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    23537 results match your criteria British journal of pharmacology[Journal]

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    Early treatment with Resolvin E1 facilitates myocardial recovery from ischemia in mice.
    Br J Pharmacol 2017 Sep 19. Epub 2017 Sep 19.
    Department of Pharmacology, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
    Background And Purpose: An appropriate inflammatory response is necessary for cardiac healing after acute myocardial infarction (MI). Resolvin E1 (RvE1) is an anti-inflammatory and pro-resolution lipid mediator derived from eicosapentaenoic acid. The purpose of this study was to investigate the potential effects of RvE1 on cardiac function recovery after MI in mice. Read More

    A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels.
    Br J Pharmacol 2017 Sep 19. Epub 2017 Sep 19.
    Biomedical Institute, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen, Denmark.
    Background And Purpose: Small conductance Ca(2+) -activated K(+) (KCa 2) channels represent a promising atrial-selective target for treatment of atrial fibrillation (AF). Here, we establish the mechanism of KCa 2 inhibition by the new compound AP14145.

    Experimental Approach: Using site directed mutagenesis binding determinants for AP14145 inhibition were explored. Read More

    Targeting nociceptive TRP channels to treat chronic pain: current state of the field.
    Br J Pharmacol 2017 Sep 19. Epub 2017 Sep 19.
    Clinical Laboratories, Baptist Medical Center, Jacksonville, FL, USA.
    Control of chronic pain is frequently inadequate and/or associated with intolerable adverse effects, prompting a frantic search for new therapeutics and new therapeutic targets. Nearly two decades of preclinical and clinical research supports the involvement of Transient Receptor Potential (TRP) channels in temperature perception, nociception and sensitization. Although there has been considerable excitement around the therapeutic potential of this channel family since the cloning and identification of TRPV1 as the capsaicin receptor more than 20 years ago, only modulators of a few channels have been tested clinically. Read More

    Gα12 Facilitates Carbachol-Induced Shortening in Human Airway Smooth Muscle By Modulating Phosphoinositide 3-Kinase-Mediated Activation In A RhoA-Dependent Manner.
    Br J Pharmacol 2017 Sep 17. Epub 2017 Sep 17.
    Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ.
    Background And Purpose: Phosphoinositide 3-kinase (PI3K)-dependent activation of Rho kinase (ROCK) is necessary for agonist-induced human airway smooth muscle cell (HASMC) contraction, and inhibition of PI3K promotes bronchodilation of human small airways. The upstream mechanisms driving agonist-mediated PI3K/ROCK axis activation, however, remain unclear. Given the capacity of G12 family proteins to activate ROCK pathways in other cell types (Riobo and Manning, 2005), the role of G12 proteins in modulating M3 muscarinic acetylcholine receptor (M3R)-stimulated PI3K/ROCK activation and HASMC contraction was examined. Read More

    Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway.
    Br J Pharmacol 2017 Sep 14. Epub 2017 Sep 14.
    Division of Pathway Medicine, University of Edinburgh Medical School, 49 Little France Crescent, Edinburgh, Scotland, EH16 4SB.
    Background And Purpose: An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. Read More

    Phosphodiesterase 1a inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries.
    Br J Pharmacol 2017 Sep 14. Epub 2017 Sep 14.
    Synaptic Transmission, H. Lundbeck A/S, Valby, Denmark.
    Background And Purpose: Phosphodiesterase 1 (PDE1), a subfamily of cyclic nucleotide phosphodiesterases consisting of three isoforms, PDE1A, PDE1B, and PDE1C, has been implicated in regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform-preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896, and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone. Read More

    p53-mediated regulation of bile acid disposition attenuates cholic acid-induced cholestasis in mice.
    Br J Pharmacol 2017 Sep 14. Epub 2017 Sep 14.
    School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
    Background And Purpose: Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic diseases. Here we investigated the role of p53 in the regulation bile acid disposition and cholestasis. Read More

    Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding.
    Br J Pharmacol 2017 Sep 14. Epub 2017 Sep 14.
    Division of Structural Biology, The Institute of Cancer Research, London, SW7 3RP, UK.
    The Wnt/β-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of posttranslational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP-ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β-catenin signalling by PARylation was discovered relatively recently. Read More

    Nucleoside/nucleotide reverse transcriptase inhibitors attenuate angiogenesis and lymphangiogenesis by impairing receptor tyrosine kinases signalling in endothelial cells.
    Br J Pharmacol 2017 Sep 14. Epub 2017 Sep 14.
    Institute of Genetics and Regenerative Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
    Background And Purpose: Cardiovascular disease associated with antiretroviral therapy (ART) has become a major clinical challenge for HIV-positive patients. However, the role of ART in blood vessel growth is largely unknown. Here, we examined an integral component of ART, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), and investigated their effects on key microvascular functions, including angiogenesis and lymphangiogenesis. Read More

    Activation of G Protein-Coupled Estrogen Receptor 1 At the Onset of Reperfusion Protects the Myocardium Against Ischemia/Reperfusion Injury by Reducing Mitochondrial Dysfunction and Mitophagy.
    Br J Pharmacol 2017 Sep 14. Epub 2017 Sep 14.
    Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, TX, 78229, USA.
    Background And Purpose: Recent evidence indicates that Gper1 (G Protein-coupled Estrogen Receptor 1) mediates acute pre-ischemic estrogen-induced protection of the myocardium from ischemia/reperfusion injury via a signaling cascade that includes PKC translocation, ERK1/2 /GSK-3β phosphorylation and the inhibition of the mitochondrial permeability transition pore (mPTP) opening. Here, we investigated the impact and mechanism involved in post-ischemic Gper1 activation in ischemia/reperfusion injury. We determined whether Gper1 activation at the onset of reperfusion confers cardioprotective effects by protecting against mitochondrial impairment and mitophagy. Read More

    Tetrandrine antagonizes acute megakaryoblastic leukemia growth by forcing autophagy-mediated differentiation.
    Br J Pharmacol 2017 Sep 13. Epub 2017 Sep 13.
    Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, P R China.
    Background And Purpose: The dismal prognosis of acute megakaryoblastic leukemia (AMKL) urges for development of novel therapeutic methods. Inducing megakaryoblasts to undergo terminal differentiation was recently shown to be effective as a treatment for AMKL. This encouraged us to identify a potent anti-leukemia compound to induce megakaryocyte differentiation. Read More

    Beyond symptomatic effects: Donepezil's potential for neuroprotection and disease modification in Alzheimer's disease.
    Br J Pharmacol 2017 Sep 13. Epub 2017 Sep 13.
    Eisai Singapore Pte. Ltd., Singapore.
    Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. Read More

    Pharmacology of cognition: a panacea for neuropsychiatric disease?
    Br J Pharmacol 2017 Oct;174(19):3133-3135
    School of Psychology, University of Nottingham, Nottingham, UK.
    Linked Articles: This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit Read More

    Importance of the second extracellular loop for melatonin MT1 receptor function and absence of melatonin binding in GPR50.
    Br J Pharmacol 2017 Sep 12. Epub 2017 Sep 12.
    Inserm, U1016, Institut Cochin, Paris, France.
    Background And Purpose: Recent crystal structures of G protein-coupled receptors (GPCRs) highlight the previously unappreciated role of the 2(nd) extracellular (E2) loop in ligand binding and gating and receptor activation. Here we studied the role of the E2 loop in the activation of the melatonin MT1 receptor (MT1 ) and in the inactivation of the closely related orphan GPR50 receptor.

    Experimental Approach: Chimeric MT1 -GPR50 receptors were generated and analyzed for 2-[(125) I]iodomelatonin binding, Gi /cAMP signaling and β-arrestin 2 recruitment assisted by computational molecular dynamics (MD) simulations. Read More

    Repurposing a novel parathyroid hormone (PTH) analog to treat hypoparathyroidism.
    Br J Pharmacol 2017 Sep 12. Epub 2017 Sep 12.
    Musculoskeletal Research, Lilly Research Laboratories, Eli Lilly & Co.
    Background And Purpose: Human parathyroid hormone (PTH) is critical for maintaining physiologic calcium homeostasis, and plays an important role in the formation and maintenance of bone. Full-length PTH and a truncated peptide form are approved for treatment of hypoparathyroidism and osteoporosis, respectively. Our initial goal was to develop an improved PTH therapy for osteoporosis, but clinical development was halted. Read More

    Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation.
    Br J Pharmacol 2017 Sep 9. Epub 2017 Sep 9.
    Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012, Bern, Switzerland.
    Background And Purpose: Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterised by high lethality and substantial cognitive disabilities in survivors. Here, we study the capacity of an established therapeutic agent, magnesium, to improve survival in pneumococcal meningitis by modulating the neurological effects of the major pneumococcal pathogenic factor pneumolysin.

    Experimental Approach: We used mixed primary glial and acute brain slice cultures, pneumolysin injection in infant rats, a mouse meningitis model, and complementary approaches such as Western blot, a black lipid bilayer conductance assay and live imaging of primary glial cells. Read More

    Selective targeting of M-type potassium channel Kv7.4 demonstrates its key role in regulating of dopaminergic neuronal excitability and depression-like behaviour.
    Br J Pharmacol 2017 Sep 8. Epub 2017 Sep 8.
    Department of Pharmacology, Hebei Medical University; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, China.
    Background And Purpose: The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) is implicated in the development of depression, and firing patterns of VTA DA neurons are key determinants in this process. Here, we describe a crucial role of the M-type potassium channel Kv7.4 in modulation of VTA DA neuronal excitability and in the development of depressive behaviour in mice. Read More

    Melatonin: does it have utility in the treatment of haematological neoplasms?
    Br J Pharmacol 2017 Sep 7. Epub 2017 Sep 7.
    Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China.
    Melatonin, discovered in 1958 in the bovine pineal tissue, is an indoleamine that modulates circadian rhythms and has a wide variety of other functions. Haematological neoplasms are the leading cause of death in children and adolescents throughout the world. Research has demonstrated that melatonin is a low-toxicity protective molecule against experimental haematological neoplasms, but the mechanisms remain poorly defined. Read More

    GPCR signaling from within the cell.
    Br J Pharmacol 2017 Sep 5. Epub 2017 Sep 5.
    Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
    Traditionally, signal transduction from G protein-coupled receptors (GPCRs) is thought to emanate from the cell surface where receptor interactions with external stimuli can be transformed into a broad range of cellular responses. However, emergent data show that numerous GPCRs are also associated with various intracellular membranes where they may couple to different signaling systems, display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution. Although many GPCRs can be activated at the cell surface and subsequently endocytosed and transported to a unique intracellular site, other intracellular GPCRs can be activated in situ either via de novo ligand synthesis, diffusion of permeable ligands or active transport of nonpermeable ligands. Read More

    'Principles of Pharmacology in the Eye'.
    Br J Pharmacol 2017 Sep 2. Epub 2017 Sep 2.
    UCL School of Pharmacy, London, WC1N 1AX, UK.
    The eye is a highly specialised organ that is subject to a huge range of pathology. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e. Read More

    Light-induced regulation of ligand-gated channel activity.
    Br J Pharmacol 2017 Aug 31. Epub 2017 Aug 31.
    Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, Barcelona, 08028, Spain.
    The control of ligand-gated receptors with light using photochromic compounds has evolved from the first handcrafted examples to truly engineered receptors whose development is supported on rational design, high-resolution protein structures, comparative pharmacology and molecular biology manipulations. Photoswitchable regulators have been designed and characterized for a large number of ligand-gated receptors in the mammalian nervous system, including nicotinic acetylcholine, glutamate and gamma amino butyric acid receptors. They conform a well-equipped toolbox to investigate synaptic and neuronal circuits in all-optical experiments. Read More

    Widespread brain distribution and activity following anti-BACE1 intracerebroventricular infusion in nonhuman primates.
    Br J Pharmacol 2017 Aug 31. Epub 2017 Aug 31.
    Department of Neuroscience, Genentech, Inc, South San Francisco, CA, 94080.
    Background And Purpose: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. Intracerebroventricular (i.c. Read More

    Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity.
    Br J Pharmacol 2017 Aug 29. Epub 2017 Aug 29.
    Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain.
    Background And Purpose: Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing, and storage. While the biological effects of decarboxylated cannabinoids such as Δ(9) -tetrahydrocannabinol (Δ(9) -THC) have been extensively investigated, the bioactivity of Δ(9) -THCA is largely unknown, despite its occurrence in different Cannabis preparations. Read More

    Neonicotinoid insecticides differently modulate acetycholine-induced currents on mammalian α7 nicotinic acetylcholine receptor.
    Br J Pharmacol 2017 Aug 29. Epub 2017 Aug 29.
    LBLGC, UPRES EA 1207-USC INRA 1328, Université d'Orléans, 1 rue de Chartres, BP, 6759-45067, Orléans, France.
    Background And Purpose: Neonicotinoid insecticides are described as poor agonists of mammalian nicotinic acetylcholine receptors. In this paper, we provide evidence that they diffenrently act on mammalian nicotinic receptors.

    Experimental Approach: Two-electrode voltage-clamp electrophysiology was used to characterized the pharmacology of neonicotinoid insecticides on α7 receptors expressed in Xenopus oocytes. Read More

    Opioid and hypocretin neuromodulation of VTA neuronal subpopulations.
    Br J Pharmacol 2017 Aug 28. Epub 2017 Aug 28.
    Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1.
    The current view of the midbrain dopaminergic system is evolving towards a complex system of subpopulations of neurons with distinct afferent and efferent connections, and importantly, functionally different intrinsic characteristics. Recent literature on the phenotypic diversity of dopaminergic neurons has outlined that VTA dopamine neurons are not as anatomically or electrophysiologically homogenous as they were once thought to be. Instead, the midbrain dopaminergic system is now understood to be composed of anatomically and functionally heterogeneous dopaminergic subpopulations receiving specific afferent input and with different axonal projections. Read More

    Chloroquine is a Potent Pulmonary Vasodilator that Attenuates Hypoxia-induced Pulmonary Hypertension.
    Br J Pharmacol 2017 Aug 28. Epub 2017 Aug 28.
    State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
    Background And Purpose: Sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling are two major causes of elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. The purpose of this study was to investigate whether chloroquine (CHQ) induces relaxation in the pulmonary artery (PA) and attenuates hypoxia-induced pulmonary hypertension (HPH).

    Experimental Approach: Isometric tension was measured in rat PA rings preconstricted with phenylephrine or high K(+) solution. Read More

    α-Spinasterol: a cyclooxygenase inhibitor and a TRPV1 antagonist presents an antinociceptive effect in clinically relevant models of pain in mice.
    Br J Pharmacol 2017 Aug 28. Epub 2017 Aug 28.
    Graduate Program in Biological Sciences: Biochemistry Toxicology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
    Background And Purpose: Postoperative pain is one of the most common manifestations of acute pain, which is an important problem faced by patients after surgery. Moreover, neuronal trauma or chemotherapeutic treatment often causes neuropathic pain, which induces disabling and distress symptoms. Both painful conditions remain inadequately treated. Read More

    Distinct in vivo target occupancy by bivalent- and induced-fit like binding drugs.
    Br J Pharmacol 2017 Aug 24. Epub 2017 Aug 24.
    Department Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Pleinlaan 2, B-1050, Brussels, Belgium.
    Background And Purpose: Optimal drug therapy often requires long-lasting target occupancy. While this attribute was customarily linked to the drug's pharmacokinetic properties, their dissociation rate is now increasingly recognised to contribute as well. Nearly all the earlier PK-PD simulations encompassed single-step binding drugs and focussed on koff . Read More

    Hyperhomocysteinemia and Vascular Injury: The Advance of Mechanisms and Drug Targets.
    Br J Pharmacol 2017 Aug 24. Epub 2017 Aug 24.
    Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P. R. China.
    Homocysteine (Hcy) is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinemia (HHcy), the pathogenic elevation of plasma Hcy as a result of an imbalance of Hcy metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification, and aneurysm. Hcy-lowering therapy via dietary supplementation with folic acids and vitamin B exhibits a stronger effect on vascular disease prevention in regions in which the population has a low folate consumption than in areas exposed to folate fortification. Read More

    Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar-to-ductal metaplasia.
    Br J Pharmacol 2017 Aug 17. Epub 2017 Aug 17.
    Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Zurich, Switzerland.
    Background And Purpose: Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. Read More

    Differential binding of tetrodotoxin and its derivatives to voltage-sensitive sodium channel subtypes (Nav 1.1 to Nav 1.7).
    Br J Pharmacol 2017 Aug 18. Epub 2017 Aug 18.
    Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
    Background And Purpose: The development of subtype-selective ligands to inhibit voltage-sensitive sodium channels (VSSCs) has been attempted with the aim of developing therapeutic compounds. Tetrodotoxin (TTX) is a toxin from pufferfish that strongly inhibits VSSCs. Many TTX analogues have been identified from marine and terrestrial sources, although their specificity for particular VSSC subtypes has not been investigated. Read More

    Rubiarbonone C inhibits platelet-derived growth factor-induced proliferation and migration of vascular smooth muscle cells through the FAK, MAP kinase, and STAT3 Tyr(705) signaling pathways.
    Br J Pharmacol 2017 Aug 18. Epub 2017 Aug 18.
    Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon, 34134, Republic of Korea.
    Background And Purpose: The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) are important steps in cardiovascular diseases, including neointimal lesion formation, myocardial infarction, and atherosclerosis. Here, we evaluated the rubiarbonone C-mediated signaling pathways that regulate PDGF-induced VSMC proliferation and migration.

    Experimental Approach: Cell proliferation and migration were measured in cells treated with rubiarbonone C followed by PDGF-BB treatment using the MTT assay, [(3) H]-thymidine incorporation, flow cytometry, and wound healing migration assay, matrix metalloproteinase (MMP) gelatin zymography, a fluorescence assay for F-actin. Read More

    NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia.
    Br J Pharmacol 2017 Aug 15. Epub 2017 Aug 15.
    Department of Pharmacology, Second Military Medical University, Shanghai, China.
    Background And Purpose: Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischaemia; however, a major limitation of tPA is the haemorrhagic transformation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation.

    Experimental Approach: Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h. Read More

    Olodaterol shows anti-fibrotic efficacy in in vitro and in vivo models of pulmonary fibrosis.
    Br J Pharmacol 2017 Aug 15. Epub 2017 Aug 15.
    Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.
    Background And Purpose: Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of β2 -adrenoceptors (β2 -AR) has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of β2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting β2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts (HLF) and in murine models of pulmonary fibrosis. Read More

    Olaparib, a clinically used poly(ADP-ribose) polymerase inhibitor protects against oxidant-induced cardiac myocyte death in vitro and improves cardiac contractility during early phase after heart transplantation in a rat model in vivo.
    Br J Pharmacol 2017 Aug 14. Epub 2017 Aug 14.
    Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
    Background And Purpose: Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) have recently been approved for human use for oncological indications. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effect of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in-vivo model of cardiac transplantation.

    Experimental Approach: H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen-peroxide (H2 O2 ) or with glucose-oxidase (GOx, which generates H2 O2 in the tissue culture medium). Read More

    Serotonergic 5-HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.
    Br J Pharmacol 2017 Aug 14. Epub 2017 Aug 14.
    Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (EA7296), Faculté de Médecine, Fédération de Médecine Translationnelle, Université et Centre Hospitalier de Strasbourg, Strasbourg, France.
    Background: Valvular heart disease is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the serotonin system has been associated with valvular heart disease.

    Purpose And Experimental Approach: Here, we investigated the contribution of serotonin receptors in a mouse model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens dexfenfluramine and benfluorex. Read More

    Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB1 receptors.
    Br J Pharmacol 2017 Aug 14. Epub 2017 Aug 14.
    Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada.
    Background And Purpose: Effective treatments of nausea are limited. In this study we evaluated the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937, to suppress acute and anticipatory nausea in rats and examined the pharmacological mechanism of this effect.

    Experimental Approach: We investigated the potential of URB937 (administered i. Read More

    Pharmacological inhibition of FSGS-related TRPC6 gain of function mutants by semisynthetic larixol-derived compounds.
    Br J Pharmacol 2017 Aug 11. Epub 2017 Aug 11.
    Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany.
    Background And Purpose: Gain of function mutations in TRPC6 can cause autosomal dominant forms of focal segmental glomerulosclerosis (FSGS). Validated inhibitors of TRPC6 that are biologically active on FSGS-related TRPC6 mutants are eagerly sought.

    Experimental Approach: We synthesized new TRPC6-inhibiting modulators from larixol, a resiniferous constituent of Larix decidua, and tested the potency and selectivity in cell lines stably expressing various TRP channel isoforms. Read More

    Butyrate protects against disruption of the blood-milk barrier and moderates inflammatory responses in a model of mastitis induced by lipopolysaccharide.
    Br J Pharmacol 2017 Aug 11. Epub 2017 Aug 11.
    Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, China.
    Background And Purpose: Short-chain fatty acids are fermentation end products produced by gut bacteria, which have been shown to ameliorate inflammatory bowel diseases and allergic asthma. However, the mechanism involved remains largely unknown. Here, we investigate the protective effects and mechanisms of sodium butyrate (SB) on LPS-induced mastitis model. Read More

    Levothyroxine enhances glucose clearance and blunts the onset of experimental type 1 diabetes mellitus in mice.
    Br J Pharmacol 2017 Aug 11. Epub 2017 Aug 11.
    Pancreatic Islet Development and Regeneration Unit/Laboratory of Aging Biology, Centro Andaluz de Biologı́a Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain.
    Background And Purpose: Thyroid hormones induce several changes in whole body metabolism that are known to improve metabolic homeostasis. However, adverse side effects have prevented its use in the clinic. In view of the promising effects of thyroid hormones, we investigated the effects of levothyroxine supplementation on glucose homeostasis. Read More

    Discovery and Pharmacological Characterisation of a Novel Series of Highly Selective Inhibitors of Cyclin-Dependent Kinases 4 and 6 as Anticancer Agents.
    Br J Pharmacol 2017 Aug 11. Epub 2017 Aug 11.
    Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, and Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, 5001, Australia.
    Background And Purpose: Cyclin D dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle, and are actively pursued as therapeutic targets in cancer targets. We sought to discover a novel series of orally bioavailable, and highly selective small molecule inhibitors of CDK4/6.

    Experimental Approach: The discovery of pharmacological inhibitors and optimisation for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis, and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F) regulated gene expression, and in vitro biopharmaceutical and in vivo pharmacokinetic profiling. Read More

    M-type K(+) channels in peripheral nociceptive pathways.
    Br J Pharmacol 2017 Aug 11. Epub 2017 Aug 11.
    Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China.
    Pathological pain is a hyperexcitability disorder. Since the excitability of a neuron is set and controlled by a complement of ion channels it expresses, in order to understand and treat pain, we need to develop a mechanistic insight into the key ion channels controlling excitability within the mammalian pain pathways and how these ion channels are regulated and modulated in various physiological and pathophysiological settings. In this review, we will discuss the emerging data on the expression in pain pathways, functional role and modulation of a family of voltage-gated K(+) channels called 'M channels' (KCNQ, Kv 7). Read More

    Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice.
    Br J Pharmacol 2017 Aug 11. Epub 2017 Aug 11.
    Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
    Background And Purpose: Cannabis is a recreational drug leading to intoxication, following stimulation of cannabinoid CB1 receptors. However, more recently, herbs mixed with synthetic cannabinoids sometimes known as 'Spice' and 'Black Mamba' have been increasingly used, and their high CB1 receptor affinity has led not only to marked intoxication but also life-threatening complications and an increasing number of deaths. Although many studies have indicated that prophylactic treatment with CB1 receptor antagonists can block cannabimimetic effects in animals and humans, the aim of this study was to determine whether CB1 receptor antagonism could reverse physical cannabimimetic effects. Read More

    Using the affective bias test to predict drug-induced negative affect: implications for drug safety.
    Br J Pharmacol 2017 Oct 30;174(19):3200-3210. Epub 2017 Aug 30.
    School of Physiology and Pharmacology, Biomedical Sciences, University Walk, University of Bristol, Bristol, UK.
    Background And Purpose: Predicting the risk of drug-induced adverse psychiatric effects is important but currently not possible in non-human species. We investigated whether the affective bias test (ABT) could provide a preclinical method with translational and predictive validity.

    Experimental Approach: The ABT is a bowl-digging task, which quantifies biases associated with learning and memory. Read More

    Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis.
    Br J Pharmacol 2017 Aug 3. Epub 2017 Aug 3.
    Tianjin Key Laboratory of Metabolic Diseases and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
    Background And Purpose: Atherosclerosis results from a maladaptive inflammatory response initiated by the intramural retention of LDL in susceptible areas of the arterial vasculature. The ω-3 polyunsaturated fatty acids (ω-3) have protective effects in atherosclerosis; however, their molecular mechanism is still largely unknown. The present study used a metabolomic approach to reveal the atheroprotective metabolites of ω-3 and investigate the underlying mechanisms. Read More

    Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats.
    Br J Pharmacol 2017 Aug 3. Epub 2017 Aug 3.
    Department of Cardiovascular Physiology, Interdepartmental Chair of Experimental and Clinical Physiology, Medical University of Lodz, Lodz, Poland.
    Background And Purpose: Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia. The specific effects of these compounds within the orofacial region are largely unknown. In this study, we tried to determine whether an increase in cannabinoid and opioid concentration in the CSF affects impulse transmission between the motor centres localized in the vicinity of the third and fourth cerebral ventricles. Read More

    Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca(2+) currents.
    Br J Pharmacol 2017 Aug 2. Epub 2017 Aug 2.
    Institute of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, University of Graz, Graz, Austria.
    Background And Purpose: The antioxidant 5-hydroxymethylfurfural (5-HMF) exerts documented beneficial effects in several experimental pathologies and is currently tested as an antisickling drug in clinical trials. In the present study, we examined the cardiovascular effects of 5-HMF and elucidated the mode of action of the drug.

    Experimental Approach: The cardiovascular effects of 5-HMF were studied with pre-contracted porcine coronary arteries and rat isolated normoxic-perfused hearts. Read More

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