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British Journal of Pharmacology

Hannah Ceuleers, Nikita Hanning, Jelena Heirbaut, Samuel Van Remoortel, Michelle De Bruyn, Jurgen Joossens, Pieter van der Veken, Anne-Marie Lambeir, Sven M Francque, Joris G De Man, Jean-Pierre Timmermans, Koen Augustyns, Ingrid De Meester, Benedicte Y De Winter
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 0.9% NaCl. Colonoscopies were performed on day 3, to confirm colitis, and later on until mucosal healing. Visceral hypersensitivity was quantified by visceromotor responses (VMR) to colorectal distension, 30 min after intraperitoneal injection of the serine protease inhibitors nafamostat, UAMC-00050 or UAMC-01162...
June 17, 2018: British Journal of Pharmacology
Virág Bogdándi, Tomoaki Ida, Thomas R Sutton, Christopher Bianco, Tamás Ditrói, Grielof Koster, Hillary A Henthorn, Magda Minnion, John P Toscano, Albert van der Vliet, Michael D Pluth, Martin Feelisch, Jon M Fukuto, Takaaki Akaike, Péter Nagy
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...
June 17, 2018: British Journal of Pharmacology
Xuan Liu, Tao Shen, Blaine H M Mooers, Frank Hilberg, Jie Wu
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...
June 16, 2018: British Journal of Pharmacology
Jiajia Dong, Olajide E Olaleye, Rongrong Jiang, Jing Li, Chuang Lu, Feifei Du, Fang Xu, Junling Yang, Fengqing Wang, Weiwei Jia, Chuan Li
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...
June 16, 2018: British Journal of Pharmacology
Guo-Sheng Xiao, Yan-Hui Zhang, Yan Wang, Hai-Ying Sun, Clive M Baumgarten, Gui-Rong Li
BACKGROUND AND PURPOSE: Adrenergic regulation of cell volume-regulated chloride current (ICl.vol ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of ICl.vol in human atrial myocytes. EXPERIMENTAL APPROACH: A conventional whole-cell patch voltage-clamp technique was utilized to record membrane current in human atrial myocytes. ICl.vol was evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T). KEY RESULTS: ICl...
June 13, 2018: British Journal of Pharmacology
Linlin Zhong, Tuan Tran, Tyler D Baguley, Sang Jun Lee, Adam Henke, Andrew To, Sijia Li, Shan Yu, Fabio A Grieco, Jason Roland, Peter G Schultz, Decio L Eizirik, Nikki Rogers, Arnab K Chartterjee, Matthew S Tremblay, Weijun Shen
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...
June 11, 2018: British Journal of Pharmacology
Jeremy D Hill, Viviana Zuluaga-Ramirez, Sachin Gajghate, Malika Winfield, Yuri Persidsky
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 (CB1 R) or cannabinoid 2 receptor (CB2 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...
June 11, 2018: British Journal of Pharmacology
Philip Wenzel
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. All these facets offer the possibility to pharmacologically target monocytes and may represent novel therapeutic avenues to treat hypertension, attenuate hypertension-associated end organ damage or prevent development or deterioration of high blood pressure...
June 8, 2018: British Journal of Pharmacology
Lichen Bao, Jun Yin, Wen Gao, Qun Wang, Wenbing Yao, Xiangdong Gao
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. However, the challenges in developing FGF21 as a novel medicine include its short plasma half-life and poor drug-like properties. Here, we explored the therapeutic effects of PsTag600-FGF21, an engineered long-acting FGF21 fusion protein, in NASH mice and revealed some of the mechanisms responsible for this activity...
June 2, 2018: British Journal of Pharmacology
Hussein N Rubaiy, Melanie J Ludlow, Karsten Siems, Katherine Norman, Richard Foster, Dietmar Wolf, John A Beutler, David J Beech
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 Ca2+ measurement or whole-cell or excised membrane patch-clamp electrophysiology...
June 2, 2018: British Journal of Pharmacology
Adrián Viudez-Martínez, María S García-Gutiérrez, Ana Isabel Fraguas-Sánchez, Ana Isabel Torres-Suárez, Jorge Manzanares
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.o.) and/or CBD (20 mg/kg/day; s.c.) on ethanol consumption and motivation to drink were evaluated in the oral-ethanol self-administration paradigm in C57BL/6 mice...
June 2, 2018: British Journal of Pharmacology
Yanhua Cheng, Paul M Vanhoutte, Susan W S Leung
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...
June 2, 2018: British Journal of Pharmacology
Jon M Fukuto
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. Indeed, the pharmacological potential for HNO as a treatment for heart failure, among other uses, has garnered this curious molecule tremendous recent attention...
June 2, 2018: British Journal of Pharmacology
Anyue Yin, Akihiro Yamada, Wiro B Stam, Johan G C van Hasselt, Piet H van der Graaf
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...
June 2, 2018: British Journal of Pharmacology
Javier Fernández-Ruiz
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...
June 1, 2018: British Journal of Pharmacology
Nicholas Don-Doncow, Yun Zhang, Hana Matuskova, Anja Meissner
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. Amongst other cell types, lymphocytes express distinct profiles of G-protein-coupled receptors for sphingosine-1-phosphate (S1P) - a bioactive phospholipid that is involved in many critical cell processes and most importantly, majorly regulates T-cell development, lymphocyte recirculation, tissue homing patterns, and chemotactic responses...
June 1, 2018: British Journal of Pharmacology
Lijun Zhang, Jae Hong Seo, Huan Li, Ghilsoo Nam, Hyun Ok Yang
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...
May 30, 2018: British Journal of Pharmacology
Kieran Rea, Fiona McGowan, Louise Corcoran, Michelle Roche, David P Finn
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...
May 30, 2018: British Journal of Pharmacology
Tara Elizabeth Scott, Barbara K Kemp-Harper, Adrian J Hobbs
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. Inflammasomes are important regulators of inflammation, releasing pro-inflammatory cytokines interleukin (IL)-1βand IL-18 in response to exogenous pathogen- and endogenous damage-associated molecular patterns...
May 30, 2018: British Journal of Pharmacology
Tero A H Järvinen, Erkki Ruoslahti
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. We have generated a recombinant, multi-functional, fusion-protein consisting of DCN as a therapeutic domain and vascular homing and cell penetrating peptide as a targeting vehicle...
May 30, 2018: British Journal of Pharmacology
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