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Journal of Pharmacology and Experimental Therapeutics

James Watt, Alexander W Alund, Casey F Pulliam, Kelly E Mercer, Larry J Suva, Jin-Ran Chen, Martin J J Ronis
Chronic alcohol consumption increases bone resorption and decreases bone formation. A major component of ethanol (EtOH) pathology in bone is the generation of excess reactive oxygen species (ROS). The ROS-generating NADPH oxidase 4 (NOX4) is proposed to drive much of the EtOH-induced suppression of bone formation. Here, 13-week old male WT and NOX4 -/- mice were pair-fed (PF) a high fat (35%) Lieber-DeCarli liquid diet with or without EtOH at 30% of their total calories for 12 weeks. Micro-CT analysis of trabecular and cortical bone demonstrated significant decreases in bone volume/total volume (BV/TV%) and cortical thickness in WT, EtOH-fed mice compared to pair-fed (PF) controls...
April 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Shinji Mima, Chihaya Kakinuma, Tamami Higuchi, Kazunori Saeki, Takayuki Yamada, Rena Uematsu, Miki Ishino, Nobuko Kito, Hiroki Nishikawa, Hidenobu Kuniyoshi, Takuya Matsumoto, Hideyasu Fujiwara, Linda J Paradiso, Yasuhiro Shimada, Hiroyuki Iwamura
We report in this paper that FF-10502, a pyrimidine nucleoside antimetabolite with a chemical structure similar to gemcitabine, shows beneficial anticancer activity via novel mechanism of action on dormant cells. The growth-inhibition of pancreatic cancer cell lines by FF-10502 (IC50, 60-330 nM) was moderately weaker than that by gemcitabine in vitro. In contrast, an in vivo orthotopic implantation model in mice with established human pancreatic cancer cell line, SUIT-2, revealed no mortality with FF-10502 intravenous treatment, which was related with regression of implanted tumor and little metastasis, whereas 75% of the mice treated with gemcitabine died by day 128...
April 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Dong Yan, Omar Hamed, Taruna Joshi, Mahmoud M Mostafa, Kyla C Jamieson, Radhika Joshi, Robert Newton, Mark A Giembycz
The contribution of gene expression changes to the adverse and therapeutic effects of β2-adrenoceptor agonists in asthma was investigated using human airway epithelial cells as a therapeutically-relevant target. Operational model fitting established that the long-acting β2-adrenoceptor agonists (LABA), indacaterol, salmeterol, formoterol and picumeterol were full agonists on BEAS-2B cells transfected with a cAMP response element reporter, but differed in efficacy (indacaterol≥formoterol>salmeterol≥picumeterol)...
April 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Mitesh Patel, Marta Johnson, Caroline J Sychterz, Gareth J Lewis, Cory Watson, Harma Ellens, Joseph W Polli, Maciej J Zamek-Gliszczynski
Atovaquone, an anti-protozoal and anti-pneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent non-specific binding and incomplete solubility in bile, atovaquone is still concentrated 100-fold in bile, consistent with active biliary excretion. Mechanisms of atovaquone hepatobiliary disposition were studied using a multi-experimental in vitro and in vivo approach...
April 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Constanze Schmidt, Felix Wiedmann, Anne-Rike Gaubatz, Antonius Ratte, Hugo A Katus, Dierk Thomas
Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K2P) potassium channels regulate cardiac action potential repolarization. Recently, K2P3.1 (TASK-1) has been implicated in atrial fibrillation (AF) pathophysiology and was suggested as atrial-selective antiarrhythmic drug target. We hypothesized that blockade of cardiac K2P channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K2P channels were screened for interactions with cardiac glycosides...
April 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Ayse Ufuk, Rachel E Kosa, Hongying Gao, Yi-An Bi, Sweta Modi, Dana Gates, A David Rodrigues, Larry M Tremaine, Manthena V S Varma, J Brian Houston, Aleksandra Galetin
Hepatic organic anion transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share >90% degree of gene and amino acid sequence identity with human orthologs, we evaluated the in vitro-in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using cynomolgus monkey hepatocytes showed active uptake Km values of 2.0 and 3.9 µM for OATP1B probe substrates, pitavastatin and rosuvastatin, respectively...
April 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Adrian J Mogg, Thomas Eessalu, Megan Johnson, Rebecca Wright, Helen E Sanger, Hongling Xiou, Michael Crabtree, Alex Smith, Ellen Colvin, Douglas Schober, Donald Gehlert, Cynthia Jesudason, Paul Goldsmith, Michael P Johnson, Christian C Felder, Vanessa N Barth, Lisa M Broad
In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable and validated biomarkers. One valuable approach to assessing target engagement is to utilize PET tracers...
April 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Jenny V Tobin, Daniel P Zimmer, Courtney Shea, Peter Germano, Sylvie G Bernier, Guang Liu, Kim Long, Joy Miyashiro, Sheila Ranganath, Sarah Jacobson, Kim Tang, G-Yoon Jamie Im, James Sheppeck, Joel D Moore, Kristine Sykes, James Wakefield, Renee Sarno, Ali R Banijamali, Albert T Profy, G Todd Milne, Mark G Currie, Jaime L Masferrer
Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophosphate (cGMP) upon binding of nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications of diabetes, and have been associated with other disease states and aging. sGC stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling. The pharmacological characterization of IW-1973, a novel clinical-stage sGC stimulator, is described...
April 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Vidya Ramakrishnan, Donald E Mager
The objective of this study is to evaluate the heterogeneity in pharmacodynamic response in four in vitro multiple myeloma cell lines to treatment with bortezomib, and to assess whether such differences are associated with drug-induced intracellular signaling protein dynamics identified via a logic-based network modeling approach. The in vitro pharmacodynamic efficacy of bortezomib was evaluated through concentration-effect and cell proliferation dynamical studies in U266, RPMI8226, MM.1S, and NCI-H929 myeloma cell lines...
April 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Stefania Petrosino, Massimo Vaia, Roberta Verde, Teresa Iuvone, Vincenzo Di Marzo
Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation. Cannabinoid type-2 (CB2) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD). We investigated if non-psychotropic cannabinoids like cannabidiol (CBD) produced similar effects in this experimental model of ACD...
April 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Sean L Hammond, Katriana A Popichak, Xi Li, Lindsay G Hunt, Evan H Richman, Pranav Damale, Edwin Chong, Donald S Backos, Stephen Safe, Ronald B Tjalkens
The orphan nuclear receptor, Nurr1 (NR4A2), regulates inflammatory gene expression in glial cells, as well as genes associated with homeostatic and trophic function in dopaminergic neurons. Despite these known functions of Nurr1, an endogenous ligand has not been discovered. We postulated that activation of Nurr1 would suppress activation of glia and thereby protect against loss of dopamine (DA) neurons following subacute lesioning with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our previous studies have shown that a synthetic Nurr1 ligand, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12), suppresses inflammatory gene expression in primary astrocytes and induces a dopaminergic phenotype in neurons...
April 6, 2018: Journal of Pharmacology and Experimental Therapeutics
Yun-Ping Mu, Da-Cen Lin, Si-Yi Zheng, Hai-Xia Jiao, James Sham, Mo-Jun Lin
Pulmonary hypertension (PH) is characterized by enhanced vasoconstriction and vascular remodeling, which are attributable to the alteration of Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). It is well established that store-operated Ca2+ entry (SOCE) is augmented in PASMCs during PH and it plays crucial roles in PH development. Our previous studies showed that the melastatin-related transient receptor potential 8 (TRPM8) is down-regulated in PASMCs of PH animal models; and activation of TRPM8 causes relaxation of pulmonary arteries (PAs)...
April 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Xiangqing Xu, Yaqin Wei, Qiang Guo, Song Zhao, Zhiqiang Liu, Ting Xiao, Yani Liu, Yinli Qiu, Yuanyuan Hou, Guisen Zhang, Kewei Wang
Multi-target antidepressants selectively inhibiting monoaminergic transporters and 5-HT2A receptors have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors (SSRIs). In the present study, we synthesized a series of novel 3-(benzo[d] [1, 3] dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which H05 was identified as a lead compound with potent inhibition effects on both serotonin (Ki=4.81 nM) and norepinephrine (Ki=6.72 nM) transporters and moderate 5-HT2A antagonist activity (IC50=60...
April 3, 2018: Journal of Pharmacology and Experimental Therapeutics
Pui Yan Ho, Zhijian Duan, Neelu Batra, Joseph L Jilek, Mei-Juan Tu, Jing-Xin Qiu, Zihua Hu, Theodore Wun, Primo N Lara, Ralph W DeVere White, Hong-Wu Chen, Ai-Ming Yu
Noncoding RNAs (ncRNAs) produced in live cells may better reflect intracellular ncRNAs for research and therapy. Attempts were made to produce biological ncRNAs, but at low yield or success rate. Here we first report a new ncRNA bioengineering technology, using more stable ncRNA carrier (nCAR) containing a pre-miR-34a derivative identified by rational design and experimental validation. This approach offered a remarkable higher-level expression (40-80% of total RNAs) of recombinant ncRNAs in bacteria, and gave an 80% success rate (33 out of 42 ncRNAs)...
March 30, 2018: Journal of Pharmacology and Experimental Therapeutics
Shu-Hui Chuang, Doodipala Samba Reddy
Neurosteroids are powerful modulators of GABA-A receptors. Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor-mediated phasic currents...
March 30, 2018: Journal of Pharmacology and Experimental Therapeutics
Ming-Fen Ho, Edroaldo Lummertz da Rocha, Cheng Zhang, James Ingle, Paul Goss, Lois Shepherd, Michiaki Kubo, Liewei Wang, Hu Li, Richard Weinshilboum
TCL1A single nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is estradiol (E2) inducible and plays a critical role in the regulation of cytokines, chemokines and toll like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective estrogen receptor modulators, e.g, 4-hydroxytamoxifen (4OH-TAM)...
March 28, 2018: Journal of Pharmacology and Experimental Therapeutics
Keith Morrison, Franck Haag, Roland Ernst, Marc Iglarz, Martine Clozel
Selexipag is a selective non-prostanoid prostacyclin (PGI2 ) receptor (IP receptor) agonist that is approved for the treatment of pulmonary arterial hypertension (PAH). In contrast to selexipag, PGI2 analogs used in the clinic are non-selective agonists at prostanoid receptors and can also activate contractile EP3 receptors. Leg pain is a common side effect in patients receiving treatment with PGI2 analogs and peripheral vasoconstriction can be responsible for side effects related to muscular ischemia. This study tested the hypothesis that PGI2 analogs could cause paradoxical vasoconstriction of the femoral artery via EP3 receptor activation but that only vasorelaxation would be observed in response to selexipag and its active metabolite ACT-333679...
March 27, 2018: Journal of Pharmacology and Experimental Therapeutics
Christopher S Rabender, Ninu Bruno, Asim Alam, Gobalakrishnan Sundaresan, Jamal Zweit, Ross B Mikkelsen
Previously we demonstrated that nitric oxide synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor, sepiapterin (SP), inhibits tumor progression. Endothelial dysfunction characterizes the poorly functional vasculature of solid tumors and since NO is critical for regulation of endothelial function we asked whether SP, by recoupling NOS, improves tumor vasculature structure and function enhancing chemotherapeutic delivery and response to radiotherapy...
March 26, 2018: Journal of Pharmacology and Experimental Therapeutics
Natasha D Bush, Logan K Townsend, David C Wright
Olanzapine (OLZ) is an antipsychotic drug used in the treatment of schizophrenia. While effective in reducing psychoses, OLZ causes acute increases in blood glucose. The acute effects of OLZ on hyperglycaemia are likely caused by reductions in insulin secretion, insulin resistance and increased hepatic glucose production. 5'AMP-activated protein kinase (AMPK) is an energy sensor activated during exercise that can increase insulin sensitivity and insulin-independent glucose uptake in muscle. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) is a pharmacological agent that, among other effects, can activate AMPK in vivo...
March 26, 2018: Journal of Pharmacology and Experimental Therapeutics
Tae Woo Jung, Eun Jung Kyung, Hyoung-Chun Kim, Yong Kyu Shin, Sung Hoon Lee, Eon Sub Park, Ahmet Hacimuftuoglu, A M Abd El-Aty, Ji Hoon Jeong
Docosahexaenoic acid (DHA) and its bioactive compounds may have suppressive effects on inflammation, endoplasmic reticulum (ER) stress, and insulin resistance. Protectin DX (PDX), a double lipoxygenase product from docosahexaenoic acid (DHA) has shown a suppressive effect on inflammation and insulin resistance. However, the effects of PDX on ER stress and hepatic steatosis have not been elucidated yet. Herein we have found that PDX could stimulate the AMP-activated protein kinase (AMPK) phosphorylation, thereby upregulating oxygen-regulated protein 150 (ORP150) expression in a dose-dependent manner...
March 23, 2018: Journal of Pharmacology and Experimental Therapeutics
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