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    Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post-inflammatory rat model for irritable bowel syndrome.
    Br J Pharmacol 2018 Jun 17. Epub 2018 Jun 17.
    Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
    Background And Purpose: Serine proteases are suggested as important players in visceral pain. We investigated their effect by using newly developed serine protease inhibitors with a well-characterized inhibitory profile in a post-inflammatory IBS rat model.

    Experimental Approach: Colitis rats received intrarectal TNBS and controls 0. Read More

    Speciation of Reactive Sulfur Species and their Reactions with Alkylating Agents: Do we have any clue about what is present inside the cell?
    Br J Pharmacol 2018 Jun 17. Epub 2018 Jun 17.
    Department of Molecular Immunology and Toxicology, National Institute of Oncology, Ráth György utca 7-9, Budapest, Hungary, 1122.
    Background And Purpose: Posttranslational modifications of cysteine (Cys) residues represent a major aspect of redox biology, and their reliable detection is key in providing mechanistic insights. The metastable character of these modifications and cell lysis-induced artifactual oxidation render current state-of-the-art protocols to rely on alkylation-based stabilization of labile Cys derivatives before cell/tissue rupture. An untested assumption in these procedures is that for all Cys derivatives alkylation rates are faster than their dynamic interchange. Read More

    Drug resistance profiles of mutations in the RET kinase domain.
    Br J Pharmacol 2018 Jun 16. Epub 2018 Jun 16.
    Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
    Background And Purpose: RET alterations are found in thyroid and lung cancer. While RET tyrosine kinase inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer (NSCLC), the impact of mutations in the RET kinase domain on drug sensitivity was largely uncharacterized.

    Experimental Approach: We identified and analyzed mutations in the RET kinase domain that conferred resistance to the TKIs cabozantinib, lenvatinib, vandetanib, and nintedanib using RET kinase-dependent BaF3/KIF5B-RET (BaF3/KR) cells. Read More

    Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic OATP1B1/1B3.
    Br J Pharmacol 2018 Jun 16. Epub 2018 Jun 16.
    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
    Background And Purpose: Intravenous glycyrrhizin, having anti-inflammatory and hepatoprotective properties, is incorporated into the management of liver diseases in China. This investigation was designed to elucidate the molecular mechanism underlying hepatobiliary excretion of glycyrrhizin and to investigate its potential for drug-drug interactions on organic anion-transporting polypeptides (OATP)1B.

    Experimental Approach: Human hepatic transporters were characterized for glycyrrhizin at the cellular and vesicular levels and compared with rat hepatic transporters. Read More


    Norepinephrine upregulates volume-regulated chloride current by PKA-independent cAMP/Epac pathway in human atrial myocytes.
    Br J Pharmacol 2018 Jun 13. Epub 2018 Jun 13.
    Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, China.
    Background And Purpose: Adrenergic regulation of cell volume-regulated chloride current (I ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of I in human atrial myocytes.

    Experimental Approach: A conventional whole-cell patch voltage-clamp technique was utilized to record membrane current in human atrial myocytes. Read More

    A Novel Inhibitor of iNOS Dimerization Protects Against Cytokine-Induced Rat β-cell Dysfunction.
    Br J Pharmacol 2018 Jun 11. Epub 2018 Jun 11.
    California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Road, La Jolla, California, 92037, United States.
    Background And Purpose: β-cell apoptosis is a major feature of type 1 diabetes and pro-inflammatory cytokines are key drivers of the deterioration of β-cell mass through induction of apoptosis. Mitochondrial stress plays a critical role in mediating apoptosis by releasing cytochrome C into the cytoplasm, directly activating caspase-9 and its downstream signaling cascade. We aim to identify new compounds that protect β cells from cytokine-induced activation of the intrinsic (mitochondrial) pathway of apoptosis. Read More

    Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis.
    Br J Pharmacol 2018 Jun 11. Epub 2018 Jun 11.
    Lewis Katz School of Medicine, Temple University, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA.
    Background And Purpose: The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 receptor (CB R) or cannabinoid 2 receptor (CB R). The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis. Read More

    Monocytes as immune targets in arterial hypertension.
    Br J Pharmacol 2018 Jun 8. Epub 2018 Jun 8.
    University Medical Center Mainz, Center for Cardiology - Cardiology I, Langenbeckstrasse 1, 55131, Mainz, Germany.
    The role of myelomonocytic cells appears to be critical for initiation, progression and manifestation of arterial hypertension. Monocytes can induce vascular inflammation as well as tissue remodeling and (mal) adaptation by secreting chemokines and cytokines, producing reactive oxygen species, expressing coagulation factors and by transforming into macrophages. A multitude of adhesion molecules promote infiltration and accumulation of monocytes into the kidney, heart, brain and vasculature in hypertension. Read More

    Nicotinic acetylcholine receptors.
    Br J Pharmacol 2018 Jun;175(11):1785-1788
    Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece.
    This themed section of the British Journal of Pharmacology is the product of a conference that focussed on nicotinic ACh receptors (nAChRs) that was held on the Greek island of Crete from 7 to 11 May 2017. 'Nicotinic acetylcholine receptors 2017' was the fourth in a series of triennial international meetings that have provided a regular forum for scientists working on all aspects of nAChRs to meet and to discuss new developments. In addition to many of the regular participants, each meeting has also attracted a new group of scientists working in a fast-moving area of research. Read More

    A long-acting FGF21 alleviates hepatic steatosis and inflammation in NASH mice partly through an FGF21- adiponectin- IL17A axis.
    Br J Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.
    Background And Purpose: NASH is the most severe form of NAFLD and is a serious public health problem around the world. There are currently no approved treatments for NASH. FGF21 has recently emerged as a promising drug candidate for metabolic diseases. Read More

    Tonantzitlolone is a Nanomolar Potency Activator of TRPC1/4/5 Channels.
    Br J Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    School of Medicine, University of Leeds, Leeds, LS2 9JT.
    Background And Purpose: The diterpene ester tonantzitlonone (TZL) is a natural product which displays cytotoxicity towards certain types of cancer cell such as renal cell carcinoma cells. The effect is similar to that of (-)-Englerin A (EA) and so, although it is chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels of the TRPC1, TRPC4 and TRPC5 type (TRPC1/4/5 channels).

    Experimental Approach: Renal cell carcinoma A498 cells natively expressing TRPC1 and TRPC4, modified HEK 293 cells over expressing TRPC4, TRPC5, TRPC4-TRPC1 or TRPC5-TRPC1 concatemer, TRPC3 or TRPM2 or CHO cells over expressing TRPV4 were studied by intracellular Ca measurement or whole-cell or excised membrane patch-clamp electrophysiology. Read More

    Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.
    Br J Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550, Alicante, Spain.
    Background And Purpose: The aim of this study was to explore if the administration of naltrexone (NTX) together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.

    Experimental Approach: The effects of low doses of NTX (0.7 mg/kg; p. Read More

    Apolipoprotein E favors the blunting by high-fat diet of IP receptor activation in the mouse aorta.
    Br J Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, SAR, China.
    Background And Purpose: Nitric oxide (NO)-mediated, endothelium-dependent relaxations of isolated arteries are blunted by aging and high-fat diet, as well as by apolipoprotein E deletion. The present study was designed to test the hypothesis that apolipoprotein E deletion impairs endothelium-dependent responses to prostacyclin (IP) receptor activation.

    Experimental Approach: Five weeks old ApoE and ApoE mice were fed normal chow or high-fat diet for 29 weeks. Read More

    A Recent History of HNO (Nitroxyl) Chemistry, Pharmacology and Therapeutic Potential.
    Br J Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    Department of Chemistry, Sonoma State University, Rohnert Park, CA, 94928.
    Due to the excitement surrounding the discovery of nitric oxide (NO) as an endogenously generated signaling molecule, numerous other nitrogen oxides were also investigated as possible physiological mediators. Among these was nitroxyl (HNO). Over the past 25 years or so, a significant amount of work by this lab and many others has discovered that HNO possesses unique chemical properties and important pharmacological utility. Read More

    Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin on vasoconstriction.
    Br J Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
    Background And Purpose: Development of combination therapies has received significant interest in recent years. Previously a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction, and performed inter-species scaling to humans using this mechanism-based model. Read More

    The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid-based therapies to improve on the poor current therapeutic outcomes.
    Br J Pharmacol 2018 Jun 1. Epub 2018 Jun 1.
    Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
    At the beginning of the 21st century, the therapeutic management of neurodegenerative disorders remains a major biomedical challenge, particularly given the worldwide aging of the population over the past 50 years that is expected to continue in the forthcoming years. This review will focus on the promise of cannabinoid based therapies to address this challenge. Such promise is based on the broad neuroprotective profile of cannabinoids, which may cooperate to combat excitotoxicity, oxidative stress, glia-driven inflammation and protein aggregation. Read More

    The emerging alliance of sphingosine-1-phosphate signaling and immune cells: from basic mechanisms to implications in hypertension.
    Br J Pharmacol 2018 Jun 1. Epub 2018 Jun 1.
    Department of Experimental Medical Sciences, Lund University, Sweden.
    The immune system plays a considerable role in hypertension. Particularly, T-lymphocytes are recognized as important players in its pathogenesis. Despite substantial experimental efforts the molecular mechanisms underlying the nature of T-cell activation contributing to an onset of hypertension or disease perpetuation are still elusive. Read More

    A novel synthetic phosphodiesterase 5 inhibitor, KJH-1002, ameliorates scopolamine-induced cognitive impairments in mice by activating the cGMP/CREB signaling pathway and attenuating oxidative damage.
    Br J Pharmacol 2018 May 30. Epub 2018 May 30.
    Natural Products Research Center, Korea Institute of Science and Technology, 679 Saimdang-ro, Gangneung, Gangwon-do, 25451, Korea.
    Background And Purpose: Inhibition of PDE5 has been demonstrated to improve synaptic plasticity and memory via enhancing of cGMP expression, thus activating the cGMP/CREB signaling pathway. This study aimed to investigate the ameliorating effect of PDE5 inhibitor on scopolamine-induced cognitive dysfunction using memory-related behavioral tests and biochemical assays.

    Experimental Approach: After the mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine administration. Read More

    The prefrontal cortical endocannabinoid system modulates fear-pain interactions in a subregion-specific manner.
    Br J Pharmacol 2018 May 30. Epub 2018 May 30.
    Pharmacology and Therapeutics, National University of Ireland Galway, University Road, Galway, Ireland.
    Background And Purpose: The emotional processing and coordination of top-down responses to noxious and conditioned aversive stimuli involves the medial prefrontal cortex (mPFC). Evidence suggests that subregions of the mPFC, (infralimbic (IL), prelimbic (PrL), anterior cingulate (ACC) cortices), differentially alter the expression of contextually-induced fear and nociceptive behaviour. We investigated the role of the endocannabinoid system in the IL, PrL and ACC in formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA) and conditioned fear in the presence of nociceptive tone. Read More

    Inflammasomes: a novel therapeutic target in pulmonary hypertension?
    Br J Pharmacol 2018 May 30. Epub 2018 May 30.
    William Harvey Research Institute, Barts & the London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
    Pulmonary hypertension (PH) is a rare, progressive pulmonary vasculopathy characterised by increased mean pulmonary arterial pressure, pulmonary vascular remodelling and right ventricular failure. Current treatments are not curative and new therapeutic strategies are urgently required. Clinical and pre-clinical evidence has established that inflammation plays a key role in PH pathogenesis, and recently inflammasomes have been suggested to be central to this process. Read More

    Generation of multi-functional target organ specific anti-fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin.
    Br J Pharmacol 2018 May 30. Epub 2018 May 30.
    Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
    Extracellular matrix (ECM) molecules play important roles in regulating processes such as cell proliferation, migration, differentiation and survival. Decorin (DCN) is a proteoglycan that binds to ("decorates") collagen fibrils in the ECM. DCN also interacts with multiple growth factors and their receptors, the most notable of these interactions being its inhibitory activity on transforming growth factor-β (TGF-β), the growth factor responsible for fibrosis formation. Read More

    The Reaction of Hydrogen Sulfide with Disulfides: Formation of a Stable Trisulfide and Implications to Biological Systems.
    Br J Pharmacol 2018 May 29. Epub 2018 May 29.
    Department of Chemistry, Sonoma State University, Rohnert Park, CA, 94928, USA.
    Background And Purpose: The signaling associated with hydrogen sulfide (H S) remains to be established and recent studies have alluded to the possibility that H S-derived species play important roles. Of particular interest are hydropersulfides (RSSH) and related polysulfides (RSS R, n>1). This work elucidates the fundamental chemical relationship between these sulfur species as well as examine their biological effects. Read More

    Sulfite protects neurons from oxidative stress.
    Br J Pharmacol 2018 May 29. Epub 2018 May 29.
    National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
    Background And Purpose: Hydrogen sulfide (H S) and polysulfides (H S ) are signaling molecules that mediate various physiological responses including cytoprotection. Their oxidized metabolite sulfite (SO ) exists in blood and tissues. However, its physiological role remains unclear. Read More

    Immune Cell Trafficking, Lymphatics, and Hypertension.
    Br J Pharmacol 2018 May 24. Epub 2018 May 24.
    Department of Medical Physiology, Texas A&M College of Medicine, College Station, Texas, 77843-1114, United States of America.
    Activated immune cell infiltration into organs contributes to the development and maintenance of hypertension. Studies targeting specific immune cell populations or reducing their inflammatory signaling have demonstrated a reduction in blood pressure. Lymphatic vessels play a role in immune cell trafficking and resolving inflammation, but little is known about their role in hypertension. Read More

    EFFECT OF ENDOCANNABINOID SIGNALLING ON CELL FATE: LIFE, DEATH, DIFFERENTIATION AND PROLIFERATION OF BRAIN CELLS.
    Br J Pharmacol 2018 May 24. Epub 2018 May 24.
    Department of Life Sciences, University of Roehampton, Whitelands College, London, SW15 4JD, UK.
    Cell fate events are regulated by different endogenous developmental factors such as cell microenvironment, external or remote signals and epigenetic regulation. Among the many regulatory factors, endocannabinoid associated signalling pathways are known to lead several of these events in the developing nervous system and in the adult brain. Interestingly, endocannabinoids exert its modulatory actions in health and pathological conditions. Read More

    The Isothiocyanate Sulforaphane Modulates Platelet Function and Protects Against Cerebral Thrombotic Dysfunction.
    Br J Pharmacol 2018 May 24. Epub 2018 May 24.
    Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, Louisiana, USA.
    Background And Purpose: Platelet activation provides a critical link between inflammation and thrombosis. Sulforaphane (SFN), a naturally occurring isothiocyanate, has been shown to display both anti-inflammatory and anti-thrombotic actions in the systemic microvasculature. As inflammation promotes thrombosis and vice versa, this study investigates whether SFN is able to reduce inflammatory potentiation of thrombotic events, suppress platelet activation and thrombus formation in the cerebral microvasculature. Read More

    PF-06526290 can both enhance and inhibit conduction through voltage-gated sodium channels.
    Br J Pharmacol 2018 May 23. Epub 2018 May 23.
    Icagen Inc., Durham, NC, 27703, USA.
    Background And Purpose: Pharmacological agents that either inhibit or enhance flux of ions through voltage-gated sodium (Na ) channels may provide opportunities for treatment of human health disorders. During studies to characterize agents that modulate Na 1.3 function, we identified a compound that appears to exhibit both enhancement and inhibition of sodium ion conduction that appeared to be dependent on the gating state that the channel was in. Read More

    Drug-Gut Microbiota Interactions: Implications for Neuropharmacology.
    Br J Pharmacol 2018 May 21. Epub 2018 May 21.
    Department of Pharmacology and Therapeutics, University College Cork.
    The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the impact that drugs can have on the function and composition of the gut microbiome. Read More

    Luteolin ameliorates rat myocardial ischemia-reperfusion injury through peroxiredoxin II activation.
    Br J Pharmacol 2018 May 21. Epub 2018 May 21.
    Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou, Henan, 450001, P. R. China.
    Background And Purpose: Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin (LUT), a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanism, especially the role of LUT on the antioxidant enzymes (e.g. Read More

    Modulation of serine/threonine phosphatases by melatonin: therapeutic approaches in neurodegenerative diseases.
    Br J Pharmacol 2018 May 20. Epub 2018 May 20.
    Instituto-Fundación Teófilo Hernando and Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain.
    Melatonin is an endogenous hormone produced by the pineal gland as well as many other tissues and organs. The natural decline in melatonin levels with aging strongly contributes to the development of neurodegenerative disorders. Neurodegenerative diseases share common mechanisms of toxicity such as proteinopathy, mitochondrial dysfunction, metal dyshomeostasis, oxidative stress, neuroinflammation, and an imbalance in the phosphorylation/dephosphorylation ratio. Read More

    Platelets, autotaxin and lysophosphatidic acid signaling: win-win factors for cancer metastasis.
    Br J Pharmacol 2018 May 19. Epub 2018 May 19.
    INSERM, UMR_S1033, Université Claude Bernard Lyon-1, Lyon, France.
    Platelets play a crucial role in the survival of metastatic cells in the blood circulation. Interaction of tumor cells with platelets leads to the production of plethoric factors among which our review will focus on lysophosphatidic acid (LPA) because platelets are the highest producers of this bioactive lysophospholipid in the organism. LPA promotes platelet aggregation and blocking platelet function leads to inhibition of breast cancer cell metastasis through decreased LPA signaling. Read More

    Human Monocyte Transciptional Profiling Identifies Interleukin 18 Receptor Accessory Protein and Lactoferrin as Novel Immune Targets in Hypertension.
    Br J Pharmacol 2018 May 18. Epub 2018 May 18.
    Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
    Background And Purpose: Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of select genes to identify novel therapeutic targets for hypertension.

    Experimental Approach: Next-generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Read More

    Cardiomyocyte programmed necrosis: mitochondria, death receptor and beyond.
    Br J Pharmacol 2018 May 18. Epub 2018 May 18.
    State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
    Excessive death of cardiac myocytes leads to multiple cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of multiple organs, including the heart. Read More

    Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor-driven transcription of hepatic lipogenic genes in vivo.
    Br J Pharmacol 2018 May 18. Epub 2018 May 18.
    Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
    Background And Purpose: Agonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol-driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by concomitant LXR-induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co-activator of LXR activity. Read More

    Central adenosine A receptors inhibit cough via suppression of excitatory glutamatergic and tachykininergic neurotransmission.
    Br J Pharmacol 2018 May 16. Epub 2018 May 16.
    Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
    Background And Purpose: The A adenosine receptor is reported to mediate several excitatory effects in the airways and has inhibitory effects in the central nervous system. In this study, we investigated the role of peripheral and central A adenosine receptors in regulating cough and airway obstruction.

    Experimental Approach: Drugs were administered to guinea pigs via the inhaled or intracerebroventricular (i. Read More

    Salt, inflammation, IL-17 and hypertension.
    Br J Pharmacol 2018 May 16. Epub 2018 May 16.
    Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
    Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Read More

    Hydrogen sulfide pathway and skeletal muscle: an introductory review.
    Br J Pharmacol 2018 May 16. Epub 2018 May 16.
    Department of Pharmacy, School of Medicine, University of Naples 'Federico II', Naples, 80131, Italy.
    The presence of the H S pathway in skeletal muscle (SKM) has recently been established. SKM expresses the three constitutive H S-generating enzymes in animals and humans, and it actively produces H S. The main, recognized molecular targets of H S, that is, potassium channels and PDEs, have been evaluated in SKM physiology in order to hypothesize a role for H S signalling. Read More

    Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells.
    Br J Pharmacol 2018 May 10. Epub 2018 May 10.
    Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan.
    Cysteine persulfide and polysulfide are produced in cells and exist in abundance in both low MW and protein fractions. However, the mechanism of regulation of the formation of cellular cysteine polysulfides and the physiological functions of cysteine persulfides/polysulfides produced in cells are not fully understood. We recently demonstrated that cysteinyl-tRNA synthetase (CARS) is a novel cysteine persulfide synthase. Read More

    Arrhythmic hazard map for a 3D whole-ventricles model under multiple ion channel block.
    Br J Pharmacol 2018 May 10. Epub 2018 May 10.
    UT-Heart Inc., 3-25-8 Nozawa, Setagaya-ku, Tokyo, 154-0003, Japan.
    Background And Purpose: To date, proposed in silico models for preclinical cardiac safety testing are limited in their predictability and usability. We previously reported a multi-scale heart simulation that accurately predicts arrhythmogenic risk for benchmark drugs.

    Experimental Approach: We extend this approach and report the first comprehensive hazard map of drug-induced arrhythmia based on the exhaustive in silico electrocardiogram (ECG) database of drug effects, developed using a petaflop computer. Read More

    Targeting the dopamine D receptor or its downstream signalling by inhibiting phosphodiesterase-1 improves cognitive performance.
    Br J Pharmacol 2018 May 3. Epub 2018 May 3.
    CNS Discovery Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, 88397, Germany.
    Background And Purpose: Insufficient prefrontal dopamine 1 (D ) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D receptor-dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D receptor function.

    Experimental Approach: Cognitive performance of the D receptor agonist, SKF38393, was studied in the T-maze continuous alternation task and 5-choice serial reaction time task. Read More

    A novel cross-species inhibitor to study the function of CatSper Ca channels in sperm.
    Br J Pharmacol 2018 May 3. Epub 2018 May 3.
    University Hospital Münster, Centre of Reproductive Medicine and Andrology, Münster, Germany.
    Background And Purpose: Sperm from many species share the sperm-specific Ca channel CatSper (cation channel of sperm) that controls the intracellular Ca concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling CatSper activity and the role of the channel during fertilization differ among species. However, a lack of suitable pharmacological tools has hampered the elucidation of the function of CatSper. Read More

    High-frequency autonomic modulation: a new model for analysis of autonomic cardiac control.
    Br J Pharmacol 2018 May 3. Epub 2018 May 3.
    Laboratoire PHYMEDEXP,INSERM U1046, CNRS UMR 9214, Université de Montpellier, CHU Arnaud de Villeneuve, Montpellier Cedex 05, 34295, France.
    Background And Purpose: Increase in high-frequency beat-to-beat heart rate oscillations by torsadogenic hERG blockers appears to be associated with signs of parasympathetic and sympathetic co-activation which cannot be assessed directly using classic methods of heart rate variability analysis. The present work aimed to find a translational model that would allow this particular state of the autonomic control of heart rate to be assessed.

    Experimental Approach: High-frequency heart rate and heart period oscillations were analysed within discrete 10 s intervals in a cohort of 200 healthy human subjects. Read More

    PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial-mesenchymal transition.
    Br J Pharmacol 2018 May 3. Epub 2018 May 3.
    Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
    Background And Purpose: PEP06, a polypeptide modified from endostatin, was investigated for its antitumour effects on colorectal cancer (CRC) and the possible mechanisms of this antitumour activity were examined in in vitro and in vivo models.

    Experimental Approach: After PEP06 treatment, cell proliferation and migration assays were performed in CRC cells. Epithelial-mesenchymal transition (EMT) progression was determined by Western blotting, immunofluorescent staining and immunohistochemistry in vitro and in a residual xenograft model. Read More

    Tolerance to high-internalizing δ opioid receptor agonist is critically mediated by arrestin 2.
    Br J Pharmacol 2018 May 3. Epub 2018 May 3.
    Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
    Background And Purpose: Opioid δ receptor agonists are potent antihyperalgesics in chronic pain models, but tolerance develops after prolonged use. Previous evidence indicates that distinct forms of tolerance occur depending on the internalization properties of δ receptor agonists. As arrestins are important in receptor internalization, we investigated the role of arrestin 2 (β-arrestin 1) in mediating the development of tolerance induced by high- and low-internalizing δ receptor agonists. Read More

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