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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/28302862/arresting-the-development-of-addiction-the-role-of-%C3%AE-arrestin2-in-drug-abuse
#1
Kirsten A Porter-Stransky, David Weinshenker
The protein β-arrestin2 (βarr2) directly interacts with receptors and signaling pathways that mediate the behavioral effects of drugs of abuse, making it a prime candidate for therapeutic interventions. βarr2 drives desensitization and internalization of G protein-coupled receptors, including dopamine, opioid, and cannabinoid receptors, and can also trigger G protein-independent intracellular signaling. βarr2 mediates several drug-induced behaviors, but the relationship is complex and dependent on the type of behavior (e...
March 16, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28298527/dual-inhibiton-of-bruton-s-tyrosine-kinase-and-phosphoinositide-3-kinase-p110%C3%AE-as-a-therapeutic-approach-to-treat-non-hodgkin-s-b-cell-malignancies
#2
Jennifer Alfaro, Felipe Perez de Arce, Sebastian Belmar, Glenda Fuentealba, Patricio Avila, Gonzalo Ureta, Camila Flores, Claudia Acuna, Luz Delgado, Diana Gaete, Brahmam Pujala, Anup Barde, Anjan K Nayak, Tvr Upendra, Dhananjay Patel, Shailender Chauhan, Vijay K Sharma, Stacy Kanno, Ramona G Almirez, David T Hung, Sarvajit Chakravarty, Roopa Rai, Sebastian Bernales, Kevin P Quinn, Son M Pham, Emma McCullagh
Although new targeted therapies such as ibrutinib and idelalisib have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors and possibly prolonging the duration of the response and reducing resistance...
March 15, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28289077/selective-activation-of-ampk-b1-containing-isoforms-improves-kidney-function-in-a-rat-model-of-diabetic-nephropathy
#3
Christopher T Salatto, Russell A Miller, Kimberly O Cameron, Emily Cokorinos, Allan Reyes, Jessica Ward, Matt Calabrese, Ravi Kurumbail, Francis Rajamohan, Amit S Kalgutkar, David A Tess, Andre Shavnya, Nathan E Genung, David J Edmonds, Aditi Jatkar, Benjamin S Maciejewski, Marina Amaro, Harmeet Gandhok, Mara Monetti, Katherine Cialdea, Eliza Bollinger, John M Kreeger, Timothy M Coskran, Alan C Opsahl, Germaine G Boucher, Morris J Birnbaum, Paul DaSilva-Jardine, Tim Rolph
Diabetic nephropathy remains an area of high unmet medical need, with current therapies slowing, but not preventing the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both human subjects and animal models of kidney disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β1 subunit. After confirming that human and rodent kidney predominately express AMPK β1, we explore the effects of pharmacologic activation of AMPK in the ZSF-1 rat model of diabetic nephropathy...
March 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28275202/low-volume-resuscitation-for-hemorrhagic-shock-understanding-the-mechanism-of-peg-20k
#4
Valerie Plant, Dan Parrish, Ashley Limkemann, Paula Ferrada, Michel Aboutanos, Martin J Mangino
Hemorrhagic shock leads to cell and tissue swelling and no reflow from compressed capillaries. Cell impermeants, including polyethylene glycol-20,000 (PEG-20k), reverse ischemia-induced cell swelling, extend low volume resuscitation (LVR) time after shock, and increase tolerance to the low volume state. The purpose of this study was to explore the mechanisms of action of PEG-20k containing LVR solutions. We hypothesized that PEG-20k acts as both an oncotic agent and an impermeant in the microcirculation, which moves water out of the extracellular space and into the capillaries to affect peripheral capillary filling and enhanced perfusion during the low volume state...
March 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28275201/physiologically-based-pharmacokinetic-model-of-all-trans-retinoic-acid-with-application-to-cancer-populations-and-drug-interactions
#5
Jing Jing, Cara Nelson, Jisun Paik, Yoshiyuki Shirasaka, John K Amory, Nina Isoherranen
All-trans retinoic acid (atRA) is a front-line treatment for acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed...
March 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28228532/comprehensive-characterization-of-mouse-udp-glucuronosyltransferase-ugt-belonging-to-the-ugt2b-subfamily-identification-of-ugt2b36-as-the-predominant-isoform-involved-in-morphine-glucuronidation
#6
Ayumi Kurita, Yuu Miyauchi, Shin-Ichi Ikushiro, Peter Ian Mackenzie, Hideyuki Yamada, Yuji Ishii
UDP-Glucuronosyltransferases (UGTs) are classified into three subfamilies, Ugt1a, 2b, and 2a, in mice. In the Ugt1a subfamily, Ugt1a1 and 1a6 appear to correspond to human UGT1A1 and 1A6 The mouse is an important animal used for investigations but the substrate specificities of Ugt isoforms belonging to the 2b subfamily in mice remain largely unknown. To address this issue, we characterized the substrate specificity of all isoforms of the Ugt2b subfamily expressed in mouse liver. The cDNAs of Ugt1a1, Ugt2a3 and all the Ugt2b isoforms expressed in the liver were reverse-transcribed from total RNA of male FVB-mouse liver and amplified...
February 22, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28223322/eta-receptors-blockade-by-activating-etb-receptors-increases-vascular-permeability-and-induces-exaggerated-fluid-retention
#7
Magali Vercauteren, Frederic Trensz, Anne Pasquali, Christophe Cattaneo, Daniel S Strasser, Patrick Hess, Marc Iglarz, Martine Clozel
Endothelin receptor antagonists have been associated with fluid retention. It has been suggested that, of the two endothelin receptor subtypes, ETB receptors should not be blocked, because of their involvement in natriuresis and diuresis. Surprisingly, clinical data suggest that ETA-selective antagonists pose a greater risk of fluid overload than dual antagonists. The purpose of this study was to evaluate the contribution of each endothelin receptor to fluid retention and vascular permeability in rats. Sitaxentan and ambrisentan as ETA-selective antagonists, bosentan and macitentan as dual antagonists were used as representatives of each class, respectively...
February 21, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28209723/functional-metabolic-and-dynamic-mitochondrial-changes-in-the-rat-cirrhosis-hepatocellular-carcinoma-model-and-the-protective-effect-of-ifc-305
#8
Enrique Chavez, Maria Guadalupe Lozano-Rosas, Mariana Dominguez-Lopez, Gabriela Velasco-Loyden, Jesus Rafael Rodriguez-Aguilera, Concepcion Jose-Nunez, Marietta Tuena de Gomez-Puyou, Victoria Chagoya de Sanchez
BACKGROUND: Mitochondrion is an important metabolic and energetic organelle which regulates several cellular processes. Mitochondrial dysfunction has been related with liver diseases including hepatocellular carcinoma. As a result, the energetic demand is not properly supplied and mitochondrial morphologic changes has been observed resulting in an altered metabolism. We previously demonstrated the chemopreventive effect of the hepatoprotector IFC-305. AIM: In this work we aimed to evaluate the functional, metabolic, and dynamic mitochondrial alterations in the sequential model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats and the possible beneficial effect of IFC-305...
February 16, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28196836/label-free-dynamic-mass-redistribution-reveals-low-density-pro-survival-%C3%AE-1b-adrenergic-receptors-in-human-sw480-colon-carcinoma-cells
#9
Dorathy-Ann Harris, Ji-Min Park, Kyung Soon-Lee, Cong Xu, Nephi Stella, Chris Hague
Small molecules that target the adrenergic family of G protein-coupled receptors (GPCRs) show promising therapeutic efficacy for the treatment of various cancers. Herein, we report that human colon cancer cell line SW480 expresses low-density functional α1B-adrenergic receptors (ARs) as revealed by label-free dynamic mass redistribution (DMR) signaling technology and confirmed by quantitative reverse-transcriptase polymerase chain reaction analysis. Remarkably, while endogenous α1B-ARs are not detectable via either [3H]-prazosin binding analysis or phosphoinositol hydrolysis assays, their activation leads to robust DMR and enhanced cell viability...
February 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28193636/evaluation-of-jak3-biology-in-autoimmune-disease-using-a-highly-selective-irreversible-jak3-inhibitor
#10
Fiona Elwood, David Witter, Jennifer Piesvaux, Brian Kraybill, Nathan Bays, Carla Alpert, Peter Goldenblatt, Yujie Qu, Irena Ivanovska, Hyun-Hee Lee, Chi-Sung Chiu, Hao Tang, Mark E Scott, Sujal Deshmukh, Mark Zielstorff, Alan Byford, Kalyan Chakravarty, Lauren Dorosh, Alexy Rivkin, Joel Klappenbach, Bo-Sheng Pan, Ilona Kariv, Christopher Dinsmore, Deborah Slipetz, Peter Dandliker
Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, et al., 2010) and Decernotinib(Farmer, et al., 2015;Mahajan, et al., 2015) block cytokine signaling and are efficacious in treating autoimmune diseases (Kremer, et al., 2009;Fleischmann, et al., 2015;Fleischmann, et al., 2015;Krueger, et al., 2016;Sandborn, et al., 2012). However therapeutic doses are limited due to inhibition of other JAK/STAT pathways associated with hematopoiesis, lipid biogenesis, infection and immune responses(Kahn C, 2012)...
February 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28188270/dual-mechanism-for-inhibition-of-inwardly-rectifying-kir2-x-channels-by-quinidine-involving-direct-pore-block-and-pip2-interference
#11
Christoph Koepple, Daniel Scherer, Claudia Seyler, Eberhard Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies IK1 current. While a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild type and mutant Kir2...
February 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28179474/individual-differences-in-the-relative-reinforcing-effects-of-3-4-methylenedioxypyrovalerone-mdpv-under-fixed-and-progressive-ratio-schedules-of-reinforcement-in-rats
#12
Brenda M Gannon, Kayla I Galindo, Kenner C Rice, Gregory T Collins
The recreational use of designer drugs, including synthetic cathinones (bath salts), is associated with high levels of abuse and toxicity, and represents a growing threat to public health. MDPV (3,4-methylenedioxypyrovalerone) is a cocaine-like monoamine uptake inhibitor, and one of the most widely available and abused synthetic cathinones. The present study used male Sprague-Dawley rats to directly compare: (1) the acquisition of responding for MDPV and cocaine under a fixed ratio (FR) 1 schedule of reinforcement; (2) full dose-response curves for MDPV and cocaine under FR5; and (3) progressive ratio (PR) schedules of reinforcement...
February 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28179473/dynamic-regulation-of-homer-binding-to-group-i-mglurs-by-preso1-and-converging-kinase-cascades
#13
Jia-Hua Hu, Paul F Worley, Paul J Kammermeier
In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptors (mGluRs) 1 or 5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C-termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage dependent channels can be induced by expression of Preso1, an adaptor of proline directed kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins...
February 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28179472/endothelin-confers-protection-against-high-glucose-induced-neurotoxicity-via-alleviation-of-oxidative-stress
#14
Mohamed Fouda, Abdel A Abdel-Rahman
Recent findings linked the inhibition in the neuromodulator peptide endothelin-1 (ET-1) level to the high glucose-evoked neurotoxicity. However, definitive neuroprotective role for ET-1, and the major neuronal ET (ET-3), against high glucose-evoked toxicity, and the implicated neurochemical responses triggered by their ET-A and ET-B receptors remain unknown. Here, we tested the hypothesis that ET-B activation alleviates high glucose-evoked oxidative stress and cell death. High glucose (100 mM for 48 hrs.)-evoked cell death was associated with elevation in reactive oxygen species, inhibition of catalase activity, and a paradoxical upregulation of hemeoxygenase-1 expression along with ET-A and ET-B receptors were down-regulated and up-regulated, respectively...
February 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28174211/overlapping-and-divergent-actions-of-structurally-distinct-hdac-inhibitors-in-cardiac-fibroblasts
#15
Katherine B Schuetze, Matthew S Stratton, Weston W Blakeslee, Michael F Wempe, Florence F Wagner, Edward B Holson, Yin-Ming Kuo, Andrew J Andrews, Tonya M Gilbert, Jacob M Hooker, Timothy A McKinsey
Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly impact cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiological and pathophysiological processes...
February 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28167639/therapeutic-restoration-of-endothelial-glycocalyx-in-sepsis
#16
Jong Wook Song, Joseph A Zullo, Dionysios Liveris, Matthew Dragovich, X Frank Zhang, Michael S Goligorsky
Endothelial glycocalyx (EG) is disintegrated during sepsis. We showed (Am J Pathol, 2016) that this occurs very early in the course of sepsis and its prevention improves survival of mice with sepsis. Here, we sought to investigate the possibility to pharmacologically accelerate the restoration of disintegrated EG in sepsis. We used a soilage injection model to induce polymicrobial sepsis in C57/BL6 mice and measured total body EG. En face aortic preparations were used for staining for markers of EG and atomic force microscopy (AFM) was used to measure EG in vitro...
February 6, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28167638/effects-of-repeated-ropinirole-treatment-on-phencyclidine-induced-hyperlocomotion-prepulse-inhibition-deficits-and-social-avoidance-in-rats
#17
Amanda M Maple, Tanessa Call, Phylicia C Kimmel, Ronald P Hammer
Phencyclidine (PCP), a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, provides the most complete pharmacological model of schizophrenia in humans and animals. Acute PCP causes hyperlocomotion, disrupts prepulse inhibition (PPI), and increases social avoidance in rats. We previously showed that repeated treatment with the dopamine (DA) D2-like receptor agonists, quinpirole or ropinirole, prevents agonist-induced PPI disruption. The present study examines whether repeated ropinirole treatment similarly attenuates the effects of PCP in a more complete model of schizophrenia symptoms...
February 6, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28154014/a-tumor-cell-selective-inhibitor-of-mitogen-activated-protein-kinase-phosphatases-sensitizes-breast-cancer-cells-to-lymphokine-activated-killer-cell-activity
#18
Christof T Kaltenmeier, Laura L Vollmer, Lawrence A Vernetti, Lindsay Caprio, Keanu Davis, Vasiliy N Korotchenko, Billy W Day, Michael Tsang, Keren I Hulkower, Michael T Lotze, Andreas Vogt
Dual specificity mitogen activated protein kinase (MAPK) phosphatases (DUSP-MKPs) have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of Fibroblast Growth Factor signaling (BCI-215) that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells...
February 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28148637/impact-of-nonalcoholic-fatty-liver-disease-on-toxicokinetics-of-tetrachloroethylene
#19
Joseph A Cichocki, Shinji Furuya, Kranti Konganti, Yu-Syuan Luo, Thomas J McDonald, Yasuhiro Iwata, Weihsueh A Chiu, David W Threadgill, Igor P Pogribny, Ivan Rusyn
Lifestyle factors and chronic pathological states are important contributors to inter-individual variability in susceptibility to xenobiotic-induced toxicity. Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition that can dramatically affect chemical metabolism. We examined the effect of NAFLD on toxicokinetics of tetrachloroethylene (PERC), a ubiquitous environmental contaminant that requires metabolic activation to induce adverse health effects. Mice (C57Bl/6J, male) were fed a low-fat diet (LFD), high fat diet (HFD), or methionine/folate/choline-deficient diet (MCD) to model a healthy liver, steatosis, or nonalcoholic steatohepatitis (NASH), respectively...
February 1, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28138042/control-of-neurotransmission-by-nav1-7-in-human-guinea-pig-and-mouse-airway-parasympathetic-nerves
#20
Michaela Kocmalova, Marian Kollarik, Brendan J Canning, Fei Ru, Robert A Herbstromer, Sonya Meeker, Silvia Fonquerna, Monica Aparici, Montserrat Miralpeix, Xian Chi, Baolin Li, Ben Wilenkin, Jeff McDermott, Eric Nisenbaum, Jeff Krajewski, Bradley J Undem
Little is known about the voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the α subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle. As would be expected from previous studies, tetrodotoxin potently blocked the parasympathetic responses in the airways of each species...
January 30, 2017: Journal of Pharmacology and Experimental Therapeutics
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