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British Journal of Pharmacology

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https://www.readbyqxmd.com/read/28521071/pharmacological-interventions-in-the-wnt-pathway-inhibition-of-wnt-secretion-versus-disrupting-the-protein-protein-interfaces-of-nuclear-factors
#1
REVIEW
Dario Zimmerli, George Hausmann, Claudio Cantù, Konrad Basler
Mutations in components of the Wnt pathways are a frequent cause of many human diseases, particularly cancer. Despite the fact that a causative link between aberrant Wnt signaling and many types of human cancers was established more than a decade ago, no Wnt signaling inhibitors have made it into the clinic so far. One reason for this is that no pathway-specific kinase is known. Additionally targeting the protein-protein interactions needed to transduce the signal has not met with success so far. Complicating the search for and use of inhibitors is the complexity of the cascades triggered by the Wnts and their paramount biological importance...
May 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28516479/g%C3%AE-s-signalling-of-the-cb1-receptor-and-the-influence-of-receptor-number
#2
David B Finlay, Erin E Cawston, Natasha L Grimsey, Morag R Hunter, Anisha Korde, V Kiran Vemuri, Alexandros Makriyannis, Michelle Glass
BACKGROUND AND PURPOSE: CB1 cannabinoid receptor signalling is canonically mediated through inhibitory Gαi proteins, but signalling through other G proteins occurs under some circumstances; Gαs being the most characterised secondary pathway. Determinants of this signalling switch identified to date include Gαi blockade, CB1 /D2 dopamine receptor co-stimulation, CB1 agonist class, and cell background. The aim of this study was to examine the effects of receptor number and ligand dependence on CB1 signalling...
May 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28514532/the-dickkopf1-ckap4-axis-creates-a-novel-signaling-pathway-and-may-represent-a-molecular-target-for-cancer-therapy
#3
REVIEW
Akira Kikuchi, Katsumi Fumoto, Hirokazu Kimura
Dickkopf 1 (DKK1) is a secretory protein and antagonizes oncogenic Wnt signaling by binding to the Wnt co-receptor low-density lipoprotein receptor-related proteins 6 (LRP6). DKK1 is also suggested to regulate its own signaling to associate with tumor aggressiveness. However, the underlying mechanism by which DKK1 promotes cancer cell proliferation has remained to be clarified for a long time. It has been recently found that cytoskeleton-associated protein 4 (CKAP4), which was originally reported as an endoplasmic reticulum membrane protein, acts as a novel DKK1 receptor...
May 17, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28514495/protective-effects-of-dioscin-against-cisplatin-induced-nephrotoxicity-via-regulating-mir-34a-sirt1-signal-pathway
#4
Yimeng Zhang, Xufeng Tao, Lianhong Yin, Lina Xu, Youwei Xu, Yan Qi, Xu Han, Shasha Song, Yanyan Zhao, Yuan Lin, Kexin Liu, Jinyong Peng
BACKGROUND AND PURPOSE: Dioscin has various pharmacological actions in our previous works, however, little is known concerning the role of it on cisplatin (CDDP)-induced nephrotoxicity. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against CDDP-induced nephrotoxicity. EXPERIMENTAL APPROACH: In the present study, the in vivo models of CDDP-induced nephrotoxicity in rats and mice were used, and the in vitro models on NRK-52E and HK-2 cells were developed...
May 17, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28503736/hydrogen-sulfide-pretreatment-improves-mitochondrial-function-in-myocardial-hypertrophy-via-a-sirt3-dependent-manner
#5
Guoliang Meng, Jieqiong Liu, Shangmin Liu, Qiuyi Song, Lulu Liu, Liping Xie, Yi Han, Yong Ji
BACKGROUND AND PURPOSE Hydrogen sulfide (H2 S) is a gaseous signal molecule with anti-oxidative ability. Sirtuin 3 (SIRT3) is closely associated with mitochondrial function and oxidative stress. The study was to investigate whether and how H2 S improved myocardial hypertrophy via a SIRT3-dependent manner. EXPERIMENTAL APPROACH Neonatal rat cardiomyocytes were pre-treated with NaHS (50 μM) for 4 h followed by angiotensin II (Ang II, 100 nM) for 24 h. SIRT3 was silenced with siRNA technology. SIRT 3 promoter activity and expression, cell surface, hypertrophic gene mRNA expression, mitochondrial oxygen consumption rate and membrane potential were measured...
May 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28500657/modulation-of-herg-channels-by-5-1h-indazol-5-yl-oxy-methyl-n-4-trifluoromethoxy-phenyl-pyrimidin-2-amine-itp-2-a-novel-small-molecule-activator
#6
Harinath Sale, Samrat Roy, Jayakumar Warrier, Srinivasan Thangathirupathy, Yoganand Vadari, Shruthi K Gopal, Prasad Krishnamurthy, Manjunath Ramarao
BACKGROUND AND PURPOSE: hERG channel activators have potential utility in the treatment of acquired and congenital long QT syndrome. In this article, we describe a new hERG activator, 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), with a chemical structure distinct from the previously reported compounds. EXPERIMENTAL APPROACH: We investigated the effect of ITP-2 on hERG1a and hERG1a/1b channels expressed heterologously in HEK-293 cells using conventional electrophysiological methods...
May 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28500644/autophagy-stimulation-prevents-intestinal-mucosal-inflammation-and-ameliorates-murine-colitis
#7
Dulce C Macias-Ceja, Jesús Cosín-Roger, Dolores Ortiz-Masiá, Pedro Salvador, Carlos Hernández, Juan V Esplugues, Sara Calatayud, María D Barrachina
BACKGROUND AND POURPOSE: A defective autophagy is involved in the pathogenesis of inflammatory disorders such as IBD. Cross talk interactions between autophagy and inflammation have been reported and we analyse the effects of autophagy stimulators on murine colitis. EXPERIMENTAL APPROACH: Mice were treated with intrarectal administration of TNBS (3.5 mg/20 g BW) and body weight was measured every day and histological damage score analysed two or four days after treatment...
May 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28494108/selective-%C3%AE%C2%BA-opioid-receptor-partial-agonist-hs666-produces-potent-antinociception-without-inducing-aversion-after-i-c-v-administration-in-mice
#8
Mariana Spetea, Shainnel O Eans, Michelle L Ganno, Aquilino Lantero, Michael Mairegger, Lawrence Toll, Helmut Schmidhammer, Jay P McLaughlin
BACKGROUND AND PURPOSE: The κ opioid (KOP) receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although KOP agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain-penetrant KOP receptor ligands possessing biased agonism towards G protein signalling over β-arrestin2 recruitment would produce robust antinociception with fewer liabilities of use...
May 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28493443/natural-alkaloid-bouchardatine-ameliorates-metabolic-disorders-in-high-fat-diet-fed-mice-via-stimulating-the-sirt1-lkb1-ampk-axis
#9
Yong Rao, Hong Yu, Lin Gao, Yu-Ting Lu, Zhao Xu, Hong Liu, Lian-Quan Gu, Ji-Ming Ye, Zhi-Shu Huang
BACKGROUND AND PURPOSE: Promoting energy metabolism is known to provide therapeutic effects for obesity and associated metabolic disorders. The present study evaluated the therapeutic effects of the newly-identified bouchardatine (Bou) on obesity associated metabolic disorders and the molechular mechanisms for these effects. EXPERIMENTAL APPROACH: The molecular mode of action of Bou for its effects on lipid metabolism was first examined in 3T3-L1 adipocytes and HepG2 cells...
May 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28493341/design-and-validation-of-the-first-cell-impermeant-melatonin-receptor-agonist
#10
Florence Gbahou, Erika Cecon, Guillaume Viault, Romain Gerbier, Frederic Jean-Alphonse, Angeliki Karamitri, Gérald Guillaumet, Philippe Delagrange, Robert M Friedlander, Jean-Pierre Vilardaga, Franck Suzenet, Ralf Jockers
BACKGROUND AND PURPOSE: The paradigm that G protein-coupled receptors are able to prolong or initiate cellular signaling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT1 and MT2 receptors. Different from most other hormones targeting GPCRs, melatonin and its synthetic analogs are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools. EXPERIMENTAL APPROACH: We therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability of cellular penetration...
May 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28493335/response-of-htr3a-ko-mice-to-antidepressant-treatment-and-chronic-stress
#11
Vincent Martin, Armance Riffaud, Tevrasamy Marday, Charly Brouillard, Bernard Franc, Jean-Pol Tassin, Caroline Sevoz-Couche, Raymond Mongeau, Laurence Lanfumey
BACKGROUND AND PURPOSE: It has recently been suggested that 5-HT3 receptor blockade enhances selective serotonin reuptake inhibitor (SSRI) antidepressants efficacy and may reverse stress-induced deficits in rodents. EXPERIMENTAL APPROACH: To further explore this hypothesis, we used mice lacking the 5-HT3 receptor (Htr3a KO) and their wild-type (WT) controls to assess their response in behavioural paradigms relevant to anxiety and depression. Mice were studied under basal, antidepressant treatments and chronic social defeat stress (CSDS) conditions...
May 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28480509/oxidized-low-density-lipoprotein-stimulates-epithelial-sodium-channels-in-endothelial-cells-of-mouse-thoracic-aorta
#12
Chen Liang, Qiu-Shi Wang, Xu Yang, Na Niu, Qing-Qing Hu, Bao-Long Zhang, Ming-Ming Wu, Chang-Jiang Yu, Xiao Chen, Bin-Lin Song, Zhi-Ren Zhang, He-Ping Ma
BACKGROUND AND PURPOSE: Epithelial sodium channel (ENaC) is expressed in endothelial cells and acts as a negative modulator of vasodilation. Oxidized low-density lipoprotein (ox-LDL) is a key pathological factor in endothelial dysfunction. The present study is to examine the role of ENaC in ox-LDL-induced endothelial dysfunction and its associated signal transduction pathway. EXPERIMENTAL APPROACH: Patch-clamp techniques combined with pharmacological approaches were used to examine ENaC activity in the endothelial cells of split-open mouse thoracic aorta...
May 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28477386/persistent-activation-of-%C3%AE-7-nachrs-associated-with-stable-induction-of-different-desensitized-states
#13
Roger L Papke, Clare Stokes, M Imad Damaj, Ganesh A Thakur, Khan Manther, Millet Treinin, Deniz Bagdas, Abhijit R Kulkarni, Nicole A Horenstein
BACKGROUND AND PURPOSE: GAT107 is a positive allosteric modulator and agonist (ago-PAM) of α7 nicotinic acetylcholine receptors that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel-active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non-conducting states, interestingly, both agents have been shown to be effective treatment for inflammation and inflammatory pain models...
May 6, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28477384/cognitive-deficits-caused-by-prefrontal-cortical-and-hippocampal-neural-disinhibition
#14
REVIEW
Tobias Bast, Marie Pezze, Stephanie McGarrity
We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, i.e. deficient GABA transmission, within prefrontal cortex and hippocampus for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico-hippocampal neural activity and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age-related cognitive decline...
May 6, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28477355/%C3%AE-conotoxins-active-at-%C3%AE-3-containing-nicotinic-acetylcholine-receptors-and-their-molecular-determinants-for-selective-inhibition
#15
REVIEW
Hartmut Cuny, Rilei Yu, Han-Shen Tae, Shiva N Kompella, David J Adams
Neuronal α3-containing nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (PNS) and non-neuronal tissues are implicated in a number of severe disease conditions ranging from cancer to cardiovascular diseases, and chronic pain. However, despite the physiological characterization of mouse models and cell lines, the precise pathophysiology of nAChRs outside the central nervous system (CNS) remains not well understood, in part because there is a lack of subtype-selective antagonists. α-Conotoxins isolated from cone snail venom exhibit characteristic individual selectivity profiles for nAChRs and, therefore, are excellent tools to study the determinants for nAChR-antagonist interactions...
May 6, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28476070/peripheral-inflammation-alters-n-arachidonoylphosphatidylethanolamine-20-4-nape-induced-modulation-of-nociceptive-spinal-cord-synaptic-transmission
#16
Vladimir Nerandzic, Petra Mrozkova, Pavel Adamek, Diana Spicarova, Istvan Nagy, Jiri Palecek
BACKGROUND AND PURPOSE: Endocannabinoids play an important role in modulating spinal nociceptive signalling, crucial for the development of pain. The cannabinoid receptor 1 (CB1) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) are both activated by the endocannabinoid anandamide that is a product of biosynthesis from the endogenous lipid precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE). Here we are first to report CB1 receptor- and TRPV1-mediated effects of 20:4-NAPE application on spinal synaptic transmission in control and inflammatory conditions...
May 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28476069/elac-3-12-di-o-acetyl-8-o-tigloilingol-a-plant-derived-lathyrane-diterpene-induces-subventricular-zone-neural-progenitor-cell-proliferation-through-protein-kinase-c-beta-activation
#17
Maribel Murillo-Carretero, Noelia Geribaldi-Doldán, Eugenia Flores-Giubi, Francisco García-Bernal, Elkin A Navarro, Manuel Carrasco-Viñuela, Antonio J Macías-Sánchez, Pilar Herrero-Foncubierta, Antonio Delgado-Ariza, Cristina Verástegui, Jesús Domínguez-Riscart, Mourad Daoubi, Rosario Hernández-Galán, Carmen Castro
BACKGROUND AND PURPOSE: Pharmacological strategies aimed to facilitate neuronal renewal in the adult brain, by promoting endogenous neurogenesis, constitute promising therapeutic options for pathologic or traumatic brain lesions. We have previously shown that non-tumor-promoting PKC-activating compounds (12-deoxyphorbols) promote adult neural progenitor cell (NPC) proliferation in vitro and in vivo, enhancing the endogenous neurogenic response of the brain to a traumatic injury. Here, we show for the first time that a diterpene with lathyrane skeleton can also activate PKC and promote NPC proliferation...
May 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28471519/mast-cells-mediate-early-neutrophil-recruitment-and-exhibit-anti-inflammatory-properties-via-fpr2-alx
#18
Ellen L Hughes, Felix Becker, Roderick J Flower, Julia C Buckingham, Felicity N E Gavins
BACKGROUND AND PURPOSE: In recent years, studies have focused on the resolution of inflammation, which can be achieved by endogenous anti-inflammatory agonists such as Annexin A1 (AnxA1). Here, we investigated the effects of mast cells (MCs) on early lipopolysaccharide (LPS)-induced neutrophil recruitment and the involvement of the AnxA1-Formyl peptide receptor 2/ALX (Fpr2/ALX or lipoxin A4 receptor) pathway. EXPERIMENTAL APPROACH: Intravital microscopy (IVM) was used to visualize and quantify the effects of LPS (10 µg per mouse i...
May 4, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28471490/hydroxyeicosapentaenoic-acids-and-epoxyeicosatetraenoic-acids-attenuate-early-occurrence-of-nonalcoholic-fatty-liver-disease
#19
Chunjiong Wang, Wenli Liu, Liu Yao, Xuejiao Zhang, Xu Zhang, Chenji Ye, Hongfeng Jiang, Jinlong He, Yi Zhu, Ding Ai
BACKGROUND AND PURPOSE: The ω-3 polyunsaturated fatty acids (PUFAs) mediate protective effects on several metabolic disorders. However, the functions of their metabolites in the early stage of nonalcoholic fatty liver disease (NAFLD) are largely unknown. EXPERIMENTAL APPROACH: Mice were fed a control diet, high-fat diet (HFD) or ω-3 PUFA-enriched HFD (ω3HFD) for 4 days and phenotypes were analyzed. LC-MS/MS was used to determine the eicosanoid profiles. Primary hepatocytes and peritoneal macrophages were used for the mechanism study...
May 4, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28471481/cytotoxic-lymphocytes-and-atherosclerosis-significance-mechanisms-and-therapeutic-challenges
#20
Tin Kyaw, Karlheinz Peter, Li Yi, Peter Tipping, Ban-Hock Toh, Alex Bobik
Cytotoxic lymphocytes encompass natural killer (NK) lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, NKT cells, gamma, delta (γδ)-T cells and human CD4 + CD28- T cells. These cells play critical roles in inflammatory diseases and in controlling cancers and infections. Cytotoxic lymphocytes can be activated via a number of mechanisms that may involve dendritic cells, macrophages, cytokines or surface proteins on stressed cells. Upon activation, they secrete proinflammatory cytokines as well as anti-inflammatory cytokines, chemokines and cytotoxins to promote inflammation and development of atherosclerotic lesions including vulnerable lesions, which are strongly implicated in myocardial infarctions and strokes...
May 4, 2017: British Journal of Pharmacology
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