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British Journal of Pharmacology

Michael Basler, Elmer Maurits, Gerjan de Bruin, Julia Koerner, Herman S Overkleeft, Marcus Groettrup
BACKGROUND AND PURPOSE: MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome, a special type of proteasome mainly expressed in hematopoietic cells. Targeting LMP7 has been shown to be therapeutically effective in pre-clinical models of autoimmune diseases. In this study, a recently described inhibitor of the immunoproteasome LU-005i was investigated with respect to selectivity and biological activity. EXPERIMENTAL APPROACH: The specificity of LU-005i and other immunoproteasome selective inhibitors was characterized using fluorogenic peptide substrates...
October 15, 2017: British Journal of Pharmacology
Shoraku Ryu, Mitsuhiro Hayashi, Hiroaki Aikawa, Isamu Okamoto, Yasuhiro Fujiwara, Akinobu Hamada
BACKGROUND AND PURPOSE: The penetration of the anaplastic lymphoma kinase (ALK) inhibitor alectinib in neuroblastomas and the relationship between alectinib and ALK expression are unknown. The aim of this study was to perform a quantitative investigation of the inter- and intra-tumoural distribution of alectinib in different neuroblastoma xenograft models using matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI). EXPERIMENTAL APPROACH: The distribution of alectinib in NB1 (ALK amplification) and SK-N-FI (ALK wild-type) xenograft tissues was analysed using MALDI-MSI...
October 13, 2017: British Journal of Pharmacology
Erica Smyth, Antonia Solomon, Mark A Birrell, Miranda J Smallwood, Paul G Winyard, Teresa D Tetley, Michael Emerson
No abstract text is available yet for this article.
October 10, 2017: British Journal of Pharmacology
Matthias Barton, Eric R Prossnitz
No abstract text is available yet for this article.
October 6, 2017: British Journal of Pharmacology
Helen M Heymann, Yun Wu, Yao Lu, Nir Qvit, Garrett J Gross, Eric R Gross
BACKGROUND AND PURPOSE: In light of the opioid epidemic, physicians are increasingly prescribing non-opioid analgesics to surgical patients. Transient receptor potential vanilloid 1 (TRPV1) inhibitors are potentially alternative pain therapeutics for surgery. Here we examined in rodents whether cardioprotection conferred by two occurrences during surgery, a laparotomy or morphine delivery, is mediated by TRPV1. We further tested whether an experimental analgesic peptide (known as P5) targeted against the TRPV1 C-terminus region interferes with laparotomy- or morphine-induced cardioprotection...
October 5, 2017: British Journal of Pharmacology
Brian C Jensen, Traci L Parry, Wei Huang, Ju Youn Beak, Amro Ilaiwy, James R Bain, Christopher B Newgard, Michael J Muehlbauer, Cam Patterson, Gary L Johnson, Monte S Willis
BACKGROUND AND PURPOSE: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signaling pathways that control metabolism, cell cycle progression, cell death, differentiation, and survival. It is not surprising, then, that new kinase inhibitors (KIs) developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism...
October 4, 2017: British Journal of Pharmacology
Tahlia Sundrum, Christopher S Walker
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in a wide range of functions including vasodilation, neuroprotection, nociception and neurogenic inflammation. PACAP activates three distinct receptors, the PAC1 receptor, which responds to PACAP and the VPAC1 and VPAC2 receptors, which respond to both PACAP and vasoactive intestinal polypeptide (VIP). The trigeminovascular system plays a key role in migraine and contains the trigeminal nerve, which is the major conduit of craniofacial pain...
October 4, 2017: British Journal of Pharmacology
Natalie A Duggett, Sarah J L Flatters
BACKGROUND: Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first-line treatment due to lack of treatment. The aim of this study was to characterise a clinically-relevant rat model of bortezomib-induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery. EXPERIMENTAL APPROACH: Adult male Sprague-Dawley rats were injected intraperitoneally (i...
October 3, 2017: British Journal of Pharmacology
Runisha Moodaley, David M Smith, Iain R Tough, Marcus Schindler, Helen M Cox
BACKGROUND AND PURPOSE: Free fatty acid receptor 1 (FFA1) and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation causes the release of glucagon-like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic β-cells. As these receptors are modulators of nutrient-stimulated glucose regulation, this study's aim was to compare the pharmacology of commercially available agonists (TUG424, TUG891, GW9508) with proven selective agonists (JTT, TAK-875, AZ423, Metabolex-36), in the mouse...
October 3, 2017: British Journal of Pharmacology
Sarra G Bahna, Lennard P Niles
Melatonin, the primary indoleamine hormone of the mammalian pineal gland, is known to have a plethora of neuroregulatory, neuroprotective and other properties. Melatonergic signaling is mediated by its two G protein-coupled receptors, MT1 and MT2 , which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal aging, and this reduction may be accelerated in some disease states. Depleted melatonergic signaling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes...
October 2, 2017: British Journal of Pharmacology
Abdulrahman Almatroudi, Mehrnoosh Ostovar, Christopher P Bailey, Stephen M Husbands, Sarah J Bailey
BACKGROUND AND PURPOSE: Κ-opioid receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. EXPERIMENTAL APPROACH: To determine the opioid pharmacology of BU10119 (0.3-3 mg/kg, i.p.) in vivo, the warm-water tail withdrawal assay was used in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119...
October 1, 2017: British Journal of Pharmacology
Guendalina Olivero, Tommaso Bonfiglio, Matteo Vergassola, Cesare Usai, Barbara Riozzi, Giuseppe Battaglia, Ferdinando Nicoletti, Anna Pittaluga
BACKGROUND AND PURPOSE: We recently proposed the existence of mGlu3-preferring autoreceptors in spinal cord terminals and of mGlu2-preferring autoreceptors in cortical terminals. This study aims to verify our previous conclusions and to extend their pharmacological characterization. EXPERIMENTAL APPROACH: We studied the effect of LY566332, an mGlu2 receptors positive allosteric modulator (PAM) and of LY2389575, a selective mGlu3 receptor negative allosteric (NAM) modulator, on the mGlu2/3 agonist LY379268-mediated inhibition of glutamate exocytosis [measured as KCl-evoked release of preloaded [(3) H]-D-aspartate ([(3) H]-D-Asp)]...
October 1, 2017: British Journal of Pharmacology
Arun Samidurai, Fadi N Salloum, David Durrant, Olga B Chernova, Rakesh C Kukreja, Anindita Das
BACKGROUND: Enhanced mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR, that have been rationally designed to increase water solubility of rapamycin in order to facilitate oral administration and enhance bioavailability. We examined the effect of Rapatar in improving metabolic status and protection against myocardial I/R injury in type 2 diabetic (T2D) mice...
October 1, 2017: British Journal of Pharmacology
Xiao Han, Bin Li, Xin Ye, Tunike Mulatibieke, Jianghong Wu, Juanjuan Dai, Deqing Wu, Jianbo Ni, Ruling Zhang, Jing Xue, Rong Wan, Xingpeng Wang, Guoyong Hu
BACKGROUND AND PURPOSE: Dopamine (DA) has multiple anti-inflammatory effects, but its role and molecular mechanism in acute pancreatitis (AP) is unclear. We investigated the role of DA signaling on inflammatory response in AP. EXPERIMENTAL APPROACH: We analyzed the changes of pancreatic dopaminergic system and effects of DA, antagonists and agonists of DA receptor (DRD)1 and 2 in wild-type and pancreas-specific Drd2(-/-) mice with AP (induced by caerulein and lipopolysaccharide or L-Arginine) or in pancreatic acinar cells with or without CCK stimulation...
September 30, 2017: British Journal of Pharmacology
Isabel L Jackson, Andrew Zodda, Ganga Gurung, Radmila Pavlovic, Michael D Kaytor, Michael A Kuskowski, Zeljko Vujaskovic
BACKGROUND AND PURPOSE: BIO 300 nanosuspension (Humanetics Corporation) is being developed as a medical countermeasure (MCM) for the mitigation of the delayed effects of acute radiation exposure (DEARE), specifically pneumonitis and fibrosis of the lung. The objective of this study was to determine the best dose and treatment duration of BIO 300 to mitigate lung injury and improve the likelihood for survival in C57L/J mice exposed to whole thorax lung irradiation (WTLI). EXPERIMENTAL APPROACH: Age and sex-matched C57L/J mice received a single dose of 11...
September 30, 2017: British Journal of Pharmacology
Molly S Crowe, Catheryn D Wilson, Emma Leishman, Paul L Prather, Heather B Bradshaw, Matthew L Banks, Steven G Kinsey
BACKGROUND AND PURPOSE: Gabapentin (GBP) is commonly prescribed for nerve pain but may also cause dizziness, sedation, and gait disturbances. Similarly, inhibition of the endogenous cannabinoid enzyme monoacylglycerol lipase (MAGL) has antinociceptive and anti-inflammatory properties, but also induces sedation in mice at high doses. To limit these side effects, the present study investigated the analgesic effects of coadministering a MAGL inhibitor with GBP. EXPERIMENTAL APPROACH: Mice subjected to the chronic constriction injury (CCI) model of neuropathic pain were administered the MAGL inhibitor KML29 (1-40 mg kg(-1) , i...
September 29, 2017: British Journal of Pharmacology
Lídia Ambrus, Balázs Kelemen, Tamás Szabó, Tamás Bíró, Balázs István Tóth
BACKGROUND AND PURPOSE: Heat sensitive transient receptor potential vanilloid (TRPV) channels are expressed in various epithelial tissues regulating, among else, barrier functions. Their expression is well established in the distal nephron; however, we have no data about their presence in podocytes. Since podocytes are indispensable in the formation of the glomerular filtration barrier, we investigated the presence and function of Ca(2+) -permeable TRPV1-4 channels in human podocyte cultures...
September 25, 2017: British Journal of Pharmacology
Lutz Hampe, Cheng Xu, Paul W R Harris, Jie Chen, Liu Ming, Martin Middleditch, Mazdak Radjainia, Yu Wang, Alok K Mitra
BACKGROUND AND PURPOSE: Adiponectin, an adipokine possessing profound insulin-sensitizing and anti-inflammatory properties, is a potent biotherapeutic. The trimeric adiponectin subunit assembles into hexameric and functionally important higher-molecular-weight (HMW) forms, tightly controlled by the endoplasmic reticulum protein 44 (ERp44). Obesity-induced ER stress leads to a reduction of the HMW form in serum, contributing to the development of insulin resistance and type2 diabetes. In this study, a panel of designed peptides, targeting ERp44-adiponectin interactions were tested for their effects on the circulating level of HMW adiponectin...
September 25, 2017: British Journal of Pharmacology
Diana Cunha-Reis, Joaquim Alexandre Ribeiro, Rodrigo F M de Almeida, Ana M Sebastião
BACKGROUND AND PURPOSE: Vasoactive intestinal peptide (VIP) is an important modulator of hippocampal synaptic transmission that influences both GABAergic synaptic transmission and glutamatergic cell excitability through activation of VPAC1 and VPAC2 receptors. Presynaptic enhancement of GABA release contributes to VIP modulation of hippocampal synaptic transmission. EXPERIMENTAL APPROACH: We now investigated which VIP receptors and coupled transduction pathways are involved in VIP enhancement of K(+) -evoked [(3) H]-GABA) release from rat hippocampal isolated nerve terminals...
September 25, 2017: British Journal of Pharmacology
Xueli Liu, Yuhong Wang, Hua Zhang, Li Shen, Yanfang Xu
BACKGROUND AND PURPOSE: Elevated angiotensin II (Ang II) and sympathetic activity contributes to high risk of ventricular arrhythmias in heart diseases. The rapidly activating delayed rectifier K(+) current (IKr ) carried by the hERG protein plays a critical role in cardiac repolarization; and a reduction of IKr is involved in increased cardiac arrhythmogenicity. Studies have shown that stimulation of α1A -adrenoreceptors (α1A AR) or Ang II type 1 receptor (AT1 R) inhibits IKr via protein kinase C (PKC)...
September 23, 2017: British Journal of Pharmacology
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