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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/29025979/the-melatonin-receptor-agonist-piromelatine-ameliorates-impaired-glucose-metabolism-in-chronically-stressed-rats-fed-a-high-fat-diet
#1
Jun Zhou, Deng Wang, Xiaohong Luo, Xu Jia, Maoxing Li, Laudon Moshe, Ruxue Zhang, Zhengping Jia
Modern lifestyle factors (high-caloric food rich in fat) and daily chronic stress are important risk factors for metabolic disturbances. Increased hypothalamic-pituitary-adrenal (HPA) axis activity and the subsequent excess production of glucocorticoids (GCs) in response to chronic stress (CS) leads to increases in metabolic complications, such as type 2 diabetes and insulin resistance (IR). Melatonin (MLT), which protects several regulatory components of the HPA axis from GC-induced deterioration, might improve glucose homeostasis...
October 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29025978/the-anti-vascular-endothelial-growth-factor-receptor-1-monoclonal-antibody-d16f7-inhibits-glioma-growth-and-angiogenesis-in-vivo
#2
Maria Grazia Atzori, Lucio Tentori, Federica Ruffini, Claudia Ceci, Elena Bonanno, Manuel Scimeca, Pedro Miguel Lacal, Grazia Graziani
The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor that does not play a relevant role in physiological angiogenesis in adults, while it is important in tumor angiogenesis. In high-grade glioma VEGFR-1 expression by tumor endothelium and neoplastic cells contributes to the aggressive phenotype. We recently generated an anti-VEGFR-1 monoclonal antibody (mAb) characterized by a novel mechanism of action, since it hampers receptor activation without interfering with ligand binding...
October 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29025977/an-approach-to-discovering-novel-muscarinic-m1-receptor-positive-allosteric-modulators-with-potent-cognitive-improvement-and-minimized-gastrointestinal-dysfunction
#3
Emi Kurimoto, Satoru Matsuda, Yuji Shimizu, Yuu Sako, Takao Mandai, Takahiro Sugimoto, Hiroki Sakamoto, Haruhide Kimura
Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M1 selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knock-out mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS) -induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction...
October 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29021382/sustained-activation-of-guanylate-cyclase-a-with-tdt-a-natriuretic-peptide-derivative-exhibits-cardiorenal-protection-in-dahl-salt-sensitive-hypertensive-rats
#4
Shohei Oishi, Naoko Suzuki, Yuri Hasui, Tsuyoshi Homma, Masanori Obana, Takahiro Nagayama, Yasushi Fujio
Heart failure often presents with prognosis-relevant impaired renal function. To investigate whether the chronic activation of guanylate cyclase-A (GC-A) protects both heart and kidney, we examined the effects of TDT, a neprilysin (NEP)-resistant natriuretic peptide (NP) derivative, on cardiac and renal dysfunction in Dahl salt-sensitive hypertensive rats (DS rats). Pretreatment with NEP or NEP inhibitor did not influence GC-A activation by TDT both in vitro and in vivo, resulting in a long-acting profile of TDT compared to native human atrial NP (hANP)...
October 11, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29021381/activation-of-fak-and-src-mediates-acquired-sorafenib-resistance-in-a549-human-lung-adenocarcinoma-xenografts
#5
Qingyu S Zhou, Xiaofang Guo, Riya Choksi
Despite encouraging clinical results with sorafenib monotherapy in patients with KRAS-mutant non-small cell lung cancer (NSCLC), the overall survival benefit of this drug is limited by the inevitable development of acquired resistance. The exact mechanism underlying acquired sorafenib resistance in KRAS-mutant NSCLC is unclear. In this study, the mechanism of acquired sorafenib resistance was explored using a biologically relevant xenograft model, which was established by using the A549 human lung adenocarcinoma cell line and an in-vivo derived sorafenib-resistant A549 subline (A549/SRFres)...
October 11, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28970359/investigation-of-diacylglycerol-lipase-alpha-inhibition-in-the-mouse-lipopolysaccharide-inflammatory-pain-model
#6
Jenny L Wilkerson, Giulia Donvito, Travis W Grim, Rehab A Abdullah, Daisuke Ogasawara, Benjamin F Cravatt, Aron H Lichtman
Diacylglycerol lipase (DAGL) α and β, the major biosynthetic enzymes of the endogenous cannabinoid (endocannabinoid) 2-arachidonylglycerol (2-AG), are highly expressed in the nervous system and immune system, respectively. Genetic deletion or pharmacological inhibition of DAGL-β protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages, and reverses LPS-induced allodynia in mice. In order to gain insight into the contribution of DAGL-α in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-α/-β inhibitor...
October 2, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28970358/xenobiotic-nuclear-receptors-pxr-and-car-regulate-antiretroviral-drug-efflux-transporters-at-the-blood-testis-barrier
#7
Sana-Kay Whyte-Allman, Md Tozammel Hoque, Mohammad-Ali Jenabian, Jean-Pierre Routy, Reina Bendayan
Poor antiretroviral drug (ARV) penetration in the testes could, in part, be due to the presence of ATP-binding cassette membrane-associated drug efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs) expressed at the blood-testis barrier (BTB). The functional expression of these transporters is known to be regulated by ligand-activated nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), in various tissues...
September 28, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28954811/preclinical-characterization-of-r-3-3s-4s-3-fluoro-4-4-hydroxyphenyl-piperidin-1-yl-1-4-methylbenzyl-pyrrolidin-2-one-bms-986169-a-novel-intravenous-glutamate-n-methyl-d-aspartate-2b-glun2b-receptor-negative-allosteric-modulator-with-potential-in-major-depressive
#8
Linda J Bristow, Jyoti Gulia, Michael R Weed, Bettadapura N Srikumar, Yu-Wen Li, John D Graef, Pattipati S Naidu, Charulatha Sanmathi, Jayant Aher, Tanmaya Bastia, Mahesh Paschapur, Narasimharaju Kalidindi, Kuchibholta Vijaya Kumar, Thaddeus Molski, Rick Pieschl, Alda Fernandes, Jeffrey M Brown, Digavalli V Sivarao, Kimberly Newberry, Mark Bookbinder, Joseph Polino, Deborah Keavy, Amy Newton, Eric Shields, Jean Simmermacher, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Raja Reddy Kallem, Meenakshee Sinha, Manjunath Ramarao, Reeba K Vikramadithyan, Srinivasan Thangathirupathy, Jayakumar Warrier, Joanne J Bronson, Richard E Olson, John E Macor, Charlie F Albright, Dalton King, Lorin A Thompson, Lawrence R Marcin, Michael Sinz
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), and the phosphate prodrug (BMS-986163), were identified from a drug discovery effort focused on the development of novel, intravenous, glutamate N-methyl-D-aspartate 2B receptor (GluN2B) negative allosteric modulators for treatment resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-D-aspartate receptor subtypes (IC50 = 24...
September 27, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28947488/treatment-with-sulforaphane-produces-antinociception-and-improves-morphine-effects-during-inflammatory-pain-in-mice
#9
Alejandro Redondo, Pablo Anibal Ferreira Chamorro, Gabriela Riego, Sergi Leanez, Olga Pol
The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts potent anti-oxidative and anti-inflammatory effects, however its participation in the modulation of chronic inflammatory pain and on the antinociceptive effects of μ opioid receptor (MOR) agonists has not been evaluated. We investigated whether the induction of Nrf2 could alleviate chronic inflammatory pain, augments the analgesic effects of morphine and mechanisms implicated. In male C57BL/6 mice with inflammatory pain induced by complete Freund's adjuvant (CFA) subplantarly administered, we assessed: 1) antinociceptive actions of the administration of 5 and 10 mg/kg of a Nrf2 activator, sulforaphane (SFN); 2) effects of SFN on the antinociceptive actions of morphine and on protein levels of Nrf2, heme oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) enzymes, microglial activation and inducible nitric oxide synthase (NOS2) over-expression, as well as on mitogen-activated protein kinase (MAPK) and MOR expression in the spinal cord and paw of animals with inflammatory pain...
September 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28947487/cannabinoid-cb1-discrimination-effects-of-endocannabinoids-and-catabolic-enzyme-inhibitors
#10
Michael Z Leonard, Shakiru O Alapafuja, Lipin Ji, Vidyanand G Shukla, Yingpeng Liu, Spyros P Nikas, Alexandros Makriyannis, Jack Bergman, Brian D Kangas
An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type-1 (CB1) receptor agonists such as Δ9-tetrahydrocannabinol are increasingly utilized for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition...
September 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28935700/mitochondrial-based-therapeutics-for-the-treatment-of-spinal-cord-injury-mitochondrial-biogenesis-as-a-potential-pharmacological-target
#11
Natalie E Scholpa, Rick G Schnellmann
Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, directly reducing the ability of mitochondria to maintain homeostasis, leading to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury post-SCI represents a potentially effective therapeutic strategy...
September 21, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28928122/discovery-and-preclinical-characterization-of-gsk1278863-daprodustat-a-small-molecule-hypoxia-inducible-factor-hif-prolyl-hydroxylase-inhibitor-for-anemia
#12
Jennifer L Ariazi, Kevin J Duffy, David F Adams, Duke M Fitch, Lusong Luo, Melissa Pappalardi, Mangatt Biju, Erin Hugger DiFilippo, Tony Shaw, Ken Wiggall, Connie Erickson-Miller
Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients with a variety of underlying pathologies such as chronic kidney disease (CKD). Treatment with recombinant human EPO (rHuEPO) at supraphysiological concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients and presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF)1α and HIF2α control the physiological response to hypoxia and invoke a program of increased erythropoeisis...
September 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28928121/novel-pharmacological-probes-reveal-abhd5-as-a-locus-of-lipolysis-control-in-white-and-brown-adipocytes
#13
Elizabeth A Rondini, Ljiljana Mladenovic-Lucas, William R Roush, Geoff Halvorsen, Alex E Green, James G Granneman
Current knowledge regarding acute regulation of adipocyte lipolysis is largely based on receptor-mediated activation or inhibition of pathways that influence intracellular levels of cyclic AMP (cAMP), thereby affecting protein kinase A (PKA) activity. We recently identified synthetic ligands of α-β-hydrolase domain containing 5 (ABHD5) that directly activate adipose triglyceride lipase (ATGL) by dissociating ABHD5 from its inhibitory regulator, perilipin-1 (PLIN1). In the current study we used these novel ligands to determine the direct contribution of ABHD5 to various aspects of lipolysis control in white (3T3-L1) and brown adipocytes...
September 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28928120/creation-of-a-claudin-2-binder-and-its-tight-junction-modulating-activity-in-a-human-intestinal-model
#14
Mutsumi Takigawa, Manami Iida, Shotaro Nagase, Hidehiko Suzuki, Akihiro Watari, Minoru Tada, Yoshiaki Okada, Takefumi Doi, Masayoshi Fukasawa, Kiyohito Yagi, Jun Kunisawa, Masuo Kondoh
Disruption of the gastrointestinal epithelial barrier is a hallmark of chronic inflammatory bowel diseases (IBDs). The transmembrane protein claudin 2 (CLDN2) is a component of epithelial tight junctions (TJs). In the intestines of patients with IBDs, the expression of the pore-forming TJ protein CLDN2 is upregulated. Although CLDN2 is involved in these leaky barriers, whether it can be a target to enhance TJ integrity is unknown because a CLDN2-specific inhibitor has not been developed. Here, we used DNA immunization to generate a monoclonal antibody (mAb) that recognized an extracellular loop of CLDN2...
September 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28928119/8-aminoguanosine-exerts-diuretic-natriuretic-and-glucosuric-activity-via-conversion-to-8-aminoguanine-yet-has-direct-antikaliuretic-effects
#15
Edwin K Jackson, Zaichuan Mi
8-Aminoguanosine induces diuresis, natriuresis, glucosuria, and antikaliuresis. These effects could be mediated via 8-aminoguanosine's metabolism to 8-aminoguanine. Here we tested this hypothesis in anesthetized rats. First, we demonstrated that at 85-115 min post intravenous administration, 8-aminoguanosine and 8-aminoguanine (33.5 µmol/kg) significantly increased urine volume [ml/30min: 8-aminoguanosine from 0.3±0.1 to 0.9±0.1 (mean±SEM; n=7); 8-aminoguanine from 0.3±0.1 to 1.5±0.2 (n=8)], sodium excretion (µmol/30min: 8-aminoguanosine from 12±5 to 109±21; 8-aminoguanine from 18±8 to 216±31), and glucose excretion (µg/30min: 8-aminoguanosine from 18±3 to 159±41; 8-aminoguanine from 17±3 to 298±65)...
September 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28916659/hybrid-of-dna-targeting-chlorambucil-with-pt-iv-species-to-reverse-drug-resistances
#16
Feihong Chen, Gang Xu, Xiaodong Qin, Xiufeng Jin, Shaohua Gou
Two hybrids were designed and prepared by addition of a chlorambucil unit to an axial position of the Pt(IV) complex derived from DN603 or DN604 which was recently found to exhibit significant anticancer activity and low toxicity. Cytotoxicity of two compounds against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound 5 had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drugs resistances. Mechanistic investigation suggested that the potent antitumor activity of 5 arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand breaks (DSBs) repair...
September 15, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28912346/the-blood-pressure-lowering-effect-of-20-hete-blockade-in-cyp4a14-mice-is-associated-with-natriuresis
#17
Varunkumar Pandey, Victor Garcia, Ankit Gilani, Priyanka Mishra, Frank Fan Zhang, Mahesh P Paudyal, John R Falck, Alberto Nasjletti, Wen-Hui Wang, Michal L Schwartzman
20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) has been linked to pro- and anti-hypertensive actions through its ability to promote vasoconstriction and inhibit Na transport in the ascending limb of the loop of Henle, respectively. In this study, we assessed the effects of 20-HETE blockade on blood pressure, renal hemodynamics and urinary sodium excretion in Cyp4a14(-/-) male mice, which display androgen-driven 20-HETE-dependent hypertension. Administration of 20-SOLA, a water-soluble 20-HETE antagonist, in the drinking water normalized blood pressure of male Cyp4a14(-/-) hypertensive mice (124± vs 153± mmHg) while having no effect on age-matched normotensive wild-type male mice...
September 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28912345/a-novel-bibenzyl-compound-20c-protected-mice-from-mptp-p-toxicity-by-regulating-alpha-synuclein-related-inflammatory-response
#18
Qiu-Shuang Zhang, Yang Heng, Ying Chen, Piao Luo, Lu Wen, Zhao Zhang, Yu-He Yuan, Nai-Hong Chen
The novel bibenzyl compound 20C plays a neuroprotective role in vitro, but its effects in vivo have not been elucidated. In this study, we estimated the efficacy of 20C in vivo using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p) mouse model from behavior, dopamine and neuron, and then the possible mechanisms for these effects were further investigated. The experimental results showed that 20C improved behavioral deficits, attenuated dopamine depletion, reduced dopaminergic neuron loss, protected blood brain barrier structure, ameliorated α-synuclein dysfunction, suppressed glial activation, and regulated both NF-κB signaling and the NLRP3 inflammasome pathway...
September 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28904003/preclinical-pharmacology-and-pharmacokinetics-of-inhaled-hexadecyl-treprostinil-c16tr-a-pulmonary-vasodilator-prodrug
#19
Michel R Corboz, Zhili Li, Vladimir Malinin, Adam J Plaunt, Donna M Konicek, Franziska G Leifer, Kuan-Ju Chen, Charles E Laurent, Han Yin, Marzena C Biernat, Dany Salvail, Jianguo Zhuang, Fadi Xu, Aidan Curran, Walter R Perkins, Richard W Chapman
This report describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (> 10 µM) in receptor binding and enzyme inhibition assays including binding to EP2, DP1, IP and EP4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by adenosine diphosphate (ADP) in rat blood...
September 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28882879/acalabrutinib-acp-196-a-covalent-bruton-tyrosine-kinase-btk-inhibitor-with-a-differentiated-selectivity-and-in-vivo-potency-profile
#20
Tjeerd Barf, Todd Covey, Raquel Izumi, Bas van de Kar, Michael Gulrajani, Bart van Lith, Maaike van Hoek, Edwin de Zwart, Diana Mittag, Dennis Demont, Saskia Verkaik, Fanny Krantz, Paul G Pearson, Roger Ulrich, Allard Kaptein
Several small-molecule BTK inhibitors are in development for B-cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib (1, ACP-196). Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential...
September 7, 2017: Journal of Pharmacology and Experimental Therapeutics
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