DOCSLIB.ORG

Detecting Spatial and Temporal Distributions of Lipids And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Detecting Spatial and Temporal Distributions of Lipids And DETECTING SPATIAL AND TEMPORAL DISTRIBUTIONS OF LIPIDS AND PROTEINS DURING EMBRYO IMPLANTATION BY MALDI IMAGING MASS SPECTROMETRY By Kristin Elizabeth Burnum Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Biochemistry December, 2008 Approved: Richard M. Caprioli H. Alex Brown Daniel C. Liebler Jennifer A. Pietenpol Michael R. Waterman This work is dedicated to my parents, Kathy and Steve, who gave me everything ii ACKNOWLEDGEMENTS I would like to thank my mentor, Richard Caprioli, for all his guidance and support throughout my graduate school career. To each of my committee members, Sudhansu K. Dey, H. Alex Brown, Daniel Liebler, Jennifer Pietenpol, and Michael Waterman, thank you for all your guidance and input to help progress this project to its successful completion. This work was supported in part by grants GM58008-9 and DOD W81XWH-05-1-0179 (RMC), HD12304 (SKD), U54 GM69338 (HAB). I would also like to acknowledge support from the NICHD Reproductive Biology Training Grant (2T HD007043-31A2) and the NCI Breast Cancer Research Training Grant (CA78136-07). iii TABLE OF CONTENTS Page DEDICATION ................................................................................................................................... ii ACKNOWLEDGMENTS ................................................................................................................... iii LIST OF TABLES ............................................................................................................................ vii LIST OF FIGURES ......................................................................................................................... viii LIST OF TECHNOLOGICAL ABBREVIATIONS ............................................................................... xi LIST OF BIOLOGICAL ABBREVIATIONS ....................................................................................... xii Chapter I. INTRODUCTION .......................................................................................................................... 1 A. Embryo Implantation ..................................................................................................... 1 B. Imaging Mass Spectrometry .......................................................................................... 2 i. The Technology ........................................................................................................ 4 ii. Reproducibility ......................................................................................................... 8 iii. Data processing and Analysis ................................................................................. 9 iv. Biological Applications of IMS ................................................................................ 10 a. Molecular Images of Disease .................................................................. 11 b. Proteome Response to Drug Administration ........................................... 14 c. In situ Proteomics .................................................................................... 16 d. Phospholipid Imaging .............................................................................. 18 e. New Insights into Biology ........................................................................ 20 C. Summary and Research Objectives ............................................................................. 21 II. STAGES OF MOUSE EMBRYO IMPLANTATION .................................................................... 31 iv III. DETECTING SPATIAL AND TEMPORAL DISTRIBUTIONS OF PHOSPHOLIPIDS DURING EMBRYO IMPLANTATION BY MALDI IMAGING MASS SPECTROMETRY ......................... 35 A. Overview ...................................................................................................................... 35 B. Introduction .................................................................................................................. 36 C. Results ......................................................................................................................... 38 i. Spatial remodeling of phospholipids during early pregnancy ................................... 38 ii. Determining the presence of isobaric ions (same nominal mass but different exact masses) in day 8 implantation sites by FTICR IMS ................................................ 41 iii. In-situ identification of phospholipids by tandem MS .............................................. 42 iv. Distinguishing spatial distribution of isobaric phospholipids (identical masses) in day 8 implantation sites by tandem IMS ................................................................. 42 v. Validation of MALDI IMS phospholipid expression patterns by liquid chromatography-electrospray ionization tandem MS quantitation .......................... 43 vi. Colocalization of arachidonate-containing phospholipids with cyclooxygenase 2 .. 44 D. Discussion .................................................................................................................... 45 E. Materials and Methods ................................................................................................. 47 F. Acknowledgements ...................................................................................................... 50 IV. DETECTING SPATIAL AND TEMPORAL DISTRIBUTIONS OF PROTEINS DURING EMBRYO IMPLANTATION BY MALDI IMAGING MASS SPECTROMETRY ......................... 67 A. Overview ...................................................................................................................... 67 B. Introduction .................................................................................................................. 67 C. Results ......................................................................................................................... 68 i. Protein signatures differ within specific regions of implantation and interimplantation sites ......................................................................................................................... 68 ii. Validation of MALDI IMS protein expression patterns ............................................. 71 a. Correlating protein images with mRNA localization using in situ___ hybridization ............................................................................................ 71 v b. Immunohistochemistry and activity assays confirm protein identification and spatial distribution ............................................................................. 72 c. Isotope Coded Affinity Tag (ICAT) based profiling confirms profiling and imaging mass spectrometry experimental results .................................... 73 iii. Exploring Protein Expression along the Z-axis of a day 6 implantation site ........... 74 iv. Characterizing differential proteome profiles in the Pla2g4a null mice ................... 74 D. Discussion .................................................................................................................... 76 E. Materials and Methods ................................................................................................. 79 F. Acknowledgements ...................................................................................................... 87 IV. CONCLUSIONS AND PERSPECTIVES .............................................................................. 102 A. Discussion of protein and phospholipid localization patterns during early pregnancy 102 B. Future outlook: advancements in IMS ....................................................................... 106 IV. REFERENCES ..................................................................................................................... 118 vi LIST OF TABLES Table Page 1. Assignment of lipid molecular species in MS/MS positive ion mode .................................. 63 2. Assignment of lipid molecular species in MS/MS negative ion mode ................................ 64 3. LC-ESI-MS/MS quantitation of phospholipids in the M and AM poles of day 8 implantation sites ................................................................................................................................... 65 4. Proteins which show differential expression patterns between the various cell types on day 6 of pregnancy ................................................................................................................. 100 vii LIST OF FIGURES Figure Page 1. Mouse embryo implantation ............................................................................................... 24 2. Scheme of a typical direct tissue imaging experiment ....................................................... 25 3. Imaging mass spectrometry analysis of a glioma tumor mouse brain ............................... 26 4. Whole-body protein analysis of rat sagittal tissue section by imaging mass spectrometry 27 5. Examples of on-tissue tryptic digestion and subsequent matrix-assisted laser desorption/ionization imaging mass spectrometry analysis ............................................... 28 6. Imaging mass spectrometry analysis of a sagittal mouse brain to determine the spatial localization of multiple phosphatidylcholine species .......................................................... 29 7. Optical images of a day 6 and day 8 pregnant mouse uterus along with the corresponding ion images ........................................................................................................................
Load more

Recommended publications
  • (Apis Mellifera) ELISABETH P
    J. Insect Ph.vsiol. Vol. 42, No. 9, pp. 823-828, 1996 Pergamon Copyright 0 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved PII: SOO22-1910(96)00045-5 0022-1910196 $15.00 + 0.00 Effects of Two Proteinase Inhibitors on the Digestive Enzymes and Survival of Honey Bees (Apis mellifera) ELISABETH P. J. BURGESS,*1 LOUISE A. MALONE,* JOHN T. CHRlSTELLERt Received I1 December 1995; revised und accepted 1 March 1996 Two endopeptidase inhibitors, BPTI (bovine pancreatic trypsin inhibitor) and SBTI (Kunitz soybean trypsin inhibitor), were found to significantly reduce the longevity of adult honey bees (&is mellifera L.) fed the inhibitors ad lib in sugar syrup at l.O%, 0.5% or O.l%, but not at 0.01% or 0.001% (w:v). Bees were taken from frames at emergence, kept in cages at 33”C, and provided with a pollen/protein diet, water and syrup. In vivo activity levels of three midgut endopeptidases (trypsin, chymotrypsin and elastase) and the exopeptidase leucine aminopeptidase (LAP) were determined in bees fed either BPTI or SBTI at l.O%, 0.3% or 0.1% (w:v) at two time points: the 8th day after emergence and when 75% of bees had died. LAP activity levels increased significantly in bees fed with either inhibitor at all concen- trations. At day 8, bees fed BPTI at all concentrations had significantly reduced levels of trypsin, chymotrypsin and elastase. At the time of 75% mortality, bees fed BPTI at each concentration had reduced trypsin levels, but only those fed the inhibitor at the highest dose level had reduced chymotrypsin or elastase activity.
    [Show full text]
  • Human Placenta Exosomes: Biogenesis, Isolation, Composition, and Prospects for Use in Diagnostics
    International Journal of Molecular Sciences Review Human Placenta Exosomes: Biogenesis, Isolation, Composition, and Prospects for Use in Diagnostics Evgeniya E. Burkova 1,* , Sergey E. Sedykh 1,2 and Georgy A. Nevinsky 1,2 1 SB RAS Institute of Chemical Biology and Fundamental Medicine, 630090 Novosibirsk, Russia; [email protected] (S.E.S.); [email protected] (G.A.N.) 2 Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia * Correspondence: [email protected]; Tel.: +7-(383)-363-51-27 Abstract: Exosomes are 40–100 nm nanovesicles participating in intercellular communication and transferring various bioactive proteins, mRNAs, miRNAs, and lipids. During pregnancy, the placenta releases exosomes into the maternal circulation. Placental exosomes are detected in the maternal blood even in the first trimester of pregnancy and their numbers increase significantly by the end of pregnancy. Exosomes are necessary for the normal functioning of the placenta and fetal development. Effects of exosomes on target cells depend not only on their concentration but also on their intrinsic components. The biochemical composition of the placental exosomes may cause various complications of pregnancy. Some studies relate the changes in the composition of nanovesicles to placental dysfunction. Isolation of placental exosomes from the blood of pregnant women and the study of protein, lipid, and nucleic composition can lead to the development of methods for early diagnosis of pregnancy pathologies. This review describes the biogenesis of exosomes, methods Citation: Burkova, E.E.; Sedykh, S.E.; of their isolation, analyzes their biochemical composition, and considers the prospects for using Nevinsky, G.A. Human Placenta exosomes to diagnose pregnancy pathologies.
    [Show full text]
  • Treatment Protocol Copyright © 2018 Kostoff Et Al
    Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention.
    [Show full text]
  • Combined Neprilysin and Renin–Angiotensin System Inhibition in Heart Failure with Reduced Ejection Fraction: a Meta-Analysis
    European Journal of Heart Failure (2016) doi:10.1002/ejhf.603 Combined neprilysin and renin–angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis Scott D. Solomon1*, Brian Claggett1, John J.V. McMurray2, Adrian F. Hernandez3, and Gregg C. Fonarow4 1Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2University of Glasgow, Glasgow, UK; 3Duke University, Durham, NC, USA; and 4Ronald Reagan-UCLA Medical Center, Los Angeles, CA, USA Received 1 March 2016; revised 25 May 2016; accepted 3 June 2016 Aims The combined neprilysin/renin–angiotensin system (RAS) inhibitor sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization, cardiovascular death, and all-cause mortality in a large outcomes trial. While sacubitril/valsartan is the only currently available drug in its class, there are two prior clinical trials in heart failure with omapatrilat, another combined neprilysin/RAS inhibitor. Using all available evidence can inform clinicians and policy-makers. ..................................................................................................................................................................... Methods We performed a meta-analysis using data from three trials in heart failure with reduced EF that compared combined and results neprilysin/RAS inhibition with RAS inhibition alone and reported clinical outcomes: IMPRESS (n = 573), OVERTURE (n = 5770), and PARADIGM-HF (n = 8399). We assessed the pooled hazard ratio (HR) for all-cause death or heart failure hospitalization, and for all-cause mortality in random-effects models, comparing combined neprilysin/RAS inhibition with ACE inhibition alone. The composite outcome of death or heart failure hospitalization was reduced numerically in patients receiving combined neprilysin/RAS inhibition in all three trials, with a pooled HR of 0.86, 95% confidence interval (CI) 0.76–0.97, P = 0.013.
    [Show full text]
  • Metabolic Actions of Natriuretic Peptides and Therapeutic Potential in the Metabolic Syndrome
    Pharmacology & Therapeutics 144 (2014) 12–27 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: G. Eisenhofer Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome Nina Schlueter a,AnitadeSterkea, Diana M. Willmes a, Joachim Spranger a, Jens Jordan b,AndreasL.Birkenfelda,⁎ a Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Charité, University School of Medicine, Berlin, Germany b Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany article info abstract Available online 27 April 2014 Natriuretic peptides (NPs) are a group of peptide-hormones mainly secreted from the heart, signaling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure Keywords: as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including Natriuretic peptides activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white ANP adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect BNP against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive Insulin resistance heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement Diabetes fi Obesity of NP in the pathophysiology of metabolic disease. Based upon these ndings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications.
    [Show full text]
  • 904 Genetics of Human Complement Component C4
    [Frontiers in Bioscience 6, d904-913, August 1, 2001] GENETICS OF HUMAN COMPLEMENT COMPONENT C4 AND EVOLUTION THE CENTRAL MHC O. Patricia Martinez,1 Natalie Longman-Jacobsen,1 Richard Davies,1 Erwin K. Chung,2 Yan Yang,2 Silvana Gaudieri,1 Roger L. Dawkins,1 and C. Yung Yu2 1 Centre for Molecular Immunology and Instrumentation, University of Western Australia, PO Box 5100, Canning Vale WA 6155, Australia, 2 Children’s Research Institute, Columbus, Ohio, and Department of Pediatrics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 700 Children’s Drive, Columbus Ohio 43205 TABLE OF CONTENTS 1. Abstract 2. The Genetic Diversity and the Nomenclature of Human C4A and C4B 3. Evolution of the MHC-Complement Proteins and the Central MHC 4. Paralogy Mapping Could Help Identify Candidate Genes for MHC – Associated Diseases: Prospects for the Central MHC 5. Acknowledgments 6. References 1. ABSTRACT 2. THE GENETIC DIVERSITY AND THE NOMENCLATURE OF HUMAN C4A AND C4B The two classes of human complement The human complement component C4 is one of component C4 proteins C4A and C4B manifest differential the most complex and polymorphic molecules. The chemical reactivities and binding affinities towards target activated product of C4, C4b, is a non-catalytic subunit C3 surfaces and complement receptor CR1. There are multiple, and C5 convertase in the classical and lectin pathways polymorphic allotypes of C4A and C4B proteins. A (reviewed in refs. 1, 2). Downstream of C4, the complex multiplication pattern of C4A and C4B genes with complement pathway includes the generation of variations in gene size, gene dosage and flanking genes anaphylatoxins C3a and C5a, and the assembly of the exists in the population.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,342,350 B1 Tanzi Et Al
    USOO6342350B1 (12) United States Patent (10) Patent No.: US 6,342,350 B1 Tanzi et al. (45) Date of Patent: Jan. 29, 2002 (54) ALPHA-2-MACROGLOBULIN DIAGNOSTIC with Chinese late onset Alzheimer's Disease,” Neuroscience TEST Letters 269:173–177 (1999). Dodel, R.C., et al., “C-2 Macroglobulin and the Risk of (75) Inventors: Rudolph E. Tanzi, Hull; Bradley T. Alzheimer's Disease,” Neurology 54:438-442 (2000). Hyman, Swampscott; George W. Dow, D.J., et al., “C-2 Macroglobulin Polymorphism and Rebeck, Somerville; Deborah L. Alzheimer Disease risk in the UK,” Nature Genetics Blacker, Newton, all of MA (US) 22:16–17 (May 1999). (73) Assignee: The General Hospital Corporation, Du, Y., et al., “c-Macroglobulin Attenuates B-Amyloid Boston, MA (US) Peptide 1-40 Fibril Formation and Associated Neurotoxicity of Cultured Fetal Rat Cortical Neurons,” J. of Neurochem. (*) Notice: Subject to any disclaimer, the term of this 70: 1182–1188 (1998). patent is extended or adjusted under 35 Gauderman, W.J., et al., “Family-Based Association Stud U.S.C. 154(b) by 0 days. ies.” Monogr: Natl. Canc. Inst. 26:31-37 (1999). Hampe, J., et al., “Genes for Polygenic Disorders: Consid (21) Appl. No.: 09/148,503 erations for Study Design in the Complex Trait of Inflam (22) Filed: Sep. 4, 1998 matory Bowel Disease,” Hum. Hered 50:91-101 (Mar.-Apr. 2000). Related U.S. Application Data Horvath, S., and Laird, N.M., “A Discordant-Sibship Test (60) Provisional application No. 60/093,297, filed on Jul. 17, for Disequilibrium and Linkage: No Need for Parental 1998, and provisional application No.
    [Show full text]
  • The Evolution of Heart Failure with Reduced Ejection Fraction Pharmacotherapy: What Do We Have and Where Are We Going?
    Pharmacology & Therapeutics 178 (2017) 67–82 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: M. Curtis The evolution of heart failure with reduced ejection fraction pharmacotherapy: What do we have and where are we going? Ahmed Selim, Ronald Zolty, Yiannis S. Chatzizisis ⁎ Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, NE, USA article info abstract Available online 21 March 2017 Cardiovascular diseases represent a leading cause of mortality and increased healthcare expenditure worldwide. Heart failure, which simply describes an inability of the heart to meet the body's needs, is the end point for many Keywords: other cardiovascular conditions. The last three decades have witnessed significant efforts aiming at the discovery Heart failure of treatments to improve the survival and quality of life of patients with heart failure; many were successful, Reduced ejection fraction while others failed. Given that most of the successes in treating heart failure were achieved in patients with re- Pharmacotherapy duced left ventricular ejection fraction (HFrEF), we constructed this review to look at the recent evolution of Novel drugs HFrEF pharmacotherapy. We also explore some of the ongoing clinical trials for new drugs, and investigate poten- tial treatment targets and pathways that might play a role in treating HFrEF in the future. © 2017 Elsevier Inc. All rights reserved. Contents 1. Introduction..............................................
    [Show full text]
  • Expression of POMC, Detection of Precursor Proteases, and Evidence
    ORIGINAL ARTICLE See related commentary on page 1934 Human Mast Cells in the Neurohormonal Network: Expression of POMC, Detection of Precursor Proteases, and Evidence for IgE-Dependent Secretion of a-MSH Metin Artuc1, Markus Bo¨hm2, Andreas Gru¨tzkau1, Alina Smorodchenko1, Torsten Zuberbier1, Thomas Luger2 and Beate M. Henz1 Human mast cells have been shown to release histamine in response to the neuropeptide a-melanocyte- stimulating hormone (a-MSH), but it is unknown whether these cells express proopiomelanocortin (POMC) or POMC-derived peptides. We therefore examined highly purified human skin mast cells and a leukemic mast cell line-1 (HMC-1) for their ability to express POMC and members of the prohormone convertase (PC) family known to process POMC. Furthermore, we investigated whether these cells store and secrete a-MSH. Reverse transcriptase-PCR (RT-PCR) analysis revealed that both skin mast cells and HMC-1 cells express POMC mRNA and protein. Expression of the POMC gene at the RNA level in HMC-1 cells could be confirmed by Northern blotting. Transcripts for both PC1 and furin convertase were detectable in skin-derived mast cells and HMC-1 cells, as shown by RT-PCR. In contrast, PC2 transcripts were detected only in skin mast cells, whereas transcripts for paired basic amino acid converting enzyme 4 (PACE4) were present only in HMC-1 cells. Radio- immunoassays performed on cell lysates and cell culture supernatants from human skin-derived mast cells disclosed immunoreactive amounts of a-MSH in both fractions. Stimulation with an anti-IgE antibody significantly reduced intracellular a-MSH and increased extracellular levels, indicating IgE-mediated secretion of this neuropeptide.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub
    US 20110263526A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub. Date: Oct. 27, 2011 (54) NITRICOXIDE RELEASING PRODRUGS OF CD7C 69/96 (2006.01) THERAPEUTICAGENTS C07C 319/22 (2006.01) CD7C 68/02 (2006.01) (75) Inventor: Apparao SATYAM, Mumbai (IN) A6IP 29/00 (2006.01) A6IP 9/00 (2006.01) (73) Assignee: PIRAMAL LIFE SCIENCES A6IP37/08 (2006.01) LIMITED, Mumbai (IN) A6IP35/00 (2006.01) A6IP 25/24 2006.O1 (21) Appl. No.: 13/092.245 A6IP 25/08 308: A6IP3L/04 2006.O1 (22) Filed: Apr. 22, 2011 A6IP3L/2 308: Related U.S. Application Data 39t. O 308: (60) Provisional application No. 61/327,175, filed on Apr. A6IP3/10 (2006.01) 23, 2010. A6IPL/04 (2006.01) A6IP39/06 (2006.01) Publication Classification A6IP3/02 (2006.01) (51) Int. Cl. A6IP 9/06 (2006.01) A 6LX 3L/7072 (2006.01) 39t. W 308: A6 IK3I/58 (2006.01) A6IP II/08 (2006.015 A6 IK3I/55 (2006.01) A63/62 (2006.015 A6 IK 3/495 (2006.01) A6 IK 3/4439 (2006.01) (52) U.S. Cl. ........... 514/50: 514/166; 514/172: 514/217; A6 IK 3L/455 (2006.01) 514/255.04: 514/338; 514/356; 514/412; A6 IK 3/403 (2006.01) 514/420; 514/423: 514/510,536/28.53:540/67; A6 IK 3/404 (2006.01) 540/591; 544/396; 546/273.7: 546/318: 548/452: A6 IK 3/40 (2006.01) 548/500: 548/537; 549/464; 558/275 A6 IK3I/265 (2006.01) C7H 9/06 (2006.01) (57) ABSTRACT CO7I 71/00 (2006.01) CO7D 22.3/26 (2006.01) The present invention relates to nitric oxide releasing pro C07D 295/14 (2006.01) drugs of known drugs or therapeutic agents which are repre CO7D 40/12 (2006.01) sented herein as compounds of formula (I) wherein the drugs CO7D 213/80 (2006.01) or therapeutic agents contain one or more functional groups C07D 209/52 (2006.01) independently selected from a carboxylic acid, an amino, a CO7D 209/26 (2006.01) hydroxyl and a sulfhydryl group.
    [Show full text]
  • The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis
    REVIEW published: 07 August 2015 doi: 10.3389/fimmu.2015.00387 The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis Yannick Waumans, Lesley Baerts, Kaat Kehoe, Anne-Marie Lambeir and Ingrid De Meester* Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium Edited by: Research from over the past 20 years has implicated dipeptidyl peptidase (DPP) IV and Heidi Noels, its family members in many processes and different pathologies of the immune system. RWTH Aachen University, Germany Jürgen Bernhagen, Most research has been focused on either DPPIV or just a few of its family members. It is, RWTH Aachen University, Germany however, essential to consider the entire DPP family when discussing any one of its mem- Reviewed by: bers. There is a substantial overlap between family members in their substrate specificity, Rafael Franco, University of Barcelona, Spain inhibitors, and functions. In this review, we provide a comprehensive discussion on the Catherine Anne Abbott, role of prolyl-specific peptidases DPPIV, FAP, DPP8, DPP9, dipeptidyl peptidase II, prolyl Flinders University, Australia carboxypeptidase, and prolyl oligopeptidase in the immune system and its diseases. We Mark Gorrell, University of Sydney, Australia highlight possible therapeutic targets for the prevention and treatment of atherosclerosis, *Correspondence: a condition that lies at the frontier between inflammation
    [Show full text]
  • Does the Use of Protease Inhibitors Further Improve in Vivo Distribution?
    Targeting of the Cholecystokinin-2 Receptor with the Minigastrin Analog 177Lu-DOTA-PP-F11N: Does the Use of Protease Inhibitors Further Improve In Vivo Distribution? Alexander W. Sauter*1,2, Rosalba Mansi*3, Ulrich Hassiepen4, Lionel Muller4, Tania Panigada4, Stefan Wiehr2, Anna-Maria Wild2, Susanne Geistlich5, Martin B´eh´e5, Christof Rottenburger1, Damian Wild1, and Melpomeni Fani3 1Division of Nuclear Medicine, University Hospital Basel, Basel, Switzerland; 2Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tuebingen, Germany; 3Division of Radiopharmaceutical Chemistry, University Hospital Basel, Basel, Switzerland; 4Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, Basel, Switzerland; and 5Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland performance of 177Lu-DOTA-MG11 in the presence of inhibitors. The Patients with metastatic medullary thyroid cancer (MTC) have limited human application of single compounds without unessential additives systemic treatment options. The use of radiolabeled gastrin analogs is preferable. Preliminary clinical data spotlight the stomach as a po- targeting the cholecystokinin-2 receptor (CCK2R) is an attractive tential dose-limiting organ besides the kidneys. approach. However, their therapeutic efficacy is presumably decreased Key Words: medullary thyroid cancer; cholecystokinin-2 receptor; by their enzymatic degradation in vivo. We aimed to investigate whether gastrin; peptide receptor radionuclide therapy; 177Lu-DOTA-PP-F11N 177 177 the chemically stabilized analog Lu-DOTA-PP-F11N ( Lu-DOTA- J Nucl Med 2019; 60:393–399 (DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) performs better than refer- DOI: 10.2967/jnumed.118.207845 ence analogs with varying in vivo stability, namely 177Lu-DOTA-MG11 177 177 ( Lu-DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2)and Lu-DOTA- 177 PP-F11 ( Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), and whether the use of protease inhibitors further improves CCKR2 targeting.
    [Show full text]