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    The role of bradykinin receptor type 2 for spontaneous extravasation in mice skin: Implications for non-allergic angio-oedema.
    Br J Pharmacol 2018 Feb 21. Epub 2018 Feb 21.
    Institute of Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany.
    Background And Purpose: Non-allergic angio-oedema is a life threatening disease mediated by activation of bradykinin type 2 receptors (B2). The aim of this study was to investigate whether activation of B2 by endogenous bradykinin contributes to physiologic extravasation. This may shed new light on the assumption that treatment with an ACEi results in an alteration of the vascular barrier function predisposing to non-allergic angio-edema. Read More

    An evaluation of the operational model when applied to quantify functional selectivity.
    Br J Pharmacol 2018 Feb 19. Epub 2018 Feb 19.
    Otago Pharmacometrics Group, National School of Pharmacy, University of Otago, Dunedin, New Zealand.
    Background And Purpose: Functional selectivity describes the ability of ligands to differentially regulate multiple signalling pathways when coupled to a single receptor and the operational model is commonly used to analyse these data. Here, we assess the mathematical properties of the operational model and evaluate the impact of fixing parameters on model performance.

    Experimental Approach: The operational model was evaluated using both a mathematical identifiability analysis and simulation. Read More

    In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: Autophagy may be required for regrowth of endometriosis.
    Br J Pharmacol 2018 Feb 19. Epub 2018 Feb 19.
    CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.
    Background And Purpose: A high recurrence rate after medical treatment is a major clinical problem for patients with endometriosis. In the present study, we evaluated the in vitro effects of combined treatment with MK2206 (an AKT inhibitor) + chloroquine on cell growth and regrowth of endometriotic stromal cells, and the in vivo effects on endometriotic implants in a mouse xenograft model of endometriosis.

    Experimental Approach: We evaluated the effects of autophagy inhibition by knockdown of the ATG13, Beclin-1, and ATG12 genes and pharmacologic agents (chloroquine, bafilomycin A1, or 3-methyalanine) individually and in combination with MK2206 on cell growth and/or cell regrowth of endometriotic stromal cells in vitro. Read More

    Species-specific susceptibility to cannabis-induced convulsions.
    Br J Pharmacol 2018 Feb 19. Epub 2018 Feb 19.
    Division of Pharmacology, School of Chemistry, Food and Nutritional Sciences, and Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, RG6 6AP, UK.
    Background And Purpose: Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ-tetrahydrocannabinol (Δ-THC), variously reported to be pro- and anti-convulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different Δ-THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. Read More

    Dihydrodiosgenin protects against experimental acute pancreatitis and associated lung injury through mitochondrial protection and PI3Kγ/Akt inhibition.
    Br J Pharmacol 2018 Feb 19. Epub 2018 Feb 19.
    Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, 610041, China.
    Background And Purpose: Acute pancreatitis (AP) is a painful and burdensome exocrine pancreatic disorder with no specific drug treatment. Diosgenyl saponin extracts from Dioscorea zingiberensis C. H. Read More

    Cannabinoids in arterial, pulmonary and portal hypertension - mechanisms of action and potential therapeutic significance.
    Br J Pharmacol 2018 Feb 18. Epub 2018 Feb 18.
    Department of Pharmacology and Toxicology, University of Bonn, Germany.
    The endocannabinoid system is overactivated in arterial, pulmonary and portal hypertension. In this paper, we present limited clinical data concerning the role of cannabinoids in human hypertension including polymorphism of endocannabinoid system components. We underline differences between the acute cannabinoid administration and their potential hypotensive effect after chronic application in experimental hypertension. Read More

    Mechanisms of imidazoline Ireceptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission.
    Br J Pharmacol 2018 Feb 16. Epub 2018 Feb 16.
    Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.
    Background And Purpose: Although studies have established the antinociceptive efficacies of imidazoline Ireceptor (IR) agonists, its exact post-receptor mechanism remains unknown. This study tested the hypothesis that monoaminergic transmission is critical for IR agonist-induced antinociception.

    Experimental Approach: The von Frey filament test was used to examine the antinociceptive effects of the IR agonists 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Read More

    GPCRS IN CONTEXT: SEXUAL DIMORPHISM IN THE CARDIOVASCULAR SYSTEM.
    Br J Pharmacol 2018 Feb 16. Epub 2018 Feb 16.
    Molecular Pharmacology Laboratory, Division of Molecular Cardiology & Biophysics, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
    Cardiovascular disease remains the largest cause of mortality worldwide and there is a clear gender gap in disease occurrence: men are predisposed to earlier onset of cardiovascular disease, including atherosclerosis and hypertension, than are women. Oestrogen may be a driving factor for female-specific cardioprotection, though androgens and sex chromosomes are also likely to contribute to sexual dimorphism in the cardiovascular system. Many G protein-coupled receptor (GPCR)-mediated processes are involved in cardiovascular homeostasis and some exhibit clear sex-divergence. Read More

    Alterations in melatonin and serotonin signalling in the colonic mucosa of mice with dextran-sodium sulfate-induced colitis.
    Br J Pharmacol 2018 Feb 15. Epub 2018 Feb 15.
    School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Brighton, UK.
    Background And Purpose: Inflammatory bowel disease (IBD) is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal serotonin (5-HT) signalling occur in animal models of colitis and in humans suffering from IBD. Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Read More

    Aucubin protects against pressure overload-induced cardiac remodelling via β3-AR-nNOS cascades.
    Br J Pharmacol 2018 Feb 15. Epub 2018 Feb 15.
    Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China.
    Background And Purpose: Aucubin, the predominant component of Eucommia ulmoides Oliv., plays an indispensable role in regulating oxidative stress. Considering that oxidative stress has previously been demonstrated to contribute to acute and chronic myocardial injury, we tested the effects of aucubin on cardiac remodelling and heart failure. Read More

    1,3,6,7-tetrahydroxy-8-prenylxanthone ameliorates inflammatory responses resulted in by the paracrine interaction of adipocytes and macrophages.
    Br J Pharmacol 2018 Feb 15. Epub 2018 Feb 15.
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China.
    Background And Purpose: Chronic inflammation in adipose tissue is critical in the onset and development of insulin resistance and type 2 diabetes. Macrophage infiltration into adipose tissue and pro-inflammatory polarization play key roles in adipose tissue inflammation. The fruit hull of mangosteen (Garcinia mangostana) has been used in traditional medicine for treatment of various inflammatory diseases. Read More

    CRFreceptor-deficiency eliminates social behaviour deficits and vulnerability induced by cocaine.
    Br J Pharmacol 2018 Feb 6. Epub 2018 Feb 6.
    Univ. Bordeaux, INCIA, UMR 5287, 33000, Bordeaux, France.
    Background And Purpose: Poor social behaviour and vulnerability to stress are major clinical features of stimulant use disorders. The corticotropin-releasing factor (CRF) system mediates stress responses and might underlie substance use disorders; however, its implication in social impairment induced by stimulant substances remains unknown. CRF signalling is mediated by two receptor types, CRFand CRF. Read More

    DUAL OXIDASE: A NOVEL THERAPEUTIC TARGET IN ALLERGIC DISEASE.
    Br J Pharmacol 2018 Feb 5. Epub 2018 Feb 5.
    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, U.S.A.
    NADPH oxidases represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS), and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces, and have therefore been considered to have important roles in innate host defense pathways. Recent studies have shed important insights into the host defense mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. Read More

    Functional interplay between LXR and AMPKα inhibits atherosclerosis in apoE deficient mice - A new anti-atherogenic strategy.
    Br J Pharmacol 2018 Feb 2. Epub 2018 Feb 2.
    College of Biomedical Engineering, Hefei University of Technology, Hefei, China.
    Background And Purpose: LXR agonist (T317) reduces atherosclerosis while inducing fatty liver. Metformin activates energy metabolism by activating AMPKα. In this study, we determined if the interaction between metformin and T317 can inhibit atherosclerosis without activation of hepatic lipogenesis. Read More

    Anti-inflammatory therapies in myocardial infarction: failures, hopes, and challenges.
    Br J Pharmacol 2018 Feb 2. Epub 2018 Feb 2.
    The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
    In the infarcted heart, damage-associated molecular patterns released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and upregulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct from dead cells and matrix debris and activate reparative myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodeling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Read More

    The current state of GPCR-based drug discovery to treat metabolic disease.
    Br J Pharmacol 2018 Feb 2. Epub 2018 Feb 2.
    Quantitative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
    One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of G-protein coupled receptors (GPCRs). This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer, and type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. Read More

    Acute ethanol exposure has bidirectional actions on the endogenous neuromodulator adenosine in rat hippocampus.
    Br J Pharmacol 2018 Jan 23. Epub 2018 Jan 23.
    Department of Mathematics, University of Warwick, Coventry, CV4 7AL, UK.
    Background And Purpose: Ethanol is a widely used recreational drug with complex effects on physiological and pathological brain function. In epileptic patients the use of ethanol can modify seizure initiation and subsequent seizure activity with reports of ethanol being both pro and anti-convulsant. One proposed target of ethanol's actions is the neuromodulator adenosine, which is released during epileptic seizures to feedback and inhibit the occurrence of subsequent seizures. Read More

    Resolvin E1, resolvin D1 and resolvin D2 inhibit constriction of rat thoracic aorta and human pulmonary artery induced by the thromboxane mimetic U46619.
    Br J Pharmacol 2018 Jan 20. Epub 2018 Jan 20.
    From the Academic Units of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, United Kingdom.
    Background And Purpose: Omega-6 fatty acid-derived lipid mediators such as prostanoids, thromboxane and leukotrienes have well-established roles in regulating both inflammation and smooth muscle contractility. Resolvins are derived from omega-3 fatty acids and have important roles in promoting the resolution of inflammation, but their activity on smooth muscle contractility is unknown. We investigated whether resolvin E1 (RvE1), resolvin D1 (RvD1) and resolvin D2 (RvD2) can modulate contractions of isolated segments of rat thoracic aorta (RTA) or human pulmonary artery (HPA) induced by the α-adrenoceptor agonist phenylephrine or the stable thromboxane Amimetic U46619. Read More

    Cambogin suppresses dextran sulphate sodium-induced colitis by enhancing Treg cell stability and function.
    Br J Pharmacol 2018 Jan 20. Epub 2018 Jan 20.
    School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
    Background And Purpose: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract, and an impaired immune response plays a critical role in IBD. The current drugs and therapies for IBD treatment are of limited use, therefore, there is a need to find novel drugs or therapies for this disease. We investigated the effect of cambogin in a mouse model of dextran sulphate sodium (DSS)-induced colitis and whether cambogin attenuates inflammation via a Treg-cell-mediated effect on the immune response. Read More

    In Vivo Effects of μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Peptidomimetics Following Acute and Repeated Administration.
    Br J Pharmacol 2018 Jan 19. Epub 2018 Jan 19.
    Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI, 48109.
    Background And Purpose: Mu opioid receptor (μ-receptor) agonists are used for pain management, but produce adverse effects including tolerance, dependence, and euphoria. The co-administration of a μ-receptor agonist with a delta opioid receptor (δ-receptor) antagonist has been shown to produce antinociception with reduced development of some side effects. We characterized the effects of three μ-receptor agonist/δ-receptor antagonist peptidomimetics in vivo after acute and repeated administration to determine if this profile provides a viable alternative to traditional opioid analgesics. Read More


    Thrombospondin-4 acts on pre-synaptic calcium channel alpha-2-delta-1 subunit to induce synaptogenesis between sensory and spinal cord neurons through a T-type calcium channel dependent pathway that is blocked by early, low-dose gabapentin treatments.
    Br J Pharmacol 2018 Jan 16. Epub 2018 Jan 16.
    Departments of Pharmacology, University of California School of Medicine, Irvine, CA, 92697.
    Background And Purpose: Nerve injury induces concurrent upregulation of calcium channel alpha-2-delta-1 subunit (Caαδ) and extracellular matrix protein thrombospondin-4 (TSP4) in dorsal root ganglia and dorsal spinal cord, leading to neuropathic pain state development. Interactions of these proteins promote aberrant excitatory synaptogenesis that contributes to neuropathic pain state development through unknown mechanisms. We investigated the contributory role of Caαδ/TSP4 to synaptogenesis, and pathway involved in vitro, and whether gabapentin could block this process and pain development in vivo. Read More

    LKB1/AMPK-Mediated Regulation by Gentiopicroside Ameliorates P2x7R-Dependent Alcoholic Hepatosteatosis.
    Br J Pharmacol 2018 Jan 16. Epub 2018 Jan 16.
    Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, 133002, China.
    Background And Purpose: Regulating P2x7R-NLRP3 inflammasome activation might be a potential therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process would be modulated by gentiopicroside (GPS), which is the main active secoiridoid glycoside from Gentiana manshurica Kitagawa.

    Experimental Approach: In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administrated ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. Read More

    The use of chemogenetics in behavioural neuroscience: Receptor variants, targeting approaches, and caveats.
    Br J Pharmacol 2018 Jan 16. Epub 2018 Jan 16.
    The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia.
    The last decade has seen major advances in neuroscience tools allowing us to selectively modulate cellular pathways in freely moving animals. Chemogenetic approaches such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) permit the remote control of neuronal function by systemic drug administration. These approaches have dramatically advanced our understanding of the neural control of behaviour. Read More

    Single and combined effects of plant-derived (THC, CBD) and synthetic (WIN-55,212) cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice.
    Br J Pharmacol 2018 Jan 16. Epub 2018 Jan 16.
    Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
    Background And Purpose: It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of delta-9-tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1/CB2 receptor agonists or produces these pharmacological effects on its own.

    Experimental Approach: The effects of THC or the CB1/CB2 receptor full agonist WIN55212 (WIN) alone, CBD alone, or their combination were tested across a range of doses. Read More

    Adiponectin inhibits inflammatory cytokines production by Beclin-1 phosphorylation and B-cell lymphoma 2 mRNA destabilization: role for autophagy induction.
    Br J Pharmacol 2018 Jan 14. Epub 2018 Jan 14.
    College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
    Background And Purpose: Adiponectin potently suppresses inflammatory mediator production. Autophagy is known to play a critical role in the modulation of inflammatory responses by adiponectin. However, the underlying mechanisms are not clearly understood. Read More

    Sustained plasma hepcidin suppression and iron elevation by Anticalin-derived hepcidin antagonist in cynomolgus monkey.
    Br J Pharmacol 2018 Jan 12. Epub 2018 Jan 12.
    Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud university medical center, Nijmegen, the Netherlands.
    Background And Purpose: Anaemia of chronic disease (ACD) has been linked to iron restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. Here we report the engineering of the human lipocalin-derived, small protein-based Anticalin PRS-080 hepcidin antagonist with high affinity and selectivity.

    Experimental Approach: Anticalin- and hepcidin-specific pharmacokinetic/pharmacodynamic modelling was used to design and select the suitable drug candidate based on half life extension and duration of hepcidin suppression. Read More

    Substance P as a putative efferent transmitter mediates GABAergic inhibition in mouse taste buds.
    Br J Pharmacol 2018 Jan 12. Epub 2018 Jan 12.
    Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL, 62901.
    Background And Purpose: Capsaicin-mediated modulation on taste nerve responses is thought to be produced indirectly by actions of neuropeptides, e.g., calcitonin gene-related peptide (CGRP) and substance P (SP), onto taste cells implying playing a role in taste sensitivity. Read More

    Partial rescue of F508del-cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual-acting small molecule.
    Br J Pharmacol 2018 Jan 10. Epub 2018 Jan 10.
    School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
    Background And Purpose: Rescue of F508del-cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the most common CF mutation, requires small molecules that overcome protein processing, stability and channel gating defects. Here, we investigate F508del-CFTR rescue by CFFT-004, a small molecule designed to independently correct protein processing and channel gating defects.

    Experimental Approach: Using CFTR-expressing recombinant cells and CF patient-derived bronchial epithelial cells, we studied CFTR expression by Western blotting and channel gating and stability with the patch-clamp and Ussing chamber techniques. Read More

    New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation.
    Br J Pharmacol 2018 Jan 10. Epub 2018 Jan 10.
    Department of Neurobiology, Faculty of Life Sciences, Tel-Aviv University and Neurim Pharmaceuticals, Tel Aviv, Israel.
    In mammals, a central circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, tunes the innate circadian physiological rhythms to the ambient 24 h light-dark cycle to invigorate and optimize the internal temporal order. The SCN-activated, light-inhibited production of melatonin conveys the message of darkness to the clock and induces night-state physiological functions, for example, sleep/wake blood pressure and metabolism. Clinically meaningful effects of melatonin treatment have been demonstrated in placebo-controlled trials in humans, particularly in disorders associated with diminished or misaligned melatonin rhythms, for example, circadian rhythm-related sleep disorders, jet lag and shift work, insomnia in children with neurodevelopmental disorders, poor (non-restorative) sleep quality, non-dipping nocturnal blood pressure (nocturnal hypertension) and Alzheimer's disease (AD). Read More

    Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma.
    Br J Pharmacol 2018 Jan 10. Epub 2018 Jan 10.
    Departments of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
    Background And Purpose: Systemically delivered statins can blunt airway inflammation in ovalbumin-challenged mice; however, in asthma clinical trials the beneficial effects of introducing oral statins are not compelling. We aim to reconcile this discrepancy using a clinically relevant murine model of allergic asthma, and by including a prophylactic study arm.

    Experimental Approach: Adult mice were: 1) challenged with house dust mite (HDM) alone or with subcutaneous (s. Read More

    A Natural Compound Formononetin Derived From Astragalus Membranaceus Increase Adipocyte Thermogenesis by Modulating PPARγ Activity.
    Br J Pharmacol 2018 Jan 7. Epub 2018 Jan 7.
    Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
    Background And Purpose: Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases, however, few effective and safe agents are available clinically that promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis.

    Experimental Approach: The effects of Chinese herbal medicines or indicated components from Astragalus membranaceus on adipocyte thermogenesis were analyzed by qPCR. Read More

    Inventing new therapies without reinventing the wheel: the power of drug repurposing.
    Br J Pharmacol 2018 01;175(2):165-167
    Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA.
    Linked Articles: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley. Read More

    Interferon γ treatment increases endocannabinoid and related N-acylethanolamine levels in T84 human colon carcinoma cells.
    Br J Pharmacol 2018 Jan 3. Epub 2018 Jan 3.
    Department of Pharmacology and Clinical Neuroscience, Pharmacology Unit, Umeå University, Umeå, Sweden.
    Background And Purpose: Endocannabinoids and related N-acylethanolamines (NAEs) are involved in regulation of gut function, but relatively little is known as to whether inflammatory cytokines such as IFNγ affect their levels. We have investigated this in vitro using cultures of T84 colon cancer cells.

    Experimental Approach: T84 cells, when cultured in monolayers, differentiate to form adult colonic crypt-like cells with excellent permeability barrier properties. Read More

    Expression, distribution and function of kinin Breceptor in the rat diabetic retina.
    Br J Pharmacol 2017 Dec 29. Epub 2017 Dec 29.
    École d'optométrie, Université de Montréal, Montréal, QC, Canada.
    Background And Purpose: The kinin Breceptor contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression, cellular localization and vascular inflammatory effect of Breceptors in retina of streptozotocin diabetic rats.

    Experimental Approach: The distribution of Breceptors on retinal cell types was investigated by immunocytochemistry. Read More

    The soluble guanylate cyclase stimulator IW-1973 prevents inflammation and fibrosis in experimental non-alcoholic steatohepatitis.
    Br J Pharmacol 2017 Dec 27. Epub 2017 Dec 27.
    Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona, Spain.
    Background And Purpose: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation and fibrosis. Soluble guanylate cyclase (sGC) stimulation reduces inflammation and fibrosis in experimental models of lung, kidney and heart disease. Here, we tested whether sGC stimulation is also effective in experimental NASH. Read More

    Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform.
    Br J Pharmacol 2017 Dec 26. Epub 2017 Dec 26.
    Department of Pharmacology, University of Oxford, Oxford, UK.
    Background And Purpose: Statins are amongst the most widely prescribed drugs for those at risk of cardiovascular disease, lowering cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. Although effective at preventing cardiovascular disease, statin use is associated with muscle weakness, myopathies and, occasionally, fatal rhabdomyolysis. As simvastatin, a commonly prescribed statin, promotes Carelease from sarcoplasmic reticulum (SR) vesicles, we investigated if simvastatin directly activates skeletal (RyR1) and cardiac (RyR2) ryanodine receptors. Read More

    Tanshinones that selectively block the collagenase activity of cathepsin K provide a novel class of ectosteric antiresorptive agents for bone.
    Br J Pharmacol 2017 Dec 26. Epub 2017 Dec 26.
    Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada.
    Background And Purpose: Attempts to generate active site-directed cathepsin K (CatK) inhibitors for the treatment of osteoporosis have failed because of side effects. We have previously shown that an ectosteric tanshinone CatK inhibitor isolated from Salvia miltiorrhiza blocked, selectively, the collagenase activity of CatK, without affecting the active site and demonstrated its bone-preserving activity in vivo. Here, we have characterize the antiresorptive potential of other tanshinones, which may provide a scaffold for side effect-free CatK inhibitors. Read More

    Role of signalling molecules in behaviours mediated by the δ opioid receptor agonist SNC80.
    Br J Pharmacol 2017 Dec 26. Epub 2017 Dec 26.
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
    Background And Purpose: GPCRs exist in multiple conformations that can engage distinct signalling mechanisms which in turn may lead to diverse behavioural outputs. In rodent models, activation of the δ opioid receptor (δ-receptor) has been shown to elicit antihyperalgesia, antidepressant-like effects and convulsions. We recently showed that these δ-receptor-mediated behaviours are differentially regulated by the GTPase-activating protein regulator of G protein signalling 4 (RGS4), which facilitates termination of G protein signalling. Read More

    Proton-independent activation of acid-sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis.
    Br J Pharmacol 2017 Dec 26. Epub 2017 Dec 26.
    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
    Background And Purpose: Acid-sensing ion channels (ASICs) play an important role in synaptic plasticity and learning, as well as in nociception and mechanosensation. ASICs are involved in pain and in neurological and psychiatric diseases, but their therapeutic potential is limited by the lack of ligands activating them at physiological pH.

    Experimental Approach: We extracted, purified and determined the structure of a bisbenzylisoquinoline alkaloid, lindoldhamine, (LIN) from laurel leaves. Read More

    Different contribution of chemokine N-terminal features attest a different ligand binding mode and a bias towards activation of the atypical chemokine receptor ACKR3/CXCR7 compared to CXCR4 and CXCR3.
    Br J Pharmacol 2017 Dec 22. Epub 2017 Dec 22.
    Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg.
    Background And Purpose: Chemokines and their receptors form an intricate interaction and signaling network that plays critical roles in various physiological and pathological cellular processes. The high promiscuity and apparent redundancy of this network makes probing individual chemokine/receptor interactions and functional effects, as well as targeting individual receptor axes for therapeutic applications, challenging. Despite poor sequence identity, the N-terminal regions of chemokines, which play a key role in their activity and selectivity, harbor several conserved features. Read More

    Phages of life - the path to pharma.
    Br J Pharmacol 2018 02 3;175(3):412-418. Epub 2018 Jan 3.
    School of Microbiology, University College Cork, Cork, Ireland.
    Bacteriophage (phage) therapy has encountered both enthusiasm and scepticism in the past century. New antimicrobial strategies against lethal pathogens are now a top priority for the World Health Organization, and although compassionate use of phages recently met with significant success, regulated clinical interventions seem unlikely in the near future. The hundredth anniversary of their discovery seems an appropriate time for a revival of phage therapy, particularly as the dilemma of antibiotic resistance grows. Read More

    Wheel running during chronic nicotine exposure is protective against mecamylamine-precipitated withdrawal and up-regulates hippocampal α7 nACh receptors in mice.
    Br J Pharmacol 2017 Dec 20. Epub 2017 Dec 20.
    School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.
    Background And Purpose: Evidence suggests that exercise decreases nicotine withdrawal symptoms in humans; however, the mechanisms mediating this effect are unclear. We investigated, in a mouse model, the effect of exercise intensity during chronic nicotine exposure on nicotine withdrawal severity, binding of α4β2*, α7 nicotinic acetylcholine (nAChR), μ-opioid (μ receptors) and Ddopamine receptors and on brain-derived neurotrophic factor (BDNF) and plasma corticosterone levels.

    Experimental Approach: Male C57Bl/6J mice treated with nicotine (minipump, 24 mg·kg·day) or saline for 14 days underwent one of three concurrent exercise regimes: 24, 2 or 0 h·dayvoluntary wheel running. Read More

    Identification of an (-)-englerin A analogue, which antagonizes (-)-englerin A at TRPC1/4/5 channels.
    Br J Pharmacol 2018 Mar 25;175(5):830-839. Epub 2018 Jan 25.
    School of Medicine, University of Leeds, Leeds, UK.
    Background And Purpose: (-)-Englerin A (EA) is a potent cytotoxic agent against renal carcinoma cells. It achieves its effects by activation of transient receptor potential canonical (TRPC)4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5. Read More

    Shikonin inhibits myeloid differentiation protein 2 to prevent LPS-induced acute lung injury.
    Br J Pharmacol 2018 Mar 25;175(5):840-854. Epub 2018 Jan 25.
    Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
    Background And Purpose: Acute lung injury (ALI) is a challenging clinical syndrome, which manifests as an acute inflammatory response. Myeloid differentiation protein 2 (MD2) has an important role in mediating LPS-induced inflammation. Currently, there are no effective molecular-based therapies for ALI or viable biomarkers for predicting the severity of disease. Read More

    Finding the needle in the haystack: systematic identification of psychobiotics.
    Br J Pharmacol 2017 Dec 15. Epub 2017 Dec 15.
    APC Microbiome Institute, University College Cork, Cork, Ireland.
    The brain-gut-microbiota axis is increasingly viewed as a novel paradigm in neuroscience with the capacity to generate innovative therapies for patients with psychiatric illnesses. Psychobiotics, defined as live bacteria, which when ingested in adequate amounts, confer mental health benefits, are increasingly of interest, as preclinical trials continue to show promising results. Particularly in stress-related, anxiety and depressive disorders, there is potential for psychobiotics to deliver new therapies. Read More

    Mirabegron: potential off target effects and uses beyond the bladder.
    Br J Pharmacol 2017 Dec 15. Epub 2017 Dec 15.
    Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
    The β-adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation resulted in decreased adiposity and improved metabolic outputs (such as glucose handling) in animal models of obesity and Type 2 diabetes. However, several drugs acting at the β-adrenoceptor failed in clinical trials. This was thought to be due to their lack of efficacy at the human receptor. Read More

    WNT signalling: mechanisms and therapeutic opportunities.
    Br J Pharmacol 2017 Dec;174(24):4543-4546
    Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
    This themed section of the British Journal of Pharmacology stems from the EMBO Conference: Wnt Meeting 2016 held from the 14to 16September 2016 in Brno, Czech Republic.

    Linked Articles: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary. Read More

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