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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/28515158/the-anti-psoriatic-drug-monomethylfumarate-increases-nuclear-factor-erythroid-2-related-factor-2-nrf2-levels-and-induces-aquaporin-3-aqp3-mrna-and-protein-expression
#1
Inas Helwa, Vivek Choudhary, Xunsheng Chen, Ismail Kaddour-Djebbar, Wendy B Bollag
BACKGROUND: Oxidative stress contributes to inflammatory skin diseases including psoriasis. Monomethylfumarate (MMF) is an anti-psoriatic agent with a poorly understood mechanism of action. In other cell types MMF increases the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcription factor that regulates cellular anti-oxidant responses, to reduce oxidative stress like that observed in inflammatory disorders such as multiple sclerosis. OBJECTIVE: We tested the hypothesis that MMF enhances Nrf2 activity in keratinocytes, thereby improving their capacity to counteract environmental stresses...
May 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28515157/carboxyamidotriazole-synergizes-with-sorafenib-to-combat-non-small-cell-lung-cancer-through-inhibition-of-nanog-and-aggravation-of-apoptosis
#2
Chen Chen, Rui Ju, Jing Shi, Wei Chen, Fangrui Sun, Lei Zhu, Juan Li, Dechang Zhang, Caiying Ye, Lei Guo
Lung cancer is the leading cause of cancer-related deaths in the world. In this study, we investigated the combination of carboxyamidotriazole (CAI) and sorafenib in NSCLC in vitro and in vivo, to test whether CAI enhances the antitumor effects of sorafenib and reduces its side effects. The combination index (CI) showed that co-administration of CAI and sorafenib synergistically inhibited the proliferation of NSCLC cells (Lewis lung carcinoma, A549, NCI-H1975). The cell death led by the treatment of combination drugs was attributed to apoptosis which was accompanied with activation of caspase 3 and poly ADP-ribose polymerase...
May 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28500264/s1p1-mediated-anti-ras-cardioprotection-pivotal-role-of-mast-cell-aldh2
#3
Alice Marino, Takuya Sakamoto, Pablo A Robador, Kengo Tomita, Roberto Levi
In the ischemic-reperfused (I/R) heart, renin-containing mast cells (MC) release enzymatically active renin, activating a local renin-angiotensin system (RAS), causing excessive norepinephrine release and arrhythmic dysfunction. Activation of Gi-receptors on MC, and/or ischemic preconditioning (IPC), prevent renin release, thus providing anti-RAS cardioprotection. We questioned whether sphingosine-1-phosphate (S1P), a sphingolipid produced in the I/R heart, might afford anti-RAS cardioprotection by activating Gi-coupled S1P1 receptors (S1P1R) on MC...
May 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28483800/xe991-and-linopirdine-are-state-dependent-inhibitors-for-kv7-kcnq-channels-that-favor-activated-single-subunits
#4
Derek L Greene, Seungwoo Kang, Naoto Hoshi
M-channel inhibitors, especially XE991, are increasingly being used in animal experiments. However, insufficient characterization of XE991 at times confounds the interpretation of results when using this compound. Here, we demonstrate that XE991 and linopirdine are state-dependent inhibitors that favor the activated-subunit of neuronal Kv7/KCNQ channels. We performed patch clamp experiments on homomeric Kv7.2 or heteromeric Kv7.2/3 channels expressed in Chinese hamster ovary cells in order to characterize XE991 and linopirdine...
May 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28476928/the-selexipag-active-metabolite-act-333679-displays-strong-anti-contractile-and-anti-remodeling-effects-but-low-%C3%AE-arrestin-recruitment-and-desensitization-potential
#5
John Gatfield, Katalin Menyhart, Daniel Wanner, Carmela Gnerre, Lucile Monnier, Keith Morrison, Patrick Hess, Marc Iglarz, Martine Clozel, Oliver Nayler
Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular matrix synthesis. Selexipag (Uptravi(®)) is the first non-prostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy, ACT-333679 (previously known as MRE-269), behaved as full agonist in multiple PAH-relevant receptor-distal - or downstream - cellular readouts with a maximal efficacy comparable to that of the prototypic PGI2 analog iloprost: In PASMC, ACT-333679 potently induced cellular relaxation (EC50=4...
May 5, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28476927/rational-tuning-of-visual-cycle-modulator-pharmacodynamics
#6
Philip D Kiser, Jianye Zhang, Mohsen Badiee, Junzo Kinoshita, Neal S Peachey, Gregory P Tochtrop, Krzysztof Palczewski
Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase (RPE65), the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Certain of these agents that contain primary amine groups also can also reversibly form retinaldehyde-Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration whereas effective retinal sequestration can require high drug doses with potential off-target effects...
May 5, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28473458/effects-of-acute-and-chronic-treatments-with-d2-and-d3-receptor-ligands-on-cocaine-vs-food-choice-in-rats
#7
Morgane Thomsen, Andrew C Barrett, Paul Butler, S Stevens Negus, S Barak Caine
Dopamine D3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, non-drug reinforcer. This study compared acute and chronic effects of dopamine D2- and D3-preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice...
May 4, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28473457/pharmacologic-characterization-of-amg8379-a-potent-and-selective-small-molecule-sulfonamide-antagonist-of-the-voltage-gated-sodium-channel-nav1-7
#8
Thomas J Kornecook, Ruoyuan Yin, Stephen Altmann, Xuhai Be, Virginia Berry, Christopher P Ilch, Michael Jarosh, Danielle Johnson, Josie H Lee, Sonya G Lehto, Joseph Ligutti, Dong Liu, Jason Luther, David Matson, Danny Ortuno, John Roberts, Kristin Taborn, Jinti Wang, Matthew M Weiss, Violeta Yu, Dawn X D Zhu, Robert T Fremeau, Bryan D Moyer
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglia (DRG) neurons with an IC50 of 3.1 nM in whole cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state...
May 4, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28465374/regulation-of-delta-opioid-receptor-mediated-signaling-and-antinociception-in-peripheral-sensory-neurons-by-arachidonic-acid-dependent-12-15-lipoxygenase-metabolites
#9
Laura C Sullivan, Teresa A Chavera, Xiaoli Gao, Miryam M Pando, Kelly A Berg
The function of delta opioid receptors (DOR) expressed by peripheral pain-sensing neurons (nociceptors) is regulated by both cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid (AA) metabolites (Sullivan et al., 2015). Whereas COX metabolites enhance responsiveness, LOX metabolites elicit a refractory, non-signaling state of the DOR receptor system for antinociceptive signaling. In this study, using high performance liquid chromatography tandem mass spectrometry analyses, we have found that the 12/15-LOX metabolites, 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, were elevated following treatment of adult rat primary sensory neuron cultures with AA...
May 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28465373/mashiningan-improves-opioid-induced-constipation-in-rats-by-activating-cystic-fibrosis-transmembrane-conductance-regulator-chloride-channel
#10
Yumi Harada, Seiichi Iizuka, Yayoi Saegusa, Sachiko Mogami, Naoki Fujitsuka, Tomohisa Hattori
Opioid receptor stimulants are analgesics used in patients with and without cancer; however, they often cause constipation, resulting in poor adherence and deterioration of the quality of life. Hence, suitable treatments for constipation are required. In this study, we investigated the pharmacological mechanisms of action of mashiningan (MNG), a Kampo medicine used to treat constipation, and evaluated the effect of MNG on opioid-induced constipation in rats. MNG (100 or 300 mg/kg) was orally administered to normal or codeine phosphate (CPH)-induced constipation in rats, and its effect was evaluated on the basis of fecal counts, characteristics, and weight...
May 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28465372/identification-of-4-aminopyrazolopyrimidine-metabolite-that-may-contribute-to-the-hypolipidemic-effects-of-ly2584702-in-long-evans-diet-induced-obese-rats
#11
Tom Estridge, Asim Dey, Charles Reidy, Xiaohong Yu, Yuke Zhang, Maryalice Hartley, Paul L Milligan, Najia Jin, Mark C Kowala, Jennifer K Leohr, Adrian J Fretland, Thomas E Mabry, Debra Luffer-Atlas, M Jane Luo
LY2584702 is an inhibitor of p70 S6 kinase-1 previously developed for the treatment of cancer. In two phase 1 trials in oncology patients, significant reductions of total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglyceride was observed. In the current study, we sought to understand the potential mechanism of action of this compound in regulation of lipid metabolism. In Long Evans diet induced obese (DIO) rats, oral administration of LY2584702 for 3 to 4 weeks led to robust reduction of LDL-C up to 60%...
May 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28450469/novel-phosphodiesterase-4-inhibitor-fcpr03-alleviates-lipopolysaccharide-induced-neuroinflammation-by-regulation-of-camp-pka-creb-signaling-pathway-and-nf-%C3%AE%C2%BAb-inhibition
#12
Zheng-Qiang Zou, Jia-Jia Chen, Hong-Fang Feng, Yu-Fang Cheng, Hai-Tao Wang, Zhong-Zhen Zhou, Hai-Biao Guo, Wenhua Zheng, Jiang-Ping Xu
Over activation of microglia contributes to the induction of neuroinflammation, which is highly involved in the pathology of many neurodegenerative diseases. Phosphodiesterase 4 (PDE4) represents a promising therapeutic target for anti-inflammation. However, the dose-limiting side effects, such as nausea and emesis, have impeded their clinic application. FCPR03, a novel selective PDE4 inhibitor synthesized in our laboratory, shows little or no emetic potency. However, the anti-inflammatory activities of FCPR03 in vitro and in vivo and the molecular mechanisms are still not clearly understood...
April 27, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28446518/glutaminyl-cyclase-inhibitor-pq912-improves-cognition-in-mouse-models-of-alzheimer-s-disease-studies-on-relation-to-effective-target-occupancy
#13
Torsten Hoffmann, Antje Meyer, Ulrich Heiser, Stephan Kurat, Livia Bohme, Martin Kleinschmidt, Karl-Ulrich Buhring, Birgit Hutter-Paier, Martina Farcher, Hans-Ulrich Demuth, Inge Lues, Stephan Schilling
Numerous studies suggest that the majority of Aβ peptides deposited in Alzheimer's Disease (AD) is truncated and post-translationally modified at the N-terminus. Among these modified species, pyroglutamyl-Aβ (pE-Aβ including N3pE-Aβ42) has been identified as particularly neurotoxic. The N-terminal modification renders the peptide hydrophobic, accelerates formation of oligomers and reduces degradation by peptidases leading ultimately to the accumulation of the peptide and progression of AD. It has been shown, that the formation of pyroglutamyl residues is catalysed by glutaminyl cyclase (QC)...
April 26, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28442584/apparent-cb1-receptor-rimonabant-affinity-estimates-combination-with-thc-and-synthetic-cannabinoids-in-the-mouse-in-vivo-triad-model
#14
Travis W Grim, Anthony J Morales, Brian F Thomas, Jenny L Wiley, Gregory W Endres, Sidney S Negus, Aron H Lichtman
Synthetic cannabinoids (SCs) represent an emerging class of abused drugs associated with psychiatric complications and other substantial health risks. These ligands are largely sold over the internet for human consumption presumably because of their high cannabinoid 1 receptor (CB1R) affinity and potency in eliciting similar pharmacological effects as Δ9-tetrahydrocannabinol (THC), while circumventing laws illegalizing this plant. Factors potentially contributing to the increased prevalence of SC abuse and related hospitalizations, such as increased CB1R efficacy and non-CB1R targets, highlight the need for quantitative pharmacological analyses to determine receptor mediation of the pharmacological effects of cannabinoids...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28442583/seletalisib-characterization-of-a-novel-potent-and-selective-inhibitor-of-pi3k%C3%AE
#15
Rodger A Allen, Daniel C Brookings, Mark J Powell, Jean Delgado, Lindsay K Shuttleworth, Mark Merriman, Ian J Fahy, Roohi Tewari, John P Silva, Louise J Healy, Gareth C G Davie, Breda Twomey, Rona M Cutler, Apoorva Kotian, Andrea Crosby, Gillian McCluskey, Gillian Watt, Andrew Payne
PI3Ks are key signaling enzymes regulating cellular survival, development and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a novel small molecule inhibitor of PI3Kδ that was evaluated in biochemical assays, cellular assays of adaptive and innate immunity, and an in vivo rat model of inflammation. Our findings show that seletalisib is a potent, ATP-competitive and highly selective PI3Kδ inhibitor able to block AKT phosphorylation following activation of the BCR in a B-cell line...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28442582/lx2761-a-sodium-glucose-cotransporter-1-inhibitor-restricted-to-the-intestine-improves-glycemic-control-in-mice
#16
David R Powell, Melinda G Smith, Deon D Doree, Angela L Harris, Jennifer Greer, Christopher M DaCosta, Andrea Thompson, Sabrina Jeter-Jones, Wendy Xiong, Kenneth G Carson, Nicole C Goodwin, Bryce A Harrison, David B Rawlins, Eric D Strobel, Suma Gopinathan, Alan Wilson, Faika Mseeh, Brian Zambrowicz, Zhi-Ming Ding
LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad-lib-fed mice...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28442581/sigma-receptor-effects-of-n-substituted-benztropine-analogs-implications-for-antagonism-of-cocaine-self-administration
#17
Takato Hiranita, Weimin C Hong, Theresa Kopajtic, Jonathan L Katz
Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT), but have minimal cocaine-like pharmacological effects and can block numerous effects of cocaine including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28442580/ethanol-reversal-of-tolerance-to-the-antinociceptive-effects-of-oxycodone-and-hydrocodone
#18
Joanna C Jacob, Justin L Poklis, Hamid I Akbarali, Graeme Henderson, William L Dewey
This study compared the development of tolerance and its reversal by ethanol of two orally-bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine. Oxycodone (s.c) was significantly more potent in the mouse tail withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28438778/the-dual-amylin-and-calcitonin-receptor-agonist-kbp-042-works-as-adjunct-to-metformin-on-fasting-hyperglycaemia-and-hba1c-in-a-rat-model-of-type-2-diabetes
#19
Sara Toftegaard Hjuler, Sofie Gydesen, Kim Vietz Andreassen, Morten Asser Karsdal, Kim Henriksen
KBP-042 is a dual amylin and calcitonin receptor agonist which increases glucose tolerance and insulin action, and reduces body weight in rat models of obesity and pre-diabetes. The objective of the present study was to 1) Evaluate KBP-042 as a treatment of late stage type 2 diabetes in a rat model and 2) Assess the value of adding KBP-042 to the standard of care, metformin, in order to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention and a prevention study...
April 24, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28438777/preference-for-an-opioid-benzodiazepine-mixture-over-an-opioid-alone-using-a-concurrent-choice-procedure-in-rhesus-monkeys
#20
Peter F Weed, Charles P France, Lisa R Gerak
Increased opioid abuse is contributing to a dramatic rise in overdose deaths. Benzodiazepines are frequently coabused with opioids, possibly because they increase the potency and/or effectiveness of opioids. This study used a concurrent choice procedure to determine whether monkeys would choose to self-administer a mixture of the opioid remifentanil and the benzodiazepine midazolam over remifentanil alone. Initially, three monkeys could respond on one lever for saline and on a second lever for either remifentanil alone or midazolam alone...
April 24, 2017: Journal of Pharmacology and Experimental Therapeutics
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