Helix 8 Is the Essential Structural Motif of Mechanosensitive Gpcrs
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Non-Hebbian Long-Term Potentiation of Inhibitory Synapses in the Thalamus
The Journal of Neuroscience, October 2, 2013 • 33(40):15675–15685 • 15675 Cellular/Molecular Non-Hebbian Long-Term Potentiation of Inhibitory Synapses in the Thalamus Andrea Rahel Sieber,1 Rogier Min,1 and Thomas Nevian1,2 1Department of Physiology and 2Center for Cognition, Learning and Memory, University of Bern, 3012 Bern, Switzerland The thalamus integrates and transmits sensory information to the neocortex. The activity of thalamocortical relay (TC) cells is modulated by specific inhibitory circuits. Although this inhibition plays a crucial role in regulating thalamic activity, little is known about long-term changes in synaptic strength at these inhibitory synapses. Therefore, we studied long-term plasticity of inhibitory inputs to TC cells in the posterior medial nucleus of the thalamus by combining patch-clamp recordings with two-photon fluorescence microscopy in rat brain slices.WefoundthatspecificactivitypatternsinthepostsynapticTCcellinducedinhibitorylong-termpotentiation(iLTP).ThisiLTPwas non-Hebbian because it did not depend on the timing between presynaptic and postsynaptic activity, but it could be induced by postsyn- aptic burst activity alone. iLTP required postsynaptic dendritic Ca 2ϩ influx evoked by low-threshold Ca 2ϩ spikes. In contrast, tonic postsynaptic spiking from a depolarized membrane potential (Ϫ50 mV), which suppressed these low-threshold Ca 2ϩ spikes, induced no plasticity. The postsynaptic dendritic Ca 2ϩ increase triggered the synthesis of nitric oxide that retrogradely activated presynaptic guanylylcyclase,resultinginthepresynapticexpressionofiLTP.ThedependenceofiLTPonthemembranepotentialandthereforeonthe -
Medicines Regulations 1984 (SR 1984/143)
Reprint as at 1 July 2014 Medicines Regulations 1984 (SR 1984/143) David Beattie, Governor-General Order in Council At the Government House at Wellington this 5th day of June 1984 Present: His Excellency the Governor-General in Council Pursuant to section 105 of the Medicines Act 1981, and, in the case of Part 3 of the regulations, to section 62 of that Act, His Excellency the Governor-General, acting on the advice of the Minister of Health tendered after consultation with the organisations and bodies that ap- peared to the Minister to be representatives of persons likely to be substantially affected, and by and with the advice and consent of the Executive Council, hereby makes the following regulations. Contents Page 1 Title and commencement 5 Note Changes authorised by subpart 2 of Part 2 of the Legislation Act 2012 have been made in this official reprint. Note 4 at the end of this reprint provides a list of the amendments incorporated. These regulations are administered by the Ministry of Health. 1 Reprinted as at Medicines Regulations 1984 1 July 2014 2 Interpretation 5 Part 1 Classification of medicines 3 Classification of medicines 11 Part 2 Standards 4 Standards for medicines, related products, medical 11 devices, cosmetics, and surgical dressings 5 Pharmacist may dilute medicine in particular case 12 6 Colouring substances [Revoked] 12 Part 3 Advertisements 7 Advertisements not to claim official approval 13 8 Advertisements for medicines 13 9 Advertisements for related products 15 10 Advertisements for medical devices 15 11 Advertisements -
Synthetic Nanobodies As Angiotensin Receptor Blockers
Synthetic nanobodies as angiotensin receptor blockers Conor McMahona,1, Dean P. Stausb,c,1, Laura M. Winglerb,c,1,2, Jialu Wangc, Meredith A. Skibaa, Matthias Elgetid,e, Wayne L. Hubbelld,e, Howard A. Rockmanc,f, Andrew C. Krusea,3, and Robert J. Lefkowitzb,c,g,3 aDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; bHoward Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; cDepartment of Medicine, Duke University Medical Center, Durham, NC 27710; dJules Stein Eye Institute, University of California, Los Angeles, CA 90095; eDepartment of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; fDepartment of Cell Biology, Duke University Medical Center, Durham, NC 27710; and gDepartment of Biochemistry, Duke University Medical Center, Durham, NC 27710 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved July 13, 2020 (received for review May 6, 2020) There is considerable interest in developing antibodies as functional a need for more broadly applicable methodologies to discover modulators of G protein-coupled receptor (GPCR) signaling for both antibody fragments explicitly directed to the membrane- therapeutic and research applications. However, there are few an- embedded domains with limited surface exposure. tibody ligands targeting GPCRs outside of the chemokine receptor The angiotensin II type 1 receptor (AT1R) is a GPCR that group. GPCRs are challenging targets for conventional antibody dis- exemplifies the opportunities and the challenges surrounding an- covery methods, as many are highly conserved across species, are tibody drug development. Both the endogenous peptide agonist of biochemically unstable upon purification, and possess deeply buried the AT1R (angiotensin II) and small-molecule inhibitors (angio- ligand-binding sites. -
Glucocorticoids with Ketamine and Pentobarbitone- Induced General Anaesthesia in the Rat: Possible Effects on Central Cholinergic Activity
Br. J. Pharmac. (1984), 82,339-347 Interactions of cholinesterase inhibitors and glucocorticoids with ketamine and pentobarbitone- induced general anaesthesia in the rat: possible effects on central cholinergic activity Remy S. Leeuwin, Jan K. van der Wal & Willem Spanjer Pharmacological Laboratory, University of Amsterdam, Polderweg 104,1093 KP Amsterdam, The Netherlands 1 Doses of 100, 150 and 200 igkg-1 of the cholinesterase inhibitor neostigmine reverse the anaesthetic action of ketamine. The antagonistic effect is increased as the dose is increased. The duration of anaesthesia induced by pentobarbitone is reversed by the cholinesterase inhibitor in doses of 150, 200 and 250 tig kg-1. 2 Choline, in a dose of 50mg kg-, significantly antagonizes the action of the two anaesthetics, whereas hemicholinium-3, an inhibitor of the uptake of choline and the synthesis of acetylcholine, markedly potentiates their action. 3 Dexamethasone induces a significant reduction of the duration of anaesthesia produced by ketamine and pentobarbitone. The potentiation of the anaesthetic effect caused by hemicholinium-3 is also reversed by dexamethasone. 4 The acetylcholine content in rat cerebral cortex is increased after treatment with ketamine and pentobarbitone. 5 Measurements of the course of the plasma level of pentobarbitone do not reveal alterations in the pharmacokinetic profile by either neostigmine or dexamethasone. 6 These results indicate that central cholinergic systems may somehow be involved in the anaesthesia induced by ketamine and pentobarbitone and that the interactions described in this paper may be the result of modification by neostigmine and dexamethasone of the alterations in cholinergic activity caused by the two anaesthetics. Introduction In 1977 Balmer & Wyte showed that physostigmine after completion of the operation was actually pro- antagonized the sedative effects of diazepam and longed. -
Pharmacology and Toxicology of Amphetamine and Related Designer Drugs
Pharmacology and Toxicology of Amphetamine and Related Designer Drugs U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol Drug Abuse and Mental Health Administration Pharmacology and Toxicology of Amphetamine and Related Designer Drugs Editors: Khursheed Asghar, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Errol De Souza, Ph.D. Addiction Research Center National Institute on Drug Abuse NIDA Research Monograph 94 1989 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 Pharmacology and Toxicology of Amphetamine and Related Designer Drugs ACKNOWLEDGMENT This monograph is based upon papers and discussion from a technical review on pharmacology and toxicology of amphetamine and related designer drugs that took place on August 2 through 4, 1988, in Bethesda, MD. The review meeting was sponsored by the Biomedical Branch, Division of Preclinical Research, and the Addiction Research Center, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other matieral in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. -
4 Supplementary File
Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation. -
Involvement of Sigma-1 Receptors in the Antidepressant-Like Effects of Dextromethorphan
Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan Linda Nguyen, Matthew J. Robson¤, Jason R. Healy, Anna L. Scandinaro, Rae R. Matsumoto* Department of Basic Pharmaceutical Sciences, and Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, West Virginia, United States of America Abstract Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (s1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of s1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, s1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of s receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the s1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with s1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. -
Antagonism of Histamine-Activated Adenylate Cyclase in Brain by D
Proc. Natl. Acad. Sci. USA Vol.74, No. 12, pp. 5697-5701, December 1977 Medical Sciences Antagonism of histamine-activated adenylate cyclase in brain by D-lysergic acid diethylamide (histaminergic antagonists/adenosine 3':5'-cyclic monophosphate/H2-receptors/ergots/D-2-bromolysergic acid diethylamide) JACK PETER GREEN, CARL LYNN JOHNSON, HAREL WEINSTEIN, AND SAUL MAAYANI Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, 100th Street and Fifth Avenue, New York, New- York 10029 Communicated by Vincent P. Dole, August 19, 1977 ABSTRACT D-Lysergic acid diethylamide and D-2-bro- (ED50; amount necessary to produce half-maximal response) molysergic acid diethylamide are competitive antagonists of and antagonist affinities (pA2) were not altered. the histamine activation of adenylate cyclase [ATP pyrophos- Adenylate Cyclase Assay. The assay system has been de- phate-lyase (cyclizing); E.C. 4.6.1.11 in broken cell preparations in All additions of the hippocampus and cortex of guinea pig brain. The ade- scribed (8). All assays were performed triplicate. nylate cyclase is linked to the histamine H2-receptor. Both D- were made to the assay tubes on ice. They were then transferred lysergic acid diethylamide and D-2-bromolysergic acid dieth- to a 30° shaking incubator and preincubated for 5 min to allow ylamide show topological congruency with potent H2-antago- the enzymatic activity to reach a steady state and to eliminate nists. D-2-Bromolysergic acid diethylamide is 10 times more the influence of any lag periods in hormone activation. After potent as an H2-antagonist than cimetidine, which has been the the preincubation period, 25 of [a-32PJATP (1-2 gCi) were most potent H2-antagonist reported, and D-lysergic acid di- pl ethylamide is about equipotent to cimetidine. -
Acute Restraint Stress Induces Cholecystokinin Release Via Enteric
Neuropeptides 73 (2019) 71–77 Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep Acute restraint stress induces cholecystokinin release via enteric apelin T ⁎ Mehmet Bülbüla, , Osman Sinena, Onur Bayramoğlua, Gökhan Akkoyunlub a Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey b Department of Histology and Embryology, Akdeniz University, Faculty of Medicine, Antalya, Turkey ARTICLE INFO ABSTRACT Keywords: Stress increases the apelin content in gut, while exogenous peripheral apelin has been shown to induce chole- Apelin cystokinin (CCK) release. The present study was designed to elucidate (i) the effect of acute stress on enteric Restraint stress production of apelin and CCK, (ii) the role of APJ receptors in apelin-induced CCK release depending on the Cholecystokinin nutritional status. CCK levels were assayed in portal vein blood samples obtained from stressed (ARS) and non- APJ receptor stressed (NS) rats previously injected with APJ receptor antagonist F13A or vehicle. Duodenal expressions of Fasting apelin, CCK and APJ receptor were detected by immunohistochemistry. ARS increased the CCK release which was abolished by selective APJ receptor antagonist F13A. The stimulatory effect of ARS on CCK production was only observed in rats fed ad-libitum. Apelin and CCK expressions were upregulated by ARS. In addition to the duodenal I cells, APJ receptor was also detected in CCK-producing myenteric neurons. Enteric apelin appears to regulate the stress-induced changes in GI functions through CCK. Therefore, apelin/APJ receptor systems seem to be a therapeutic target for the treatment of stress-related gastrointestinal disorders. 1. Introduction for APJ in rodents (De Mota et al., 2000; Medhurst et al., 2003). -
Targeted EDTA Chelation Therapy with Albumin Nanoparticles To
Clemson University TigerPrints All Dissertations Dissertations 8-2019 Targeted EDTA Chelation Therapy with Albumin Nanoparticles to Reverse Arterial Calcification and Restore Vascular Health in Chronic Kidney Disease Saketh Ram Karamched Clemson University, [email protected] Follow this and additional works at: https://tigerprints.clemson.edu/all_dissertations Recommended Citation Karamched, Saketh Ram, "Targeted EDTA Chelation Therapy with Albumin Nanoparticles to Reverse Arterial Calcification and Restore Vascular Health in Chronic Kidney Disease" (2019). All Dissertations. 2479. https://tigerprints.clemson.edu/all_dissertations/2479 This Dissertation is brought to you for free and open access by the Dissertations at TigerPrints. It has been accepted for inclusion in All Dissertations by an authorized administrator of TigerPrints. For more information, please contact [email protected]. TARGETED EDTA CHELATION THERAPY WITH ALBUMIN NANOPARTICLES TO REVERSE ARTERIAL CALCIFICATION AND RESTORE VASCULAR HEALTH IN CHRONIC KIDNEY DISEASE A Dissertation Presented to the Graduate School of Clemson University In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Bioengineering by Saketh Ram Karamched August 2019 Accepted by: Dr. Narendra Vyavahare, Ph.D., Committee Chair Dr. Agneta Simionescu, Ph.D. Dr. Alexey Vertegel, Ph.D. Dr. Christopher G. Carsten, III, M.D. ABSTRACT Cardiovascular diseases (CVDs) are the leading cause of death globally. An estimated 17.9 million people died from CVDs in 2016, with ~840,000 of them in the United States alone. Traditional risk factors, such as smoking, hypertension, and diabetes, are well discussed. In recent years, chronic kidney disease (CKD) has emerged as a risk factor of equal importance. Patients with mild-to-moderate CKD are much more likely to develop and die from CVDs than progress to end-stage renal failure. -
A Metabolically Stable Apelin-17 Analog Decreases AVP-Induced Antidiuresis and Improves Hyponatremia
ARTICLE https://doi.org/10.1038/s41467-020-20560-y OPEN A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia Adrien Flahault 1,3, Pierre-Emmanuel Girault-Sotias 1,3, Mathilde Keck1, Rodrigo Alvear-Perez1, ✉ Nadia De Mota1, Lucie Estéoulle2, Sridévi M. Ramanoudjame2, Xavier Iturrioz1, Dominique Bonnet 2 & ✉ Catherine Llorens-Cortes 1 1234567890():,; Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inap- propriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In col- lecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment. 1 Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM, Unit U1050, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7241, Collège de France, Paris, France. 2 Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France. -
Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin
nutrients Review Obesity, Bioactive Lipids, and Adipose Tissue Inflammation in Insulin Resistance Iwona Kojta, Marta Chaci ´nskaand Agnieszka Błachnio-Zabielska * Department of Hygiene, Epidemiology and Metabolic Disorders, Medical University of Bialystok, Jana Kili´nskiego1, 15-089 Bialystok, Poland; [email protected] (I.K.); [email protected] (M.C.) * Correspondence: [email protected] Received: 1 April 2020; Accepted: 30 April 2020; Published: 3 May 2020 Abstract: Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. The exact mechanism by which adipose tissue induces insulin resistance is still unclear. It has been demonstrated that obesity is associated with the adipocyte dysfunction, macrophage infiltration, and low-grade inflammation, which probably contributes to the induction of insulin resistance. Adipose tissue synthesizes and secretes numerous bioactive molecules, namely adipokines and cytokines, which affect the metabolism of both lipids and glucose. Disorders in the synthesis of adipokines and cytokines that occur in obesity lead to changes in lipid and carbohydrates metabolism and, as a consequence, may lead to insulin resistance and type 2 diabetes. Obesity is also associated with the accumulation of lipids. A special group of lipids that are able to regulate the activity of intracellular enzymes are biologically active lipids: long-chain acyl-CoAs, ceramides, and diacylglycerols. According to the latest data, the accumulation of these lipids in adipocytes