYDROXYLASE 2 GENE FOR FUNCTIONAL ANALYSIS IN MICE AND SEROTONERGIC DIFFERENTIATION OF EMBRYONIC STEM CELLS Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Dana Kikic, M.Sc. in Molecular biology and Physiology from Nis June, 2009 The doctorate studies were performed in the research group of Prof. Michael Bader Molecular Biology of Peptide Hormones at Max-Delbrück-Center for Molecular Medicine in Berlin, Buch Mai 2005 - September 2008. 1st Reviewer: Prof. Michael Bader 2nd Reviewer: Prof. Udo Heinemann date of defence: 13. August 2009 ACKNOWLEDGMENTS Herewith, I would like to acknowledge the persons who made this thesis possible and without whom my initiation in the world of basic science research would not have the spin it has now, neither would my scientific illiteracy get the chance to eradicate. I am expressing my very personal gratitude and recognition to: Prof. Michael Bader, for an inexhaustible guidance in all the matters arising during the course of scientific work, for an instinct in defining and following the intellectual challenge and for letting me following my own, for necessary financial support, for defining the borders of reasonable and unreasonable, for an invaluable time and patience, and an amazing efficiency in supporting, motivating, reading, correcting and shaping my scientific language during the last four years. Prof. Harald Saumweber and Prof. Udo Heinemann, for taking over the academic supervision of the thesis, and for breathing in it a life outside the laboratory walls and their personal signature.
    [Show full text]
  • Upregulated Kynurenine Pathway Enzymes in Aortic Atherosclerotic Aneurysm: Macrophage Kynureninase Downregulates Inflammation
    The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article J Atheroscler Thromb, 2021; 28: 000-000. http://doi.org/10.5551/jat.58248 Upregulated Kynurenine Pathway Enzymes in Aortic Atherosclerotic Aneurysm: Macrophage Kynureninase Downregulates Inflammation Masanori Nishimura1, 2, Atsushi Yamashita2, Yunosuke Matsuura3, Junichi Okutsu4, Aiko Fukahori4, Tsuyoshi Hirata4, Tomohiro Nishizawa5, Hirohito Ishii1, Kazunari Maekawa2, Eriko Nakamura2, Kazuo Kitamura3, Kunihide Nakamura1 and Yujiro Asada2 1Division of Cardiovascular Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 2Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 3Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan 4Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan 5Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan Aims: Inflammation and hypertension contribute to the progression of atherosclerotic aneurysm in the aorta. Vascular cell metabolism is regarded to modulate atherogenesis, but the metabolic alterations that occur in ath- erosclerotic aneurysm remain unknown. The present study aimed to identify metabolic pathways and metabo- lites in aneurysmal walls and examine their roles in atherogenesis. Methods: Gene expression using microarray and metabolite levels in the early atherosclerotic lesions and aneu- rysmal walls obtained from 42 patients undergoing aortic surgery were investigated (early lesion n=11, aneu- rysm n=35) and capillary electrophoresis–time-of-flight mass spectrometry (early lesion n=14, aneurysm n=38). Using immunohistochemistry, the protein expression and localization of the identified factors were examined (early lesion n=11, non-aneurysmal advanced lesion n=8, aneurysm n=11).
    [Show full text]
  • Sciatica and Chronic Pain
    Sciatica and Chronic Pain Past, Present and Future Robert W. Baloh 123 Sciatica and Chronic Pain Robert W. Baloh Sciatica and Chronic Pain Past, Present and Future Robert W. Baloh, MD Department of Neurology University of California, Los Angeles Los Angeles, CA, USA ISBN 978-3-319-93903-2 ISBN 978-3-319-93904-9 (eBook) https://doi.org/10.1007/978-3-319-93904-9 Library of Congress Control Number: 2018952076 © Springer International Publishing AG, part of Springer Nature 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
    [Show full text]
  • Biomarkers of Mitotoxicity After Acute Liver Injury: Further Insights Into the Interpretation of Glutamate Dehydrogenase
    Journal of Clinical and Translational Research 10.18053/Jctres/07.202101.005 MINI REVIEW Biomarkers of mitotoxicity after acute liver injury: further insights into the interpretation of glutamate dehydrogenase Mitchell R. McGill1,2* and Hartmut Jaeschke3 1. Department of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, 4301 W. Markham St, Little Rock, AR, USA, 72205 2. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR, USA, 72205 3. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, USA, 66160 *Corresponding author Mitchell R. McGill, PhD Department of Environmental Health Sciences & Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR Tel: +1 501-526-6696 Email: [email protected] Article information: Received: November 03, 2020 Revised: December 09, 2020 Accepted: December 10, 2020 Journal of Clinical and Translational Research 10.18053/Jctres/07.202101.005 ABSTRACT Background: Acetaminophen (APAP) is a popular analgesic, but overdose causes acute liver injury and sometimes death. Decades of research have revealed that mitochondrial damage is central in the mechanisms of toxicity in rodents, but we know much less about the role of mitochondria in humans. Due to the challenge of procuring liver tissue from APAP overdose patients, non-invasive mechanistic biomarkers are necessary to translate the mechanisms of APAP hepatotoxicity from rodents to patients. It was recently proposed that the mitochondrial matrix enzyme glutamate dehydrogenase (GLDH) can be measured in circulation as a biomarker of mitochondrial damage.
    [Show full text]
  • HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism
    HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism This information is current as Todd Bradley, Guang Yang, Olga Ilkayeva, T. Matt Holl, of September 29, 2021. Ruijun Zhang, Jinsong Zhang, Sampa Santra, Christopher B. Fox, Steve G. Reed, Robert Parks, Cindy M. Bowman, Hilary Bouton-Verville, Laura L. Sutherland, Richard M. Scearce, Nathan Vandergrift, Thomas B. Kepler, M. Anthony Moody, Hua-Xin Liao, S. Munir Alam, Roger McLendon, Jeffrey I. Everitt, Christopher B. Newgard, Downloaded from Laurent Verkoczy, Garnett Kelsoe and Barton F. Haynes J Immunol 2016; 197:4663-4673; Prepublished online 14 November 2016; doi: 10.4049/jimmunol.1601484 http://www.jimmunol.org/content/197/12/4663 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/11/12/jimmunol.160148 Material 4.DCSupplemental References This article cites 67 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/197/12/4663.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc.
    [Show full text]