From Purines to Purinergic Signalling: Molecular Functions and Human Diseases
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Expression of Purinergic Receptors on Microglia in the Animal Model Of
www.nature.com/scientificreports OPEN Expression of purinergic receptors on microglia in the animal model of choroidal neovascularisation Lu Li1*, Juejun Liu1, Amin Xu1, Peter Heiduschka2, Nicole Eter2 & Changzheng Chen1 To investigate the efect of P2 receptor on microglia and its inhibitor PPADS on choroidal neovascularization. Forty CX3CR1GFP/+ mice were randomly divided into 8 groups. In addition to the normal group, the rest of groups were receiving laser treatment. The retina and choroid from the second, third, fourth and ffth group of mice were taken in the 1, 4, 7, 14 days after laser treatment. The mice in the sixth and seventh group received intravitreal injection of 2 µl PPADS or PBS respectively immediately after laser treatment. The mice in the eighth group received topical application of PPADS once per day of three days. The mice in sixth, seventh and eighth group received AF and FFA examination on the fourth day after laser treatment. Immunofuorescence histochemical staining and real-time quantitative PCR were used to evaluate P2 expression and its efect on choroidal neovascularization. After laser treatment, activated microglia can express P2 receptors (P2X4, P2X7, P2Y2 and P2Y12). The expression of P2 increased on the frst day after laser damage, peaked on the fourth day (tP2X4 = 6.05, tP2X7 = 2.95, tP2Y2 = 3.67, tP2Y12 = 5.98, all P < 0.01), and then decreased. After PPADS inhibition, compared with the PBS injection group, the mRNA of P2X4, P2X7, P2Y2 and P2Y12 were decreased signifcantly in the PPADS injection group (tP2X4 = 5.54, tP2X7 = 9.82, tP2Y2 = 3.86, tP2Y12 = 7.91, all P < 0.01) and the PPADS topical application group (tP2X4 = 3.24, tP2X7 = 5.89, tP2Y2 = 6.75, tP2Y12 = 4.97, all P < 0.01). -
The Inflammasome Promotes Adverse Cardiac Remodeling Following Acute
The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse Eleonora Mezzaromaa,b,c,1, Stefano Toldoa,b,1, Daniela Farkasb, Ignacio M. Seropiana,b,c, Benjamin W. Van Tassellb,c, Fadi N. Sallouma, Harsha R. Kannana,b, Angela C. Mennaa,b, Norbert F. Voelkela,b, and Antonio Abbatea,b,2 aVCU Pauley Heart Center, bVCU Victoria Johnson Center, and cSchool of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298 Edited* by Charles A. Dinarello, University of Colorado Denver, Aurora, CO, and approved October 19, 2011 (received for review May 31, 2011) Acute myocardial infarction (AMI) initiates an intense inflamma- and increased caspase-1–mediated cell death in a more severe tory response that promotes cardiac dysfunction, cell death, and model of ischemia without reperfusion. We also describe phar- ventricular remodeling. The molecular events underlying this macologic inhibition of cryopyrin and P2X7 to prevent inflam- inflammatory response, however, are incompletely understood. masome formation and ameliorate cardiac damage as a potential In experimental models of sterile inflammation, ATP released from basis for translational investigation. dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein Results complex necessary for caspase-1 activation and amplification of Caspase-1 Is Activated in AMI. Caspase-1 mRNA synthesis in- the inflammatory response. Here we describe the presence of the creased severalfold in the heart at 3 and 7 d after AMI (Fig. S1). inflammasome in the heart in an experimental mouse model of Caspase-1 activation was also increased at 7 d as measured by AMI as evidenced by increased caspase-1 activity and cytoplasmic increased procaspase-1, increased cleaved caspase-1, and in- aggregates of the three components of the inflammasome—apo- creased cleaved/procaspase-1 ratio (Fig. -
Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the A3 and the P2Y2 Purinergic Receptors
Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the A3 and the P2Y2 Purinergic Receptors Apr. Liesbet Cosyn Thesis submitted to the Faculty of Pharmaceutical Sciences to obtain the degree of Doctor in Pharmaceutical Sciences Promoter Prof. dr. apr. Serge Van Calenbergh Academic year 2007-2008 TABLE OF CONTENTS 1 INTRODUCTION ................................................................................................. 3 1.1 Purinergic Receptors ................................................................................. 3 1.2 Adenosine Analogues and the Adenosine A3 Receptor ......................... 4 1.2.1 Adenosine................................................................................................. 4 1.2.2 The Adenosine Receptors: G-protein-Coupled Receptors........................ 7 1.2.3 Adenosine Receptor Subtypes and Their Signalling............................... 10 1.2.4 The Adenosine A3 Receptor ................................................................... 12 1.2.4.1 Adenosine A3 Receptor Agonists ................................................. 12 1.2.4.2 Adenosine A3 Receptor Antagonists ............................................ 16 1.2.4.3 Allosteric Modulation.................................................................... 21 1.2.4.4 Molecular Modeling of the Adenosine A3 Receptor...................... 22 1.2.4.5 The Neoceptor concept................................................................ 23 1.2.4.6 Therapeutic Potential of A3AR Agonists...................................... -
Regulation and Relevance for Chronic Lung Diseases
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Purinergic Signalling (2006) 2:399–408 DOI 10.1007/s11302-006-9001-7 ORIGINAL ARTICLE E-NTPDases in human airways: Regulation and relevance for chronic lung diseases Lauranell H. Burch & Maryse Picher Received: 11 January 2005 /Accepted: 21 December 2005 / Published online: 30 May 2006 # Springer Science + Business Media B.V. 2006 Abstract Chronic obstructive lung diseases are char- are characterized by higher rates of nucleotide elimi- acterized by the inability to prevent bacterial infection nation, azide-sensitive E-NTPDase activities and ex- and a gradual loss of lung function caused by recurrent pression. This review integrates the biphasic regulation inflammatory responses. In the past decade, numerous of airway E-NTPDases with the function of purine studies have demonstrated the importance of nucleo- signaling in lung diseases. During acute insults, a tide-mediated bacterial clearance. Their interaction transient reduction in E-NTPDase activities may be with P2 receptors on airway epithelia provides a rapid beneficial to stimulate ATP-mediated bacterial clear- Fon-and-off_ signal stimulating mucus secretion, cilia ance. In chronic lung diseases, elevating E-NTPDase beating activity and surface hydration. On the other activities may represent an attempt to prevent P2 hand, abnormally high ATP levels resulting from receptor desensitization and nucleotide-mediated lung damaged epithelia and bacterial lysis may cause lung damage. edema and exacerbate inflammatory responses. Air- way ATP concentrations are regulated by ecto nucle- Keywords apyrase . bacterial clearance . CD39 . oside triphosphate diphosphohydrolases (E-NTPDases) chronic obstructive lung diseases . -
PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. -
NIH Public Access Author Manuscript J Med Chem
NIH Public Access Author Manuscript J Med Chem. Author manuscript; available in PMC 2012 June 23. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Med Chem. 2011 June 23; 54(12): 4018±4033. doi:10.1021/jm101591j. Pyrimidine Nucleotides with 4-Alkyloxyimino and Terminal Tetraphosphate δ-Ester Modifications as Selective Agonists of the P2Y4 Receptor Hiroshi Maruokaa, M.P. Suresh Jayasekaraa, Matthew O. Barrettb, Derek A. Franklinb, Sonia de Castroa, Nathaniel Kima, Stefano Costanzic, T. Kendall Hardenb, and Kenneth A. Jacobsona,* aMolecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0810 bDepartment of Pharmacology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599-7365 cLaboratory of Biological Modeling, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 Abstract P2Y2 and P2Y4 receptors are G protein-coupled receptors, activated by UTP and dinucleoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We varied structurally phosphate and uracil moieties in analogues of pyrimidine nucleoside 5′-triphosphates and 5′-tetraphosphate esters. P2Y4 receptor potency in phospholipase C stimulation in transfected 1321N1 human astrocytoma cells was enhanced in N4- alkyloxycytidine derivatives. OH groups on a terminal δ-glucose phosphoester of uridine 5′- tetraphosphate were inverted or substituted with H or F to probe H-bonding effects. N4- 4 (Phenylpropoxy)-CTP 16 (MRS4062), Up4-[1]3′-deoxy-3′-fluoroglucose 34 (MRS2927) and N - (phenylethoxy)-CTP 15 exhibit ≥10-fold selectivity for human P2Y4 over P2Y2 and P2Y6 receptors (EC50 values 23, 62 and 73 nM, respectively). -
P2X7 Receptor-Induced CD23 Shedding from B Cells Aleta Pupovac University of Wollongong, [email protected]
University of Wollongong Research Online University of Wollongong Thesis Collection University of Wollongong Thesis Collections 2014 P2X7 receptor-induced CD23 shedding from B cells Aleta Pupovac University of Wollongong, [email protected] Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] P2X7 receptor-induced CD23 shedding from B cells A thesis submitted in fulfilment of the requirements for the award of the degree Doctor of Philosophy from UNIVERSITY OF WOLLONGONG by Aleta Pupovac Bachelor of Biotechnology (Adv) (Hons) Illawarra Health and Medical Research Institute School of Biological Sciences 2014 THESIS CERTIFICATION I, Aleta Pupovac, declare that this thesis, submitted in fulfilment of the requirements for the award of Doctor of Philosophy, in the Department of Biological Sciences, University of Wollongong, is wholly my own work unless otherwise referenced or acknowledged. The document has not been submitted for qualifications at any other academic institution. Aleta Pupovac 2014 i ACKNOWLEDGEMENTS I would like to thank my supervisor, Ron Sluyter, for providing me with the skills and patience to tackle science confidently in the future. Your knowledge, guidance and support were essential in the completion of this project, and have moulded me into the scientist that I always hoped to be. I will be forever grateful that you gave me the opportunity to be a part of your lab, and for your excellent supervision. A student cannot ask for a better supervisor. Also thanks to my co-supervisor Marie Ranson, for providing helpful advice over the years. -
Pharmaceutical Appendix to the Harmonized Tariff Schedule
Harmonized Tariff Schedule of the United States (2019) Revision 13 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2019) Revision 13 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. -
United States Securities and Exchange Commission Form
Use these links to rapidly review the document TABLE OF CONTENTS PART IV Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-K ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the Fiscal Year Ended December 31, 2008 or o TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission file number 000-19319 Vertex Pharmaceuticals Incorporated (Exact name of registrant as specified in its charter) Massachusetts 04-3039129 (State or other jurisdiction of (I.R.S. Employer incorporation or organization) Identification No.) 130 Waverly Street Cambridge, Massachusetts 02139-4242 (Address of principal executive offices) (Zip Code) Registrant's telephone number, including area code (617) 444-6100 Securities registered pursuant to Section 12(b) of the Exchange Act: Title of Each Class Name of Each Exchange on Which Registered Common Stock, $0.01 Par Value Per Share The Nasdaq Global Select Market Rights to Purchase Series A Junior Participating Preferred Stock Securities registered pursuant to Section 12(g) of the Exchange Act: None Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No o Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Exchange Act. Yes o No ☒ Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
A Pilot Exome-Wide Association Study of Age-Related Cataract in Koreans
Available online at www.jbr-pub.org Open Access at PubMed Central The Journal of Biomedical Research, 2016, 30(3):186-190 Original Article A pilot exome-wide association study of age-related cataract in Koreans Sang-Yong Eom1,2, Dong-Hyuk Yim1,2, Jung-Hyun Kim3, Joo-Byung Chae4, Yong-Dae Kim1,2, Heon Kim1,2, 1Center for Farmer's Safety and Health, Chungbuk National University Hospital, Cheongju, Chungbuk 28644, Republic of Korea; 2Department of Preventive Medicine, College of Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea; 3 Department of Optometry, Daejeon Health Science College, Daejeon 34504, Republic of Korea; 4 Department of Ophthalmology, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea. Abstract Age-related cataract (ARC) is the most common cause of visual impairment and blindness worldwide. A previous study reported that genetic factors could explain approximately 50% of the heritability of cataract. However, a genetic predisposition to ARC and the contributing factors have not yet been elucidated in the Korean population. In this study, we assessed the influence of genetic polymorphisms on the risk of ARC in Koreans, including 156 cataract cases and 138 healthy adults. We conducted an exome-wide association study using Illumina Human Exome-12v1.2 platform to screen 244,770 single nucleotide polymorphisms (SNPs). No SNPs reached exome-wide significance level of association (P < 1×10−6). B3GNT4 rs7136356 showed the most significant association with ARC (P = 6.54×10−5). Two loci (MUC16 and P2RY2) among the top 20 ARC-associated SNPs were recognized as probably linked to cata- ractogenesis. -
Denufosol for Cystic Fibrosis with Mild Lung Disease December 2009
Denufosol for cystic fibrosis with mild lung disease December 2009 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Denufosol for cystic fibrosis with mild lung disease Target group a • Cystic fibrosis with mild lung disease (FEV1 ≥75% of predicted normal). Technology description Denufosol (Denufosol tetrasodium, INS37217) is a second generation pyrimidine that has agonistic activity on the purinocepter Y2 (P2Y2) receptor. Stimulation of the P2Y2 receptors on the apical surface of the respiratory epithelium activates alternative chloride channels and enhances mucosal hydration and mucociliary clearance through increased chloride secretion, reduced sodium absorption and increased cilia beat frequency. Denufosol is administered at 60mg three times daily by inhalation via a nebuliser and is intended to be used as a primary or adjunctive therapy in patients with cystic fibrosis (CF) lung disease. Innovation and/or advantages Denufosol is a new class of drug with a novel mechanism of action, which may help slow the deterioration in pulmonary function associated with CF. Developer Inspire Pharmaceuticals (originator). EU licensee to be determined. Availability, launch or marketing dates, and licensing plans Denufosol is a designated orphan drug in the EU and USA. NHS or Government priority area This topic is relevant to The National Service Framework for Long-Term Conditions (2005) and The National Service Framework for Children, Young People and Maternity Services (2004).