DOCSLIB.ORG

Mathematical Modeling of Cellular Signal

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mathematical Modeling of Cellular Signal DOCTORAL THESIS FOR A DOCTORAL DEGREE AT THE GRADUATE SCHOOL OF LIFE SCIENCES, JULIUS-MAXIMILIANS-UNIVERSITÄT WÜRZBURG, SECTION BIOMEDICINE MATHEMATICAL MODELING OF CELLULAR SIGNAL TRANSDUCTION MATHEMATISCHE MODELLIERUNG DER ZELLULÄREN SIGNALTRANSDUKTION Submitted by GABY WANGORSCH from MELLRICHSTADT Würzburg, 2013 Submitted on: . Office stamp Members of the Promotionskomitee: Chairperson: Prof. Dr. Manfred Gessler Primary Supervisor: Prof. Dr. Thomas Dandekar Supervisor (Second): Prof. Dr. Ulrich Walter Supervisor (Third): Prof. Dr. Jörg Schultz Date of Public Defence: . Date of Receipt of Certificates: . To Thomas T. in Memoriam Acknowledgements This doctoral thesis comprises research results arising from interdisciplinary collaborations of the Department of Bioinformatics at the University of Würz- burg together with the University Hospital Würzburg. Starting in March 2008, I have been a fellow of the Graduate School of Life Sciences, section Biomedicine, and member of the special research area (SFB688) on mecha- nisms and imaging of cardiovascular cell-cell-interactions. First and foremost, I would like to thank all the people who have accompa- nied and supported me over the last years. All members of my supervisory committee Prof. Thomas Dandekar, Prof. Jörg Schultz and Prof. Ulrich Walter, for their support within the Doctoral Study Program "Life Sciences" of the Graduate School of Life Sciences. My primary supervisor Prof. Thomas Dandekar, for giving me the oppor- tunity to meet the dynamic research field at the interface between mathe- matics, biology and medicine. He supported me with his unwavering opti- mism and encouraging guidance during the conductance of my research. My second supervisor Prof. Walter, the former speaker of the special re- search area (SFB688) on mechanisms and imaging of cardiovascular cell- cell-interactions, for offering such a comfortable and stimulating research environment. It was fascinating to immerse into the world of platelets, being tiny and anucleate blood cells but representing a pivotal regulatory target with regard to severe cardiovascular diseases. Following this, I am grateful for the funding by the DFG project SFB688. My third supervisor Prof. Jörg Schultz for introducing me into the myste- rious world of Perl, many helpful comments on my thesis and his persistent encouragement. My external collaborators Prof. Harald Wajant (Division of Molecular In- ternal Medicine, Department of Internal Medicine II, University Hospital Würzburg) for sharing expert knowledge and data on inflammation signa- ling. Prof. Elke Butt, Dr. Jörg Geiger, Dr. Katharina Hubertus and Dr. Stepan Gambaryan (Institute of Clinical Biochemistry and Pathobiochemis- try, University of Würzburg) for fruitful discussions and providing data on platelets. My former working group at the University of Freiburg for discussions and support in data-based mathematical modeling. All associated members from the SFB688 for prosperous collaborations, in particular Prof. Stefan Frantz, Christina Pachel, Prof. Kristina Lorenz, Dr. Attila Braun, for starting and establishing interdisciplinary collaborations. My internal collaborators, for helpful and stimulating discussions and mee- tings, showing that there is much more about Bioinformatics than BLAST and alignments; Tobias Müller and Marcus Dittrich for training and support in data analysis; Nicole Philippi and Muhammad Naseem for exchanging ideas on computational modeling of biological systems; Desi and Santosh - my brave "plateleteers" - for forming such a dense and interacting clot of mutual information exchange; every thrombus may become envious of. All actual and former colleagues at the Department, especially Karin Lus- tre, Stefan Obermeier, Daniela Beißer, Christian Koetschan, Tina Schleicher, Alex the Great, Bärtierchen Frank, Michael Seidl, Astrid Fieselmann and the "plateleteers", for a very comfortable working atmosphere and many nice chats over some cups of coffee. Thanks for the unforgettable time also beyond room 116. Hopefully, the "interactions" we established during gra- duation will also have high edge scores in the future. The LATEX-command nusepackage[always]fcoffee, chocolateg and Daniel for donating the essential, motivating Leberwurscht. My "Stoogemer Mädels" together with the whole "Mühlfeld- and Werner- gang". The ties of our friendship are of incomparable value and helped a lot in managing the ups and downs in my life. My brother Klaus, for proof-reading, for always taking care of his little sister and cheering me up with his music and extraordinary cooking experiments. Lastly and surely the most, my entire family, especially my dear parents, for all their unconditional and perpetual love and support. 8 Abstract A subtly regulated and controlled course of cellular processes is essential for the healthy functioning not only of single cells, but also of organs being constituted thereof. In return, this entails the proper functioning of the whole organism. This implies a complex intra- and inter-cellular communi- cation and signal processing that require equally multi-faceted methods to describe and investigate the underlying processes. Within the scope of this thesis, mathematical modeling of cellular signa- ling finds its application in the analysis of cellular processes and signaling cascades in different organisms. First, a comprehensive systemic analysis of signaling pathways in human platelets is presented. These tiny blood cells play a key role in thrombosis and hemostasis. Based on an integrative platelet-specific data base (PlateletWeb), I developed interaction networks, qualitative and quantitative models of antagonistic signaling pathways in the platelet. On the basis of phosphoproteomic data, this afforded the in- tegration of potential substrates of key kinases into a functional network context. By means of a discrete dynamic model of central signaling cas- cades, I investigated the interplay between activatory and inhibitory signa- ling pathways towards the ultimate platelet aggregation. Extensive model simulations thereby documented the gradual activation of blood platelets to the point of aggregation. Data-based dynamic modeling of the inhibiting platelet cascade permitted quantitative model predictions of pivotal second messengers and yielded for the first time the quantification of central regu- lators. By comprehensively calibrating the dynamic model with time series data, I deciphered the feed-back regulation of second messengers (cAMP, cGMP) that lead to platelet inhibition. Model-based analyses of pathway cross-talks demonstrated the wide-ranging scope of pharmacological mo- dulation, not only in the platelet but also in other cell types such as cardio- myocytes. vii Inflammatory processes are regulated by a multitude of signaling cascades that are highly cross-linked as well. I here present a first mathematical mo- del for simulating the apoptotic cross-talk between TNF receptors, crucial mediators of inflammatory processes. In this type of signaling, the detailed and receptor-specific formation of the signal at the respective receptor is also of prime importance. Here, simulations of a structure-orientated ma- thematical model offer valuable clues about the strengths of ligand-encoded signal that is created at the particular receptor. Likewise, mathematical modeling and simulations are beneficial to decode the interplay of distinct phytohormones, as shown here using the example of Arabidopsis and pathogen Pst DC3000. Model-based forecasting together with profound validation by means of experimental data revealed multiple cross-talk for the hormone cytokinin with respect to plant immunity. Lastly, models describing intra- and inter-cellular signaling of different liver cells demonstrate the impact of combining mathematical models to func- tionally analyze the liver as a holistic cellular system. Within the framework of this thesis, I present mathematical methods for modeling cellular signaling cascades and their interplay in different orga- nisms. Resulting models form the basis for a systemic description and ana- lysis of cell-regulatory processes as well as for model-based predictions. This way, models guide further experimental investigation and are capable to indicate novel interaction points for pharmacological modulations. viii Zusammenfassung Das fein regulierte und kontrollierte Ablaufen zellulärer Prozesse ist es- sentiell für das gesunde Funktionieren einzelner Zellen, sowie der aus ih- nen bestehenden Organe. Diese wiederum bedingen das Funktionieren des gesamten Organismus. Genauso vielschichtig wie die Kommunikation und Signalverarbeitung innerhalb und zwischen den Zellen, sind die Methoden um diese Vorgänge zu beschreiben und zu untersuchen. Die mathematische Modellierung zellulärer Signalverarbeitung findet im Rahmen dieser Arbeit Anwendung in der Analyse zellulärer Prozesse und Signalkaskaden in verschiedenen Organismen. Zunächst wird eine um- fassende systemische Analyse von Signalwegen in humanen Blutplättchen gegeben. Diese kleinen Blutzellen spielen eine Schlüsselrolle in Throm- bose und Hämostase. Ausgehend von einer integrativen Blutplättchen-spe- zifischen Datenbank entwickelte ich Interaktionsnetzwerke sowie qualita- tive und quantitative Modelle zu antagonistischen Signalwegen der Blut- plättchen. Auf der Basis von Phosphoproteom-Daten war es möglich, po- tentielle Substrate wichtiger Kinasen in einen funktionellen Netzwerkkon- text zu setzen. In einem diskret-dynamischen Modell zentraler Signalkas- kaden untersuchte
Load more

Recommended publications
  • Effects of Phosphodiesterase Inhibitors on Human Lung Mast Cell and Basophil Function
    British Journal of Pharmacology (1997) 121, 287 ± 295 1997 Stockton Press All rights reserved 0007 ± 1188/97 $12.00 Eects of phosphodiesterase inhibitors on human lung mast cell and basophil function Marie C. Weston, Nicola Anderson & 1Peter T. Peachell Department of Medicine & Pharmacology, University of Sheeld, Royal Hallamshire Hospital (Floor L), Glossop Road, Sheeld S10 2JF 1 The non-hydrolysable cyclic AMP analogue, dibutyryl (Bu2)-cyclic AMP, inhibited the stimulated release of histamine from both basophils and human lung mast cells (HLMC) in a dose-dependent manner. The concentrations required to inhibit histamine release by 50% (IC50) were 0.8 and 0.7 mM in basophils and HLMC, respectively. The cyclic GMP analogue, Bu2-cyclic GMP, was ineective as an inhibitor of histamine release in basophils and HLMC. 2 The non-selective phosphodiesterase (PDE) inhibitors, theophylline and isobutyl-methylxanthine (IBMX) inhibited the IgE-mediated release of histamine from both human basophils and HLMC in a dose-dependent fashion. IBMX and theophylline were more potent inhibitors in basophils than HLMC. IC50 values for the inhibition of histamine release were, 0.05 and 0.2 mM for IBMX and theophylline, respectively, in basophils and 0.25 and 1.2 mM for IBMX and theophylline in HLMC. 3 The PDE 4 inhibitor, rolipram, attenuated the release of both histamine and the generation of sulphopeptidoleukotrienes (sLT) from activated basophils at sub-micromolar concentrations but was ineective at inhibiting the release of histamine and the generation of both sLT and prostaglandin D2 (PGD2) in HLMC. Additional PDE 4 inhibitors, denbufylline, Ro 20-1724, RP 73401 and nitraquazone, were all found to be eective inhibitors of mediator release in basophils but were ineective in HLMC unless high concentrations (1 mM) were employed.
    [Show full text]
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Rolipram, but Not Siguazodan Or Zaprinast, Inhibits the Excitatory Noncholinergic Neurotransmission in Guinea-Pig Bronchi
    Eur Respir J, 1994, 7, 306–310 Copyright ERS Journals Ltd 1994 DOI: 10.1183/09031936.94.07020306 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neurotransmission in guinea-pig bronchi Y. Qian, V. Girard, C.A.E. Martin, M. Molimard, C. Advenier Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neuro- Faculté de Médecine Paris-Ouest Labora- transmission in guinea-pig bronchi. Y. Qian, V. Girard C.A.E. Martin, M. Molimard, toire de Pharmacologie, Paris, France. C. Advenier. ERS Journals Ltd 1994. ABSTRACT: Theophylline has been reported to inhibit excitatory noncholinergic Correspondence: C. Advenier Faculté de Médecine Paris-Ouest but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might Laboratoire de Pharmacologie exert this effect through an inhibition of phosphodiesterases (PDE), and since many 15, Rue de l'Ecole de Médecine types of PDE have now been described, the aim of this study was to investigate the F-75270 Paris Cedex 06 effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) France of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazo- dan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, Keywords: C-fibres respectively. neuropeptides Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 phosphodiesterase inhibitors ms, 320 mA for 10 s) in the presence of indomethacin 10-6 M and propranolol 10-6 Received: March 11 1993 M. Two successive contractile responses were observed: a rapid cholinergic con- Accepted after revision August 8 1993 traction, followed by a long-lasting contraction due to a local release of neuropep- tides from C-fibre endings.
    [Show full text]
  • Effects of Various Selective Phosphodiesterase Inhibitors on Relaxation and Cyclic Nucleotide Contents in Porcine Iris Sphincter
    FULL PAPER Pharmacology Effects of Various Selective Phosphodiesterase Inhibitors on Relaxation and Cyclic Nucleotide Contents in Porcine Iris Sphincter Takuya YOGO1), Takeharu KANEDA2), Yoshinori NEZU1), Yasuji HARADA1), Yasushi HARA1), Masahiro TAGAWA1), Norimoto URAKAWA2) and Kazumasa SHIMIZU2) 1)Laboratories of Veterinary Surgery and 2)Veterinary Pharmacology, Nippon Veterinary and Life Science University, 7–1 Kyonan-cho 1– chome, Musashino, Tokyo 180–8602, Japan (Received 26 March 2009/Accepted 1 July 2009) ABSTRACT. The effects of various selective phosphodiesterase (PDE) inhibitors on muscle contractility and cyclic nucleotide contents in porcine iris sphincter were investigated. Forskolin and sodium nitroprusside inhibited carbachol (CCh)-induced contraction in a concen- tration-dependent manner. Various selective PDE inhibitors, vinpocetine (type 1), erythro -9-(2-hydroxy-3-nonyl)adenine (EHNA, type 2), milrinone (type 3), Ro20–1724 (type 4) and zaprinast (type 5), also inhibited CCh-induced contraction in a concentration-dependent manner. The rank order of potency of IC50 was zaprinast > Ro20–1724 > EHNA milrinone > vinpocetine. In the presence of CCh (0.3 M), vinpocetine, milrinone and Ro20–1724 increased cAMP, but not cGMP, contents. In contrast, zaprinast and EHNA both increased cGMP, but not cAMP, contents. This indicates that vinpocetine-, milrinone- and Ro20–1724-induced relaxation is correlated with cAMP, while EHNA- and zaprinast- induced relaxation is correlated with cGMP in porcine iris sphincter. KEY WORDS: cAMP, cGMP, iris sphincter, PDE inhibitor, smooth muscle. J. Vet. Med. Sci. 71(11): 1449–1453, 2009 Cyclic nucleotides are important secondary messengers, chol (CCh)-induced contraction of porcine iris sphincter and are associated with smooth muscle relaxation [7]. induced by selective PDE (type1–5) inhibitors.
    [Show full text]
  • General Pharmacology
    GENERAL PHARMACOLOGY Winners of “Nobel” prize for their contribution to pharmacology Year Name Contribution 1923 Frederick Banting Discovery of insulin John McLeod 1939 Gerhard Domagk Discovery of antibacterial effects of prontosil 1945 Sir Alexander Fleming Discovery of penicillin & its purification Ernst Boris Chain Sir Howard Walter Florey 1952 Selman Abraham Waksman Discovery of streptomycin 1982 Sir John R.Vane Discovery of prostaglandins 1999 Alfred G.Gilman Discovery of G proteins & their role in signal transduction in cells Martin Rodbell 1999 Arvid Carlson Discovery that dopamine is neurotransmitter in the brain whose depletion leads to symptoms of Parkinson’s disease Drug nomenclature: i. Chemical name ii. Non-proprietary name iii. Proprietary (Brand) name Source of drugs: Natural – plant /animal derivatives Synthetic/semisynthetic Plant Part Drug obtained Pilocarpus microphyllus Leaflets Pilocarpine Atropa belladonna Atropine Datura stramonium Physostigma venenosum dried, ripe seed Physostigmine Ephedra vulgaris Ephedrine Digitalis lanata Digoxin Strychnos toxifera Curare group of drugs Chondrodendron tomentosum Cannabis indica (Marijuana) Various parts are used ∆9Tetrahydrocannabinol (THC) Bhang - the dried leaves Ganja - the dried female inflorescence Charas- is the dried resinous extract from the flowering tops & leaves Papaver somniferum, P album Poppy seed pod/ Capsule Natural opiates such as morphine, codeine, thebaine Cinchona bark Quinine Vinca rosea periwinkle plant Vinca alkaloids Podophyllum peltatum the mayapple
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) 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. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • Selective Phosphodiesterase 4 Inhibitors
    Journal of Scientific & Indu strial Research Vol. 62, June 2003, pp 537-553 Selective Phosphodiesterase 4 Inhibitors - Emerging Trends in Astluna Therapy (Antiasthmatics-3) Ranju Gupta*, Oeepika Gandhi and Oharam Paul Jindal University In stitute of Pharmaceuti cal Sciences, Panjab Universit y, Chandigarh 160014 Considerable interest has been generated in th e potential utility of isozyme selective inhibitors of phosph odiesterases in the treatment of asthma and other inflali1matory disorders. Heterogeneity in ti ssue distribution as well as their different fun cti onal roles make these enzymes very attractive targets for medicinal chemi sts. To date at least II different fami lies of POE isozymes are known, among which POE 4 plays a major rol e in mod ul ating the activity of virtu ally all cell s involved in the inflammatory process. In hibitors of thi s enzyme family display impressive antiasthmatic ac ti vity by red ucing th e bronchial smooth mu scle tone and consid erable anti-inflammatory activity. The review details th e various classes of POE 4 inhibitors stru cturall y related to rolipram, nitraquazone and xa nthines, which appear to be very attractive models for synthesis of novel selecti ve POE 4 inhibitors potentially useful for the treatment of asthma and chronic obstructive pulmonary di seases. Rationale for the use of POE4 inhibitors in th e treatment of asthma is also discussed. Key words: Phosphodiesterase 4 inhibitors, Asthma therapy, Antiasthmatics, Isozyme, Rol ipram, Nitraquazonc. Xanthincs. Introduction Phosphodiesterase Superfamily There has been growing interest in recent years At least e leven different fami li es of POE tn the utility of selective phosphodiesterase (POE) isozymes are known based on the ir substrate inhibitors as novel targets for drug d iscovery.
    [Show full text]
  • Nivedita Singh
    Xanthine Based Inhibitors for Therapeutics Targeting Phosphodiesterase 9A A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BY NIVEDITA SINGH DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI GUWAHATI-781039, ASSAM, INDIA NOVEMBER 2016 Xanthine Based Inhibitors for Therapeutics Targeting Phosphodiesterase 9A A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BY NIVEDITA SINGH DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI GUWAHATI-781039, ASSAM, INDIA NOVEMBER 2016 TH-1894_11610615 TH-1894_11610615 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI DEPARTMENT OF BIOSCIENCE & BIOENGINEERING STATEMENT I do hereby declare that the matter embodied in this thesis entitled: “Xanthine based inhibitors for therapeutics targeting phosphodiesterase 9A”, is the result of investigations carried out by me in the Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, India, under the guidance of Dr. Sanjukta Patra and co-supervision of Prof. Parameswar Krishnan Iyer. In keeping with the general practice of reporting scientific observations, due acknowledgements have been made wherever the work described is based on the findings of other investigators. November, 2016 Ms. Nivedita Singh Roll No. 11610615 TH-1894_11610615 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI DEPARTMENT OF BIOSCIENCE & BIOENGINEERING CERTIFICATE It is certified that the work described in this thesis, entitled: “Xanthine based inhibitors for therapeutics targeting phosphodiesterase 9A”, done by Ms Nivedita Singh (Roll No: 11610615), for the award of degree of Doctor of Philosophy is an authentic record of the results obtained from the research work carried out under my supervision in the Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, India, and this work has not been submitted elsewhere for a degree.
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • Modulation of Th1/Th2 Cytokine Production by Selective And
    Pharmacological Reports Copyright © 2012 2012, 64, 179184 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences ModulationofTh1/Th2cytokineproduction byselectiveandnonselectivephosphodiesterase inhibitorsadministeredtomice MariannaSzczypka1,SebastianPloch2,Bo¿enaObmiñska-Mrukowicz1 1 2 DepartmentofBiochemistry,PharmacologyandToxicology, ITLab,FacultyofVeterinaryMedicine,Wroc³aw UniversityofEnvironmentalandLifeSciences,Norwida31, PL50-375Wroc³aw, Poland Correspondence: MariannaSzczypka,e-mail:[email protected] Abstract: Phosphodiesterase (PDE) inhibitors can modulate the functions of immune cells, including T lymphocytes, due to increased intracel- lular levels of cyclic nucleotides. The drugs (aminophylline, milrinone and sildenafil) were administered once or five times at 24 h intervalsatthefollowingdoses:20mg/kg, im,1mg/kg, im and1mg/kg, po,respectively. Th1 and Th2 cytokine levels (IL-2, IFN-g, IL-4, IL-5, TNF) were determined 12, 24 or 72 h after the last administration of the drugs. A commercial BDTM Cytometric Bead Array Mouse Th1/Th2 Cytokine Kit (CBA) was used to determine the levels of Th1/Th2 cy- tokinesintheserum. Neither of the PDE inhibitors under investigation administered once changed IFN-g, TNF and IL-4 production. A single dose of aminophyl- line decreased the production of IL-2 (after 12 h). A single dose of milrinone did not affect Th1/Th2 cytokine secretion. Sildenafil administered once decreased the production of IL-2 (after 72 h). Atemporary enhancement in the level of IL-5 was observed 12 h after a sin- gle dose of sildenafil. No changes in Th1 and Th2 cytokine production were observed after five doses of PDE inhibitors under investigation. These results indicate that nonstimulated lymphocytes Th1 and Th2 exhibited a slight sensitivity to aminophylline and sildenafil.
    [Show full text]
  • Phosphodiesterases As Therapeutic Targets for Respiratory Diseases
    University of Groningen Phosphodiesterases as therapeutic targets for respiratory diseases Zuo, Haoxiao; Cattani-Cavalieri, Isabella; Musheshe, Nshunge; Nikolaev, Viacheslav O; Schmidt, Martina Published in: Pharmacology & Therapeutics DOI: 10.1016/j.pharmthera.2019.02.002 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Zuo, H., Cattani-Cavalieri, I., Musheshe, N., Nikolaev, V. O., & Schmidt, M. (2019). Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacology & Therapeutics, 197, 225-242. https://doi.org/10.1016/j.pharmthera.2019.02.002 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Pharmacology & Therapeutics 197 (2019) 225–242 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Phosphodiesterases as therapeutic targets for respiratory diseases Haoxiao Zuo a,c,⁎, Isabella Cattani-Cavalieri a,b,d,NshungeMusheshea, Viacheslav O.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]