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British Journal of Pharmacology

Qi Zhao, Ting Zhang, Xue-Rong Xiao, Jian-Feng Huang, Yan Wang, Frank J Gonzalez, Fei Li
BACKGROUND AND PURPOSE: Sunitinib is a small molecule tyrosine kinase inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. EXPERIMENTAL APPROACH: In the present study, mice were treated with 60 mg kg-1, 150 mg kg-1, and 450 mg kg-1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, feces, and urine were analyzed using ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics...
March 15, 2019: British Journal of Pharmacology
Jared R Bagley, Karen K Szumlinski, Tod E Kippin
BACKGROUND AND PURPOSE: Addiction vulnerability involves complex gene X environment interactions leading to a pathological response to drugs. Identification of the genes mediating these interactions is an important step in understanding the underlying neurobiology and rarely have such analyses examined sex-specific influences. To dissect this interaction, we examined the impact of prenatal stress (PNS) on cocaine responsiveness in male and female mice of the BXD recombinant inbred panel...
March 15, 2019: British Journal of Pharmacology
Maura Calvani, Gennaro Bruno, Massimo Dal Monte, Romina Nassini, Filippo Fontani, Arianna Casini, Lorenzo Cavallini, Matteo Becatti, Francesca Bianchini, Francesco De Logu, Giulia Forni, Giancarlo la Marca, Lido Calorini, Paola Bagnoli, Paola Chiarugi, Alberto Pupi, Chiara Azzari, Pierangelo Geppetti, Claudio Favre, Luca Filippi
BACKGROUND AND PURPOSE: Stress-related catecholamines have a role in cancer and β-adrenoceptors, specifically β2-adrenoceptors have been identified as new targets in treating melanoma. Recently, β3-adrenoceptors have shown a pleiotropic effect on melanoma microenvironment leading to cancer progression. However, the mechanisms by which β3-adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis...
March 15, 2019: British Journal of Pharmacology
Yasuhiko Igawa, Naoki Aizawa, Martin C Michel
β3 -Adrenoceptor (β3 -AR) agonists are used in the treatment of overactive bladder syndrome (OAB). Although the relaxant response to adrenergic stimulation in human detrusor smooth muscle cells is mediated mainly via β3 -AR s, the plasma concentrations of the therapeutic dose of mirabegron, the only clinically approved β3 -AR agonist, are considerably lower than the EC50 for causing direct relaxation of human detrusor, suggesting the mechanism of action other than direct relaxation of detrusor smooth muscle...
March 14, 2019: British Journal of Pharmacology
Victoria M McLeod, Chew L Lau, Mathew D F Chiam, Thusitha W Rupasinghe, Ute Roessner, Elvan Djouma, Wah C Boon, Bradley J Turner
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease typically more common in males, implicating androgens in progression of both patients and mouse models. Androgen effects are mediated by the androgen receptor (AR) which is highly expressed in spinal motor neurons and skeletal muscles. To clarify the role of AR in ALS, we therefore examined the effect of AR antagonism in the SOD1G93A mouse model. EXPERIMENTAL APPROACH: The androgen receptor antagonist, flutamide, was administered to presymptomatic SOD1G93A mice as a slow-release subcutaneous implant (5 mg...
March 8, 2019: British Journal of Pharmacology
Shau-Yu Liu, Yun-Li Ma, Wei-Lun Hsu, Hsin-Ying Chiou, Eminy H Y Lee
BACKGROUND AND PURPOSE: PIAS1 is phosphorylated by IKKα at Ser-90 in a PIAS1 E3 ligase activity-dependent manner. Whether PIAS1 is also phosphorylated at other residues, and what potential functional significance such additional phosphorylation events might have, are not known. The transcription factor Elk-1 remains SUMOylated under basal conditions, but the role of Elk-1 SUMOylation in the brain is unknown. Here, we examined the functional significance of PIAS1-mediated Elk-1 SUMOylation in the context of Alzheimer's disease (AD) using the APP/PS1 mouse model of AD and amyloid beta (Aβ) microinjection in vivo...
March 8, 2019: British Journal of Pharmacology
Emma Mitidieri, Danila Gurgone, Elisabetta Caiazzo, Teresa Tramontano, Carla Cicala, Raffaella Sorrentino, Roberta d'Emmanuele di Villa Bianca
BACKGROUND AND PURPOSE: Among the three enzymes involved in the transsulfuration pathway only cystathionine β-synthase (CBS) converts L-cysteine into L-serine and H2 S. L-serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl-CoA by the action of serine palmitoyltransferase (SPT). Here we have investigated if L-serine is involved in the vasorelaxant effect. EXPERIMENTAL APPROACH: The presence of CBS in mice vascular endothelium was assessed by immunohistochemistry and immunofluorescence...
March 5, 2019: British Journal of Pharmacology
John L Wallace, Peter Nagy, Troy D Feener, Thibault Allain, Tamás Ditrói, David J Vaughan, Marcelo N Muscara, Gilberto de Nucci, Andre G Buret
BACKGROUND AND PURPOSE: ATB-346 is a hydrogen sulfide-releasing anti-inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of cyclo-oxygenase activity and significant analgesic and anti-inflammatory effects. In humans, ATB-346 (250 mg once daily) was found to inhibit cyclooxygenase to the same extent as naproxen (550 mg twice daily). EXPERIMENTAL APPROACH: 244 healthy volunteers completed a two-week, double-blind study, taking either ATB-346 (250 mg od) or naproxen (550 mg bid), with upper GI ulceration being examined endoscopically...
March 4, 2019: British Journal of Pharmacology
Victor Fattori, Felipe A Pinho-Ribeiro, Larissa Staurengo-Ferrari, Sergio M Borghi, Ana C Rossaneis, Rubia Casagrande, Waldiceu A Verri
BACKGROUND: MaR1 is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and spinal cord cells by MaR1 in inflammatory pain context. EXPERIMENTAL APPROACH: Mice were treated with MaR1 before intraplantar injection of carrageenan or complete Freund's Adjuvant (CFA). Mechanical hyperalgesia was assessed using the electronic von Frey and thermal hyperalgesia using a hot plate...
March 4, 2019: British Journal of Pharmacology
Yu-Meng Jia, Huan Zhou, Ting Tai, Tong-Tong Gu, Jin-Zi Ji, Qiong-Yu Mi, Bei-Bei Huang, Yi-Fei Li, Ting Zhu, Hong-Guang Xie
BACKGROUND AND PURPOSE: Vicagrel is a novel promising antiplatelet drug designed for overcoming clopidogrel resistance. Limited evidence indicated that exogenous interleukin (IL)-10 suppresses CYP3A4 activity in healthy subjects, and that IL-10 knock-out (KO) mice exhibit increased clopidogrel bioactivation compared with wild-type (WT) mice. In this study, we sought to determine whether IL-10 could play an important role in the metabolism of and platelet response to vicagrel in mice. EXPERIMENTAL APPROACH: After IL-10 KO and WT mice were administrated with vicagrel, their plasma H4 concentrations were determined by liquid chromatography-tandem mass spectrometry, and inhibition of ADP-induced whole-blood platelet aggregation by vicagrel was assessed with an aggregometer...
March 2, 2019: British Journal of Pharmacology
Alma Martelli, Eugenia Piragine, Valentina Citi, Lara Testai, Eleonora Pagnotta, Luisa Ugolini, Luca Lazzeri, Lorenzo Di Cesare Mannelli, Onorina Laura Manzo, Mariarosaria Bucci, Carla Ghelardini, Maria Cristina Breschi, Vincenzo Calderone
BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S)-releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H2 S-donor agents. Among them, Erucin, present in some edible Cruciferous plants, shows suitable H2 S-releasing properties and features of "druggability". The aim of this work was to investigate the Erucin-mediated release of H2 S inside vascular cells, its vasorelaxing effects and activity on blood pressure of normo- and hypertensive animals...
March 2, 2019: British Journal of Pharmacology
Xiaofei Chen, Chunlin Zhuang, Yibin Ren, Hao Zhang, Xia Qin, Longmiao Hu, Jing Fu, Zhenyuan Miao, Yifeng Chai, Zheng-Gang Liu, Haibing Zhang, Zhenyu Cai, Hong-Yang Wang
BACKGROUND AND PURPOSE: Necroptosis is a form of programmed, caspase-independent cell death that is mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious and degenerative diseases. Thus, identification of small molecule inhibitors for necroptosis has broad therapeutic relevance. Herein, we identified that TAK-632 was an inhibitor of necroptosis and further generated a more selective, highly potent analogue by targeting RIPK1 and RIPK3...
March 1, 2019: British Journal of Pharmacology
Ismail Suliman Elgenaidi, James Paul Spiers
BACKGROUND AND PURPOSE: Although protein phosphatases regulate several aspects of cellular function, their expression pattern and modulation under hypoxia remains poorly understood. We investigated the expression of key components of the protein phosphatase system in human cardiovascular cells under normoxic/hypoxic conditions and the mechanism by which hypoxia alters PP2A activity. EXPERIMENTAL APPROACH: Cardiovascular cell lines were cultured in cell type specific media under normoxic or hypoxic conditions (1% O2 )...
March 1, 2019: British Journal of Pharmacology
Xiangcui Chen, Qipeng Wu, Yueming Chen, Jiahao Zhang, Huachao Li, Zhicheng Yang, Yang Yang, Yanchao Deng, Luyong Zhang, Bing Liu
BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers with a disappointing prognosis. Flavonoids exert anti-cancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and the ability to enhance the anti-tumour activity of paclitaxel. EXPERIMENTAL APPROACH: NSCLC cells, normal cell lines HLF-1 and BEAS-2B, as well as immunodeficient mice were chosen as a model to study the treatment effects...
March 1, 2019: British Journal of Pharmacology
Liang Zhang, Kaouter Bouadjel, Boris Manoury, Grégoire Vandecasteele, Rodolphe Fischmeister, Véronique Leblais
BACKGROUND AND PURPOSE: PDE upregulation is associated with several vascular diseases and better understanding of the respective role of each PDE family in controlling subcellular pools of cyclic nucleotides in vascular cells is needed. We investigated the respective role of PDE1, PDE5 and PDE9 in controlling intracellular cAMP and/or cGMP concentrations ([cAMP]i , [cGMP]i ) in cultured rat aortic smooth muscle cells (RASMCs). EXPERIMENTAL APPROACH: By using a pharmacological approach with selective PDE1, PDE5 and PDE9 inhibitors (PF-04471141, sildenafil and PF-04447943, respectively), cAMP- and cGMP-PDE activities were measured by a radioenzymatic assay in protein extracts...
March 1, 2019: British Journal of Pharmacology
Michele Fiore, Claudia Cossu, Valeria Capurro, Cristiana Picco, Alessandra Ludovico, Marcin Mielczarek, Israel Carreira-Barral, Emanuela Caci, Debora Baroni, Roberto Quesada, Oscar Moran
BACKGROUND AND PURPOSE: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CFTR protein, a cAMP-dependent anion channel involved in fluid transport across epithelium. Due to their capability to replace the ion transport independently from the genetic mutation that affects the CFTR, small synthetic transmembrane anion transporters, named anionophores, are candidates as new potential CF therapeutics. EXPERIMENTAL APPROACH: With the aim of evaluating their impact on cell physiology, we have analysed the transport properties of five compounds, three prodigiosines and two tambjamines...
March 1, 2019: British Journal of Pharmacology
Ting Zhang, Mark Gillies, Ying Wang, Weiyong Shen, Bobak Bahrami, Shaoxue Zeng, Meidong Zhu, Wenjuan Yao, Fanfan Zhou, Michael Murray, Ke Wang, Ling Zhu
BACKGROUND AND PURPOSE: Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with multiple targets and effects. It protects neurons in the brain but its protective effects on photoreceptors are unclear. In this study, we evaluated the neuroprotective effect of simvastatin on photoreceptors exposed to stress induced by all-trans-retinal (atRAL). EXPERIMENTAL APPROACH: AlamarBlue and lactate dehydrogenase assays were used to evaluate the viability and metabolic activity of Y79 cells (a retinoblastoma cell line) exposed to atRAL-induced stress with or without simvastatin pre-treatment...
March 1, 2019: British Journal of Pharmacology
Marie-Lynda Bouressam, Sandra Lecat, Alexandre Raoul, Caroline Gaucher, Caroline Perrin-Sarrado, Isabelle Lartaud, François Dupuis
BACKGROUND AND PURPOSE: Angiotensin II (AngII) and nitric oxide (NO) regulate cerebral circulation. AngII AT1 receptors exert ligand-dependent and -independent (myogenic tone, MT) vasoconstriction of cerebral vessels. NO induces post-translational modifications of proteins such as S-nitrosation (redox modification of cysteine residues). In cultured cells, S-nitrosation decreases AngII affinity for AT1 . The present work evaluated the functional consequences of S-nitrosation on both AngII-dependent and AngII-independent cerebrovascular responses...
March 1, 2019: British Journal of Pharmacology
Timothy Mark Newton, James A Duce, Elliott David Bayle
The production, quality control, and degradation of proteins is a tightly controlled process necessary for cell health. In order to regulate this process cells rely upon a network of molecular chaperone proteins that bind misfolded proteins and help them fold correctly. In addition, some molecular chaperones can target terminally misfolded proteins for degradation. Neurons are particularly dependent upon this 'proteostasis' system, failures in which lead to neurodegenerative disease. In this review we identify opportunities for modulating molecular chaperone activity with small molecules, which could lower the burden of misfolded protein within neurons, reducing cell death and ameliorating the effects of neurodegeneration...
February 28, 2019: British Journal of Pharmacology
Darren C Henstridge, Julie Abildgaard, Birgitte Lindegaard, Mark A Febbraio
BACKGROUND AND PURPOSE: Men and women have many differing biological and physiological characteristics. Thus, it is no surprise, that the control of metabolic processes and the mechanisms underlying metabolic-related diseases have sex-specific components. There is a clear metabolic sexual dimorphism in that up until mid-life, men have a far greater likelihood of acquiring cardio-metabolic disease than women. Following menopause, however, this difference is reduced, suggestive of a protective role of the female sex hormones...
February 28, 2019: British Journal of Pharmacology
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