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British Journal of Pharmacology

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https://www.readbyqxmd.com/read/28199738/orthosteric-and-allosteric-potentiation-of-heteromeric-neuronal-nicotinic-acetylcholine-receptors
#1
REVIEW
Jingyi Wang, Jon Lindstrom
Heteromeric nicotinic acetylcholine receptors (nAChRs) were thought to have two orthodox agonist binding sites at two α/β subunit interfaces. Highly selective ligands are hard to achieve by targeting orthodox agonist sites because of high sequence similarity of this binding pocket among different subunits. Recently, unorthodox acetylcholine (ACh) binding sites have been discovered at some α/α and β/α subunit interfaces, such as α4/α4, α5/α4 and β3/α4. Targeting unorthodox sites may yield subtype-selective ligands which are otherwise hard to develop, such as those for (α4β2)2 α5, (α4β2)2 β3 and (α6β2)2 β3 nAChRs...
February 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28198010/phenolic-1-3-diketones-attenuate-lipopolysaccharide-induced-inflammatory-response-by-an-alternative-magnesium-mediated-mechanism
#2
Morena Zusso, Giulia Mercanti, Federica Belluti, Rita Maria Concetta Di Martino, Andrea Pagetta, Carla Marinelli, Paola Brun, Eugenio Ragazzi, Rita Lo, Stefano Stifani, Pietro Giusti, Stefano Moro
BACKGROUND AND PURPOSE: Toll-like receptor 4 (TLR4) plays a key role in the induction of inflammatory responses both in peripheral organs and the CNS. Curcumin exerts anti-inflammatory functions by interfering with LPS-induced TLR4-myeloid differentiation protein-2 (MD-2) dimerization and suppressing pro-inflammatory mediator release. However, the inhibitory mechanism of curcumin remains to be defined. EXPERIMENTAL APPROACH: Binding of bis-demethoxycurcumin (GG6) and its cyclized pyrazole analogue (GG9), which lacks the 1,3-dicarbonyl function, to TLR4-MD-2 was determined using molecular docking simulations...
February 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28195652/identification-of-the-anti-mycobacterial-functional-properties-of-piperidinol-derivatives
#3
Collette S Guy, Esther Tichauer, Gemma L Kay, Daniel J Phillips, Trisha L Bailey, James Harrison, Christopher M Furze, Andrew D Millard, Matthew I Gibson, Mark J Pallen, Elizabeth Fullam
BACKGROUND AND PURPOSE: Tuberculosis (TB) remains a major global health threat and is now the leading cause of death from a single infectious agent worldwide. The current TB drug regimen is inadequate and new anti-tubercular agents are urgently required to be able to successfully combat the increasing prevalence of drug-resistant TB. The purpose of this study was to investigate a piperidinol compound derivative that is highly active against the Mycobacterium tuberculosis bacillus. EXPERIMENTAL APPROACH: The antibacterial properties of the piperidinol compound and its corresponding bis-Mannich base analogue were evaluated against Mycobacterium smegmatis and Gram-negative organisms...
February 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28194766/significance-of-ang-1-7-coupling-with-mas1-and-other-gpcrs-to-the-renin-angiotensin-system-iuphar-review-x
#4
REVIEW
Sadashiva S Karnik, Dhanachandra Khuraijam, Kalyan Tirupula, Hamiyet Unal
Angiotensins are a group of hormonal peptides including angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee did not lay emphasis on designating MAS1 as the angiotensin 1-7 receptor on the basis of lack of classical G protein signaling and desensitization in response to angiotensin 1-7 as well as lack of consensus on confirmatory ligand pharmacological analyses...
February 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28192604/dapagliflozin-lowered-blood-glucose-reduces-respiratory-p-aeruginosa-infection-in-diabetic-mice
#5
Annika Åstrand, Cecilia Wingren, Audra Benjamin, John S Tregoning, James P Garnett, Helen Groves, Simren Gill, Maria Orogo-Wenn, Anders J Lundqvist, Dafydd Walters, David M Smith, John D Taylor, Emma H Baker, Deborah L Baines
BACKGROUND AND PURPOSE: Hyperglycaemia increases glucose concentrations in airway surface liquid (ASL) and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. EXPERIMENTAL APPROACH: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6 J (wild type, WT) or db/db (leptin receptor-deficient) mice, treated orally with dapagliflozin prior to intranasal dosing with lipopolysaccharide (LPS) or inoculation with P...
February 13, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28177527/effects-of-linagliptin-on-human-immortalized-podocytes-a-cellular-system-to-study-dipeptidyl-peptidase-4-inhibition
#6
Gianluca Miglio, Giovanna Vitarelli, Thomas Klein, Elisa Benetti
BACKGROUND AND PURPOSE: Dipeptidyl-peptidase (DPP)4 is expressed by resident renal cells, including glomerular cells. Dipeptidyl-peptidase 4 inhibitors (gliptins) exert albuminuria lowering effects, but the role of renal DPP4 as a pharmacological target has not been elucidated. To better understand the actions of gliptins, the effects of linagliptin on behaviour of immortalized human podocytes and mesangial cells have been evaluated. EXPERIMENTAL APPROACH: Expression of DPP4 was measured at both the mRNA and protein levels...
February 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28177520/broad-spectrum-efficacy-with-ly2969822-an-oral-prodrug-of-metabotropic-glutamate-2-3-mglu2-3-receptor-agonist-ly2934747-in-rodent-pain-models
#7
Michael P Johnson, Mark A Muhlhauser, Eric S Nisenbaum, Rosa M A Simmons, Beth M Forster, Kelly L Knopp, Lijuan Yang, Denise Morrow, Dominic L Li, Jeffrey D Kennedy, Steven Swanson, James A Monn
BACKGROUND AND PURPOSE: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated. EXPERIMENTAL APPROACH: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent, and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioral assessments of allodynia, hyperalgesia, or nocifensive behaviors in preclinical pain models were determined after administration of LY2969822 of 0...
February 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28176326/identification-of-novel-inhibitors-of-the-amino-acid-transporter-b-0-at1-slc6a19-a-potential-target-to-induce-protein-restriction-and-to-treat-type-2-diabetes
#8
Qi Cheng, Nishank Shah, Angelika Bröer, Stephen Fairweather, Yang Jiang, Dieter Schmoll, Ben Corry, Stefan Bröer
BACKGROUND AND PURPOSE: The neutral amino acid transporter B(0) AT1 (SLC6A19) has recently been identified as a possible target to treat type 2 diabetes and related disorders. B(0) AT1 mediates the Na(+) -dependent uptake of all neutral amino acids. For surface expression and catalytic activity, B(0) AT1 requires coexpression of collectrin (TMEM27). In this study, we established tools to identify and evaluate novel inhibitors of B(0) AT1. EXPERIMENTAL APPROACH: A CHO-based cell line was generated, stably expressing collectrin and B(0) AT1...
February 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28161890/homology-guided-mutational-analysis-reveals-the-functional-requirements-for-antinociceptive-specificity-of-crmp2-derived-peptides
#9
Aubin Moutal, Wennan Li, Yue Wang, Weina Ju, Shizhen Luo, Song Cai, Liberty François-Moutal, Samantha Perez-Miller, Jackie Hu, Erik T Dustrude, Todd W Vanderah, Vijay Gokhale, May Khanna, Rajesh Khanna
BACKGROUND AND PURPOSE: N-type voltage-gated calcium (CaV2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Despite CaV2.2 antagonism being recommended as first-line treatment for neuropathic pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms and are often mired by numerous side-effects. Collapsin response mediator protein 2 (CRMP2) targets CaV2.2 to the sensory neuron membrane, and allosterically modulates Cav2...
February 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28160606/discovery-and-pharmacological-characterization-of-succinate-receptor-sucnr1-gpr91-agonists
#10
Pierre Geubelle, Julie Gilissen, Sébastien Dilly, Laurence Poma, Nadine Dupuis, Céline Laschet, Dayana Abboud, Asuka Inoue, François Jouret, Bernard Pirotte, Julien Hanson
BACKGROUND AND PURPOSE: The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists. EXPERIMENTAL APPROACH: We screened a library of succinate analogues and analysed their activity on SUCNR1...
February 4, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28150299/role-of-pvat-on-coronary-atherosclerosis-and-vein-graft-patency-friend-or-foe
#11
REVIEW
M S Fernández Alfonso, M Gil-Ortega, I Aranguez, D Souza, M Dreifaldt, B Somoza, M R Dashwood
Perivascular adipose tissue (PVAT) releases multiple factors and adipokines with paracrine effects on both vascular structure and function. This influence is variable depending on regional differences in PVAT among blood vessels and with changes in adiposity. Considerable evidence demonstrates the association between coronary PVAT and the development and progression of coronary artery disease, associated with inflammation, oxidative stress, angiogenesis, vascular remodeling and blood clotting. However, PVAT also has a protective role on vascular grafts, especially the no-touch saphenous vein, in patients undergoing coronary artery bypass...
February 1, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28147449/exercise-effects-on-perivascular-adipose-tissue-endocrine-and-paracrine-determinants-of-vascular-function
#12
REVIEW
B C S Boa, J S Yudkin, V W M van Hinsbergh, E Bouskela, E C Eringa
Obesity is a global epidemic, accompanied by increased risk of type 2 diabetes and cardiovascular disease. Adipose tissue hypertrophy is associated with adipose tissue inflammation, which alters secretion of adipose tissue-derived bioactive products, known as adipokines. Adipokines determine vessel wall properties such as smooth muscle tone and vessel wall inflammation. Exercise is a mainstay of prevention of chronic, non-communicable diseases, type 2 diabetes and cardiovascular disease in particular. Aside from reducing adipose tissue mass, exercise has been shown to reduce inflammatory activity in this tissue...
February 1, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28146604/the-clinically-used-poly-adp-ribose-polymerase-parp-inhibitor-olaparib-improves-organ-function-suppresses-inflammatory-responses-and-accelerates-wound-healing-in-a-murine-model-of-third-degree-burn-injury
#13
Akbar Ahmad, Gabor Olah, David N Herndon, Csaba Szabo
BACKGROUND AND PURPOSE: The PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients. EXPERIMENTAL APPROACH: Mice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg/kg/day i.p.) groups...
February 1, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28146602/pharmacological-characterization-of-the-excitatory-cys-loop-gaba-receptor-family-in-c-elegans
#14
Georgina C B Nicholl, Ali K Jawad, Robert Weymouth, Haoming Zhang, Asim A Beg
BACKGROUND AND PURPOSE: Ionotropic GABA receptors are evolutionarily conserved proteins that mediate cellular and network inhibition in both vertebrates and invertebrates. A unique class of excitatory GABA receptors has been identified in several nematode species. Despite well-characterized functions in C. elegans, little is known about the pharmacology of the excitatory GABA receptors EXP-1 and LGC-35. Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, we investigated the agonist binding site and allosteric modulation of EXP-1 and LGC-35...
February 1, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28138957/role-of-inducible-nitric-oxide-synthase-in-endothelium-independent-relaxation-to-raloxifene-in-rat-aortas
#15
Chi Ming Wong, Chak Leung Au, Suk Ying Tsang, Chi Wai Lau, Xiaoqiang Yao, Zongwei Cai, Arthur Chi-Kong Chung
BACKGROUND AND PURPOSE: Raloxifene can induce both endothelium-dependent and -independent relaxation in different arteries. However, the underlying mechanisms of raloxifene to trigger endothelium-independent relaxation are still incompletely understood. The purpose of present study was to examine the roles of nitric oxide synthases (NOS) and Ca(2+) channels in the relaxant response to raloxifene in the isolated endothelium-denuded rat aorta. EXPERIMENTAL APPROACH: Changes of isometric tension, cyclic GMP, nitrite, inducible NOS protein expression and distribution in response to raloxifene in endothelium-denuded aortic rings were studied by organ baths, radioimmunoassay, Griess reaction, Western blot and immunohistochemistry, respectively...
January 31, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28128456/pharmacological-inhibition-of-complement-c5a-c5ar1-signalling-ameliorates-disease-pathology-in-the-hsod1-g93a-mouse-model-of-amyotrophic-lateral-sclerosis
#16
John D Lee, Vinod Kumar, Jenny Nt Fung, Marc J Ruitenberg, Peter G Noakes, Trent M Woodruff
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. The complement system is upregulated in ALS, with recent studies indicating that the activation product C5a may accelerate disease progression via its receptor, C5aR1. We therefore aimed to examine the therapeutic effect of C5aR1 antagonism in hSOD1(G93A) mice, the most widely used preclinical model of ALS. EXPERIMENTAL APPROACH: The selective and orally active C5aR1 antagonist, PMX205, was administered to hSOD1(G93A) mice via their drinking water, both pre- and post-disease onset...
January 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28128444/suppression-of-carboxylesterases-by-imatinib-mediated-by-the-downregulation-of-pregnane-x-receptor
#17
Wenjing Luo, Yu Xin, Xia Zhao, Feng Zhang, Changqing Liu, Hongwei Fan, Tao Xi, Jing Xiong
BACKGROUND AND PURPOSE: Imatinib mesylate (IM) is first-line anti-chronic myeloid leukemia (CML) therapy as a specific inhibitor of BCR-ABL tyrosine kinase. IM in combination with other drugs has been widely applied in CML treatment, thus the influence of IM on drug metabolism enzymes (DMEs) is crucial to be understood in suggesting rational drug administration. Carboxylesterases (CESs) are important enzymes catalyzing hydrolytic biotransformation and play vital roles in the metabolism of numerous clinical drugs...
January 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28128438/a-key-role-for-tetrahydrobiopterin-dependent-endothelial-nos-regulation-in-vascular-resistance-arteries-studies-in-endothelial-cell-tetrahydrobiopterin-deficient-mice
#18
Surawee Chuaiphichai, Mark J Crabtree, Eileen McNeill, Ashley B Hale, Lucy Trelfa, Keith M Channon, Gillian Douglas
BACKGROUND AND PURPOSE: The cofactor tetrahydrobiopterin (BH4) is a critical regulator of endothelial NOS (eNOS) function, eNOS-derived NO and reactive oxygen species (ROS) signalling in vascular physiology. To determine the physiological requirement for de-novo endothelial cell BH4 synthesis in vasomotor function in resistance arteries, we have generated a mouse model with endothelial cell-specific deletion of Gch1, encoding GTP cyclohydrolase 1 (GTPCH), an essential enzyme for BH4 biosynthesis, and evaluated BH4-dependent eNOS regulation, eNOS-derived NO and ROS generation...
January 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28128437/schisandrol-b-protects-against-cholestatic-liver-injury-through-pregnane-x-receptor
#19
Hang Zeng, Yiming Jiang, Pan Chen, Xiaomei Fan, Dongshun Li, Aiming Liu, Xiaochao Ma, Wen Xie, Peiqing Liu, Frank J Gonzalez, Min Huang, Huichang Bi
BACKGROUND AND PURPOSE: Currently, ursodeoxycholic acid is the only FDA-approved drug for limited cholestatic liver diseases, and thus the development of new therapeutic approaches is of great importance. This study aimed to evaluate the anti-cholestasis effect of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera. EXPERIMENTAL APPROACH: Hepatoprotective effect of SolB against lithocholic acid (LCA)-induced intrahepatic extrahepatic cholestasis was evaluated in mice...
January 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28127755/bisperoxovandium-pyridin-2-squaramide-targets-both-pten-and-erk1-2-to-confer-neuroprotection
#20
Zhi-Feng Zhang, Juan Chen, Xin Han, Ya Zhang, Hua-Bao Liao, Rui-Xue Lei, Yang Zhuang, Ze-Fen Wang, Zhiqiang Li, Jin-Cao Chen, Wei-Jing Liao, Hai-Bing Zhou, Fang Liu, Qi Wan
BACKGROUND AND PURPOSE: We and others have shown that inhibiting PTEN or activating Erk1/2 confer neuroprotection. We designed a compound, the bisperoxovandium (pyridin-2-squaramide) [bpV(pis)]. The purpose of this study was to determine whether and how bpV(pis) exerted its neuroprotective effect in cerebral ischemia-reperfusion injury. EXPERIMENTAL APPROACH: Malachite Green based phosphatase assay was used to measure PTEN activity. Western bolt assay was used to measure the phosphorylation level of Akt and Erk1/2 (p-Akt and p-Erk1/2)...
January 27, 2017: British Journal of Pharmacology
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