Effect of Cyanide by Sodium Nitroprusside (SNP)
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A Proposed Method for Noninvasive Assessment of Endothelial Damange Kirsten Menn
Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 11-15-2006 A Proposed Method for Noninvasive Assessment of Endothelial Damange Kirsten Menn Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Recommended Citation Menn, Kirsten, "A Proposed Method for Noninvasive Assessment of Endothelial Damange" (2006). Yale Medicine Thesis Digital Library. 272. http://elischolar.library.yale.edu/ymtdl/272 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. A PROPOSED METHOD FOR NONINVASIVE ASSESSMENT OF ENDOTHELIAL DAMAGE A Thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the Degree of Doctor of Medicine By Kirsten Alexandra Menn 2006 Abstract A PROPOSED METHOD FOR NONINVASIVE ASSESSMENT OF ENDOTHELIAL DAMAGE Kirsten A. Menn, Robert B. Schonberger, William L. Worden, Kaveh Shahmohammadi, Tyler J. Silverman, Robert Stout, Kirk Shelley, David G. Silverman, Department of Anesthesiology, Yale University, School of Medicine, New Haven, CT. Transdermal microvascular studies of endothelial cell function have typically used iontophoresis to facilitate acetylcholine absorption, but iontophoresis introduces an important confounding stimulus that can alter the behavior of the microvasculature. This study examines a non-iontophoretic technique for transdermal microvascular studies using acetylcholine and nitroglycerin and demonstrates a relatively impaired vasodilatory response to these substances in a population with known microvascular pathology. -
View, the Catalytic Center of Bnoss Is Almost Identical to Mnos Except That a Conserved Val Near Heme Iron in Mnos Is Substituted by Iie[25]
STUDY OF ELECTRON TRANSFER THROUGH THE REDUCTASE DOMAIN OF NEURONAL NITRIC OXIDE SYNTHASE AND DEVELOPMENT OF BACTERIAL NITRIC OXIDE SYNTHASE INHIBITORS YUE DAI Bachelor of Science in Chemistry Wuhan University June 2008 submitted in partial fulfillment of requirements for the degree DOCTOR OF PHILOSOPHY IN CLINICAL AND BIOANALYTICAL CHEMISTRY at the CLEVELAND STATE UNIVERSITY July 2016 We hereby approve this dissertation for Yue Dai Candidate for the Doctor of Philosophy in Clinical-Bioanalytical Chemistry Degree for the Department of Chemistry and CLEVELAND STATE UNIVERSITY’S College of Graduate Studies by Dennis J. Stuehr. PhD. Department of Pathobiology, Cleveland Clinic / July 8th 2016 Mekki Bayachou. PhD. Department of Chemistry / July 8th 2016 Thomas M. McIntyre. PhD. Department of Cellular and Molecular Medicine, Cleveland Clinic / July 8th 2016 Bin Su. PhD. Department of Chemistry / July 8th 2016 Jun Qin. PhD. Department of Molecular Cardiology, Cleveland Clinic / July 8th 2016 Student’s Date of Defense: July 8th 2016 ACKNOWLEDGEMENT First I would like to express my special appreciation and thanks to my Ph. D. mentor, Dr. Dennis Stuehr. You have been a tremendous mentor for me. It is your constant patience, encouraging and support that guided me on the road of becoming a research scientist. Your advices on both research and life have been priceless for me. I would like to thank my committee members - Professor Mekki Bayachou, Professor Bin Su, Dr. Thomas McIntyre, Dr. Jun Qin and my previous committee members - Dr. Donald Jacobsen and Dr. Saurav Misra for sharing brilliant comments and suggestions with me. I would like to thank all our lab members for their help ever since I joint our lab. -
Protein S-Nitrosylation: Methods of Detection and Cellular Regulation
Protein S-Nitrosylation: Methods of Detection and Cellular Regulation by Michael Tcheupdjian Forrester Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Jonathan S. Stamler, MD (Supervisor) ___________________________ Irwin Fridovich, PhD ___________________________ K. V. Rajagopalan, PhD ___________________________ Dennis J. Thiele, PhD ___________________________ Eric J. Toone, PhD Dissertation submitted in partial fulfillment of the requirements for the degree of doctor of philosophy in the Department of Biochemistry in the Graduate School of Duke University 2009 i v ABSTRACT Protein S-Nitrosylation: Methods of Detection and Cellular Regulation by Michael Tcheupdjian Forrester Department of Biochemistry Duke University Date:_______________________ Approved: ___________________________ Jonathan S. Stamler, MD (Supervisor) ___________________________ Irwin Fridovich, PhD ___________________________ K. V. Rajagopalan, PhD ___________________________ Dennis J. Thiele, PhD ___________________________ Eric J. Toone, PhD An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of doctor of philosophy in the Department of Biochemistry in the Graduate School of Duke University 2009 i v Copyright by Michael T. Forrester 2009 Abstract Protein S-nitrosylation—the post-translational modification of cysteine thiols into S-nitrosothiols—is a principle mechanism of nitric oxide-based signaling. Studies have demonstrated myriad roles for S-nitrosylation in organisms from bacteria to humans, and recent efforts have begun to elucidate how this redox-based modification is regulated during physiological and pathophysiological conditions. This doctoral thesis is focused on the 1) analysis of existing methodologies for the detection of protein S-nitrosylation; 2) development of new methodologies for the detection of protein S-nitrosylation and 3) discovery of novel enzymatic mechanisms by which S-nitrosylation is regulated in vivo. -
Electrochemical Measurement of Nitric Oxide from Biological Systems
ELECTROCHEMICAL MEASUREMENT OF NITRIC OXIDE FROM BIOLOGICAL SYSTEMS Rebecca Anne Hunter A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry (Analytical Chemistry). Chapel Hill 2014 Approved by: Mark H. Schoenfisch Royce W. Murray James W. Jorgenson Bruce A. Cairns Robert Maile © 2014 Rebecca Anne Hunter ALL RIGHTS RESERVED ii ABSTRACT REBECCA ANNE HUNTER: Electrochemical Detection of Nitric Oxide from Biological Systems (Under the direction of Mark H. Schoenfisch) Nitric oxide (NO) is known to be involved in a number of physiological processes, including the immune response. As such, its role in severe infection and sepsis has been investigated, but previous measurement techniques have relied on complicated instrumentation or the quantification of NO byproducts (e.g., nitrate and nitrite). Herein, the fabrication of a microfluidic amperometric sensor for the direct detection of NO in whole blood is described. These sensors were used to evaluate the potential of NO and nitrosothiols (a stable transporter) as prognostic and/or diagnostic biomarkers for infection and sepsis. The microfluidic devices facilitated the selective electrochemical measurement of NO in small volumes of blood at the point-of-care, with adequate sensitivity and limits of detection achieved in buffer, wound fluid, and whole blood. A green (530 nm) light-emitting diode was coupled to the device to enable photolysis of S-nitrosothiol species with subsequent NO detection. While inefficient photolysis prevented the measurement of nitrosothiols in whole blood, detection in serum was achieved. -
Nitric Oxide: a Key Regulator of Myeloid Inflammatory Cell Apoptosis
Cell Death and Differentiation (2003) 10, 418–430 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd Review Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis Introduction EL Taylor*,1, IL Megson2, C Haslett1 and AG Rossi1 The free radical nitric oxide (NO) was first discovered as an 1 Centre for Inflammation Research, Rayne Laboratory, University of Edinburgh, endogenous vasodilator released from the endothelium to Medical School, Teviot Place, Edinburgh EH8 9AG, UK regulate vascular tone.1 However, it is now known that NO is a 2 Centre for Cardiovascular Science, University of Edinburgh, Hugh Robson key mediator in a great number of physiological and Building, George Square, Edinburgh EH8 9XD, UK pathophysiological processes (see Quinn).2 This ubiquitous * Corresponding author: EL Taylor, Centre for Inflammation Research, Rayne Laboratory, University of Edinburgh, Medical School, Teviot Place, Edinburgh signalling molecule can regulate the rate of apoptosis, or EH8 9AG, UK. Tel.: +44 131 651 1323; Fax: +44 131 650 4384; programmed cell death, in many cell types, including human E-mail: [email protected] inflammatory cells. Whether or not cells undergo apoptosis depends on the net balance of a large number of pro- versus Received 30.4.02; revised 29.8.02; accepted 2.9.02 antiapoptotic factors. Studies have revealed that NO Edited by G. Melino has both pro and antiapoptotic properties, depending largely on the concentration and flux of NO, and the cell type under scrutiny (for reviews, see Nicotera et al.3 and Kim et Abstract al.4). -
Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics
Review Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics Joel Mintz 1,†, Anastasia Vedenko 2,†, Omar Rosete 3 , Khushi Shah 4, Gabriella Goldstein 5 , Joshua M. Hare 2,6,7 , Ranjith Ramasamy 3,6,* and Himanshu Arora 2,3,6,* 1 Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA; [email protected] 2 John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] (A.V.); [email protected] (J.M.H.) 3 Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] 4 College of Arts and Sciences, University of Miami, Miami, FL 33146, USA; [email protected] 5 College of Health Professions and Sciences, University of Central Florida, Orlando, FL 32816, USA; [email protected] 6 The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA 7 Department of Medicine, Cardiology Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA * Correspondence: [email protected] (R.R.); [email protected] (H.A.) † These authors contributed equally to this work. Abstract: Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumori- Citation: Mintz, J.; Vedenko, A.; genic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the Rosete, O.; Shah, K.; Goldstein, G.; level of production, the oxidative/reductive (redox) environment in which this radical is generated, Hare, J.M; Ramasamy, R.; Arora, H. -
A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca2+ Waves in Glia
The Journal of Neuroscience, March 1, 2000, 20(5):1767–1779 A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca2؉ Waves in Glia Nicholas J. Willmott, Kay Wong, and Anthony J. Strong Department of Clinical Neuroscience, Institute of Psychiatry, King’s College London, London SE5 8AF In this study, we highlight a role for the nitric oxide–cGMP- NO to cells, indicating that NO also induces Ca 2ϩ influx in glia. dependent protein kinase (NO–G-kinase) signaling pathway in Mechanical stress of individual glial cells resulted in an increase glial intercellular Ca 2ϩ wave initiation and propagation. Addi- in intracellular NO in target and neighboring cells and intercel- 2ϩ tion of the NO donor molsidomine (100–500 M) or puffing lular Ca waves, which were NO, cGMP, and G-kinase depen- aqueous NO onto primary glial cell cultures evoked an increase dent, because incubating cells with nitric oxide synthase, guan- 2ϩ 2ϩ in [Ca ]i in individual cells and also local intercellular Ca ylate cyclase, and G-kinase inhibitors, or NO scavengers, 2ϩ ⌬ 2ϩ 2ϩ waves, which persisted after removal of extracellular Ca . reduced [Ca ]i and the rate of Ca wave propagation in High concentrations of ryanodine (100–200 M) and antago- these cultures. Results from this study suggest that NO–G- nists of the NO–G-kinase signaling pathway essentially abro- kinase signaling is coupled to Ca 2ϩ mobilization and influx in 2ϩ gated the NO-induced increase in [Ca ]i , indicating that NO glial cells and that this pathway plays a fundamental role in the mobilizes Ca 2ϩ from a ryanodine receptor-linked store, via the generation and propagation of intercellular Ca 2ϩ waves in glia. -
Identification of S-Nitrosylation Motifs by Site-Specific Mapping of the S-Nitrosocysteine Proteome in Human Vascular Smooth Muscle Cells
Identification of S-nitrosylation motifs by site-specific mapping of the S-nitrosocysteine proteome in human vascular smooth muscle cells Todd M. Greco*, Roberto Hodara*, Ioannis Parastatidis*, Harry F. G. Heijnen†, Michelle K. Dennehy‡, Daniel C. Liebler‡, and Harry Ischiropoulos*§ *Stokes Research Institute and Departments of Pediatrics and Pharmacology, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104; †Thrombosis and Haemostasis Laboratory, Department of Cell Biology, University Medical Center Utrecht, and Institute for Biomembranes, 3584 CH, Utrecht, The Netherlands; and ‡Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232 Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved March 22, 2006 (received for review January 27, 2006) S-nitrosylation, the selective modification of cysteine residues in critical roles for nitric oxide, the targets of S-nitrosylation in proteins to form S-nitrosocysteine, is a major emerging mechanism vascular smooth muscle cells are largely unknown. To that end, by which nitric oxide acts as a signaling molecule. Even though proteomic approaches are highly informative in providing a global nitric oxide is intimately involved in the regulation of vascular assessment of the modified proteins in cells and tissues. smooth muscle cell functions, the potential protein targets for Proteomic approaches based on the biotin-switch method have nitric oxide modification as well as structural features that underlie been used to identify potential targets of S-nitrosylation in various the specificity of protein S-nitrosocysteine formation in these cells model systems including murine brain tissue (15) and RAW 264.7 remain unknown. -
Regulation of the Glutamate/Glutamine Cycle by Nitric Oxide in the Central Nervous System
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2015 Regulation of the Glutamate/glutamine Cycle by Nitric Oxide in the Central Nervous System Karthik Anderson Raju University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biochemistry Commons, Biology Commons, and the Neuroscience and Neurobiology Commons Recommended Citation Raju, Karthik Anderson, "Regulation of the Glutamate/glutamine Cycle by Nitric Oxide in the Central Nervous System" (2015). Publicly Accessible Penn Dissertations. 1962. https://repository.upenn.edu/edissertations/1962 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1962 For more information, please contact [email protected]. Regulation of the Glutamate/glutamine Cycle by Nitric Oxide in the Central Nervous System Abstract Nitric oxide (˙NO) is a critical contributor to glutamatergic neurotransmission in the central nervous system (CNS). Much of its influence is due ot the ability of this molecule to regulate protein structure and function through its posttranslational modification of cysteine esidues,r a process known as S- nitrosylation. However, little is known about the extent of this modification and its associated functional effects in the brain under physiological conditions. We employed mass spectrometry (MS)-based methodologies to interrogate the S-nitrosocysteine proteome in wild-type (WT), neuronal nitric oxide synthase-deficient (nNOS-/-), -
NCX-4040, a Unique Nitric Oxide Donor, Induces Reversal of Drug-Resistance in Both ABCB1- and ABCG2-Expressing Multidrug Human Cancer Cells
cancers Article NCX-4040, a Unique Nitric Oxide Donor, Induces Reversal of Drug-Resistance in Both ABCB1- and ABCG2-Expressing Multidrug Human Cancer Cells Birandra K. Sinha 1,*, Lalith Perera 2 and Ronald E. Cannon 1 1 Laboratory of Toxicology and Toxicokinetic, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; [email protected] 2 Laboratory of Genome Integrity and Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-984287-3382 Simple Summary: Development of resistance to chemotherapeutics during the treatment of human cancers is a serious problem in the clinic, resulting in a poor treatment outcome and survival. It is believed that overexpression of ABC efflux proteins (e.g., P-gp/ABCB1, BCRP/ABCG2 and MRP/ABCC1) on the tumor cell membrane is one of the main mechanisms for this clinical resistance. Our recent studies indicate that nitric oxide (NO), inhibits ATPase functions of ABC transporters, resulting in reversal of resistance to various anticancer drugs. In this study we have found that nitric oxide and/or active metabolite (s) generated from NCX4040, a nitric oxide donor, inhibited ABC transporter activities by inhibiting their ATPase functions, causing reversal of both adriamycin and topotecan resistance in human MDR tumor cells. We also found that nitric oxide and/or metabolites of NCX4040 significantly enhanced drug accumulations in MDR tumor cells. These Citation: Sinha, B.K.; Perera, L.; studies strongly suggest that tumor specific nitric oxide donors that deliver high amounts of nitric Cannon, R.E. -
Non-Canonical Chemical Feedback Self-Limits Nitric Oxide-Cyclic GMP Signaling in Health and Disease Vu Thao-Vi Dao1,2,9, Mahmoud H
www.nature.com/scientificreports OPEN Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease Vu Thao-Vi Dao1,2,9, Mahmoud H. Elbatreek1,3,9 ✉ , Martin Deile4, Pavel I. Nedvetsky5, Andreas Güldner6, César Ibarra-Alvarado7, Axel Gödecke8 & Harald H. H. W. Schmidt1 ✉ Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This efect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP- dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in- vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation. Te nitric oxide (NO)-cGMP signaling pathway plays several essential roles in physiology, including cardio- pulmonary homeostasis1,2. -
Soluble Guanylate Cyclase As an Alternative Target for Bronchodilator
Soluble guanylate cyclase as an alternative target for PNAS PLUS bronchodilator therapy in asthma Arnab Ghosha, Cynthia J. Koziol-Whiteb, Kewal Asosingha, Georgina Chenga, Lisa Ruplea, Dieter Gronebergc, Andreas Friebec, Suzy A. A. Comhaira, Johannes-Peter Staschd, Reynold A. Panettieri Jr.b, Mark A. Aronicaa,e, Serpil C. Erzuruma,e,1, and Dennis J. Stuehra,1 aDepartment of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; bRutgers Institute for Translational Medicine & Science, Rutgers University, New Brunswick, NJ 08901; cInstitute of Vegetative Physiology, Universität Würzburg, Wuerzburg 97070, Germany; dPharma Research Centre, Bayer Pharma AG, D-42096 Wuppertal, Germany; and eRespiratory Institute, Cleveland Clinic, Cleveland, OH 44195 Edited by Louis J. Ignarro, University of California, Los Angeles School of Medicine, Beverly Hills, CA, and approved March 11, 2016 (received for review December 10, 2015) Asthma is defined by airway inflammation and hyperresponsive- S1). Graded doses of the slow-release NO donor DETA/NO ness, and contributes to morbidity and mortality worldwide. Although [3,3-Bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene] produced bron- bronchodilation is a cornerstone of treatment, current bronchodilators chodilation in human PCLS similar to what was induced by a become ineffective with worsening asthma severity. We investigated standard β-agonist bronchodilator, Formoterol (Fig. 1B). In ad- an alternative pathway that involves activating the airway smooth dition, having a NO donor (sodium nitroprusside, SNP) present at a muscle enzyme, soluble guanylate cyclase (sGC). Activating sGC by its subeffective concentration made the preconstricted human small natural stimulant nitric oxide (NO), or by pharmacologic sGC agonists airways more responsive to lower doses of the β-agonist broncho- – – BAY 41 2272 and BAY 60 2770, triggered bronchodilation in normal dilator Isoproterenol (Fig.