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Journal of Pharmacology and Experimental Therapeutics

Richard M Kostrzewa, Karolina Wydra, Malgorzata Filip, Cynthia Crawford, Sanders A McDougall, Russell W Brown, Dasiel O Borroto-Escuela, Kjell Fuxe, Raul R Gainetdinov
Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, then behaviorally and biochemically characterized over the next 15-20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes; as well as functional links between the biologic template of the animal model; and ability of pharmacotherapeutics to modulate or reverse biological and behavioral modalities towards normality...
June 19, 2018: Journal of Pharmacology and Experimental Therapeutics
Chao-Yuan Huang, Man-Hsin Hung, Chi-Ting Shih, Feng-Shu Hsieh, Chiung-Wen Kuo, Ming-Hsien Tsai, Shih-Shin Chang, Yung-Jen Hsiao, Li-Ju Chen, Tzu-I Chao, Kuen-Feng Chen
Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiotherapy (RT)-mediated anti-cancer effects has not yet been explored. Here, we investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assay, we found that RT-induced proliferative inhibition was critically associated with SET expression. Next, we tested a novel SET antagonist, EMQA, in combination with RT...
June 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Martina Holubova, Miroslava Blechova, Anna Kakonova, Jaroslav Kunes, Blanka Zelezna, Lenka Maletinska
Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment for anorexia and cachexia. However, its biological stability is highly limited, therefore a number of both peptide and non-peptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under non-pathological conditions and in the context of lipopolysaccharide (LPS)-induced anorexia...
June 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Karim A Alkadhi
Long-term potentiation (LTP) is commonly considered as the cellular correlate of learning and memory. In learning and memory impairments, LTP is invariably markedly diminished in the hippocampus, the brain region responsible for memory formation. LTP is measured electrophysiologically in various areas of the hippocampus. Two mechanistically distinct phases of LTP have been identified: early-phase LTP (E-LTP; related to short-term memory) and late-phase LTP (L-LTP; related to long-term memory). These two forms can be severely reduced in a variety of conditions and have been shown to be rescued by treatment with nicotine...
June 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Alice Marino, Takuya Sakamoto, Xiao-Han Tang, Lorraine J Gudas, Roberto Levi
We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid β2-receptor (RARβ2), decreases oxidative stress in the liver, pancreas, and kidney of mice fed a high-fat diet (HFD). Since hyperlipidemic states are causally associated with myocardial ischemia and oxidative stress, we have now investigated the effects of AC261066 in an ex-vivo ischemia/reperfusion (I/R) injury model in hearts of two prototypic dysmetabolic mice. We found that a 6-week oral treatment with AC261066 in both genetically hypercholesterolemic (ApoE-/-) and obese (HFD-fed) wild-type mice exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of added drug...
June 15, 2018: Journal of Pharmacology and Experimental Therapeutics
Kristin M McCabe, Jason G Zelt, Martin Kaufmann, Kimberly Laverty, Emilie Ward, Henry Barron, Glenville Jones, Michael A Adams, Rachel M Holden
Patients with chronic kidney disease have a markedly increased risk for developing cardiovascular disease. Non-traditional risk factors, such as increased phosphate retention, and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol (1,25-(OH)2-D3) is a key transcriptional regulator of Matrix Gla protein (MGP), a vitamin K dependent protein that inhibits vascular calcification. The objective of this study was to determine if calcitriol treatment could inhibit the development of vascular calcification and if this inhibition was dependent on vitamin K status in a rat model of CKD...
June 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Wanghui Jing, Yasaman Safarpour, Ting Zhang, Pengqi Guo, Guoning Chen, Xiaoming Wu, Qiang Fu, Yitao Wang
Downregulation of P-glycoprotein (P-gp) is implicated in the pathophysiology of inflammatory bowel disease (IBD). Berberine, a principal isoquinoline alkaloid extracted from Berberis species, has been reported to exhibit therapeutic potential in IBD. In this study, we used a dextran sulfate sodium (DSS)-induced colitis rat model to evaluate the effect of berberine on P-gp and explore its mechanism of action. Berberine treatment improved DSS-induced colitis symptoms, attenuated inflammatory markers (myeloperoxidase, tumor necrosis factor-α, and interleukin-1β and -6), and enhanced P-gp expression in a dose-dependent manner...
June 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Michelle G Baladi, Michael J Forster, Michael B Gatch, Richard B Mailman, Danielle L Hyman, Lawrence P Carter, Aaron J Janowsky
Excessive sleepiness (ES) is associated with several sleep disorders, including narcolepsy and obstructive sleep apnea (OSA). A role for monoaminergic systems in treating these conditions is highlighted by the clinical use of United States Food and Drug Administration-approved drugs that act on these systems, such as dextroamphetamine, methylphenidate, modafinil, and armodafinil. Solriamfetol (JZP-110) is a wake-promoting agent that is currently being evaluated to treat ES in patients with narcolepsy or OSA...
June 11, 2018: Journal of Pharmacology and Experimental Therapeutics
Kazuyuki Sakamoto, Yukiko Noguchi, Koji Ueshima, Hisashi Yamakuni, Akiyoshi Ohtake, Shuichi Sato, Kenichiro Ishizu, Naomi Hosogai, Eiji Kawaminami, Masahiro Takeda, Noriyuki Masuda
Current pharmacotherapies for lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH) are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid with various biological functions. However, its exact role in the lower urinary tract and its target receptor subtype have not been fully elucidated. We investigated the role of LPA and the type 1 LPA receptor (LPA1) in urethral/prostatic contractile function and prostate cell proliferation by pharmacologically characterizing ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide), a novel LPA1 antagonist...
June 8, 2018: Journal of Pharmacology and Experimental Therapeutics
Hiroya Mizutani, Fukumitsu Sakakibara, Masahito Komuro, Eiji Sasaki
Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the USA. There is currently no globally approved pharmacological drug for the treatment of SUI patients. Therefore, a new pharmacological treatment option is required. TAS-303 is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters...
June 6, 2018: Journal of Pharmacology and Experimental Therapeutics
Marta Gomez de Cedron, Teodoro Vargas, Andres Madrona, Aranza Jimenez, Maria Jesus Perez Perez, Jose Carlos Quintela, Guillermo Reglero, Ana Rosa San-Felix, Ana Ramirez de Molina
New series of polyphenols with a hydrophilic galloyl based "head" and a hydrophobic N-acyl "tail", linked through a serinol moiety, have been synthesized and tested against colon cancer cell growth. Our structure activity relationship studies revealed that galloyl moieties are essential for growth inhibition. Moreover, the length of the N-acyl chain is crucial for the activity. Introduction of a (Z) double bond in the acyl chain increased the anti-cancer properties. Our findings demonstrate that 16, the most potent compound within this series, has inhibitory effects on colon cancer cell growth and metabolism (glycolysis and mitochondrial respiration) at the same time that activates AMPK and induces apoptotic cell death...
June 5, 2018: Journal of Pharmacology and Experimental Therapeutics
Chao Zhang, Wenfeng Zeng, Yi Yao, Bin Xu, Xiuli Wei, Luoyang Wang, Xiaozhe Yin, Apurba Kumar Barman, Fayun Zhang, Chunling Zhang, Qibin Song, Wei Liang
PURPOSE: Radiation-induced lung injury (RILI) is the main complication of radiotherapy for thoracic malignancies. Naringenin as a potent immune-modulator has been found to relieve bleomycin-induced lung fibrosis by restoring the balance of disordered cytokines. Thus, we ought to determine whether naringenin would mitigate RILI and investigate the underlying mechanism. METHODS: Animals received fractioned irradiation in thoracic area to induce RILI, ELISA and Milliplex were used for serum and bronchoalveolar lavage fluid (BALF) cytokines analysis, haematoxylin & eosin staining for pathological changes and masson trichrome staining for fibrosis determination in the lungs...
June 4, 2018: Journal of Pharmacology and Experimental Therapeutics
S Lauren Kyte, David A Gewirtz
Studies in animal models have suggested that nicotine, an agonist of nicotinic acetylcholine receptors (nAChRs), may have the potential to prevent and/or reverse the peripheral neuropathy induced by cancer chemotherapeutic drugs, such as paclitaxel and oxaliplatin. However, a large body of evidence suggests that nicotine may also stimulate lung tumor growth and/or interfere with the effectiveness of cancer chemotherapy. While the reported proliferative effects of nicotine are highly variable, the antagonism of antitumor drug efficacy is more consistent, although this latter effect has been demonstrated primarily in cell culture studies...
June 4, 2018: Journal of Pharmacology and Experimental Therapeutics
David Machover, Emma L Goldschmidt, Rosella Mollicone, Farhad Haghighi-Rad, Christophe Desterke, Yann Gaston-Mathe, Raphael Saffroy, Claude Boucheix, Julien Dairou
The present study originates from the assumption that, in tumors, levels of naturally occurring pyridoxal 5'-phosphate (PLP) are too small to allow conversion of tetra hydro pteroylglutamate (H4PteGlu) into methylene tetra hydro pteroylglutamate (CH2-H4PteGlu) in amounts required to improve inhibition of thymidylate synthase by 5-fluorouracil (FUra) through ternary complex stabilization. The hypothesis relates to the low affinity for cofactor of the PLP-dependent serine hydroxymethyl transferase (SHMT), the enzyme that catalyses formation CH2-H4PteGlu by transfer of the Cβ of serine to H4PteGlu...
June 1, 2018: Journal of Pharmacology and Experimental Therapeutics
Ben C Askew, Takeru Furuya, D Scott Edwards
SF0166, a small molecule αvβ3 antagonist, has physiochemical properties that allow distribution to the posterior segment of the eye after topical administration in an ophthalmic solution. The pharmacodynamics and pharmacokinetics of SF0166 were evaluated in several cell lines, chick chorioallantoic membrane assays, and models of ocular neovascularization in mice and pigmented rabbits. SF0166 inhibited cellular adhesion to vitronectin across human, rat, rabbit, and dog cell lines with IC50 values of 7.6 pM to 76 nM...
May 31, 2018: Journal of Pharmacology and Experimental Therapeutics
Sarah Louise Withey, Michelle R Doyle, Jack Bergman, Rajeev I Desai
Evidence suggests that the α4β2, but not the α7, subtype of nicotinic acetylcholine receptor (nAChR) plays a key role in mediating the behavioral effects of nicotine and related drugs. However, the importance of other nAChR subtypes remains unclear. The present studies were conducted to examine the involvement of nAChR subtypes by determining the effects of selected nicotinic agonists and antagonists in squirrel monkeys: a) responding for food-reinforcement; or b) discriminating the nicotinic agonist (+)-epibatidine (0...
May 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Eliza G West, Ryan Lang, Donna Sellers, Russ Chess-Williams, Catherine M McDermott
Inflammation may play a causal role in urological side effects reported following intravesical mitomycin C (MMC). Our aim was to investigate the effects of the non-steroidal anti-inflammatory drug ibuprofen (IBU) on the cytotoxic potency of MMC and the potential for IBU to protect against bladder dysfunction. Malignant (RT4, T24) and normal (UROtsa) urothelial lines were treated with MMC followed by ibuprofen, with cell viability and caspase-3 activity assessed. Female C57BL/6JArc mice (Saline/Control, MMC, Saline + IBU and MMC + IBU), received intravesical treatment (1hr) with saline or MMC (2mg/mL), with IBU (1mg/mL) delivered in drinking water (for 7-days)...
May 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Ehsan N Mohammadi, Casey O Ligon, Ada Silos-Santiago, Pei Ge, Caroline Kurtz, Carolyn Higgins, Gerhard Hannig, Beverley Greenwood-Van Meerveld
INTRODUCTION: Bladder pain syndrome (BPS) is poorly understood, however there is evidence of a female predominance and co-morbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross sensitization. METHODS: In female rats, infusion of dilute protamine sulfate (PS) into the bladder was employed to induce bladder and colonic hypersensitivity...
May 21, 2018: Journal of Pharmacology and Experimental Therapeutics
Oliver Pohl, Andre Chollet, Sung Hye Kim, Lucia Riaposova, Francois Spezia, Frederic Gervais, Philippe Guillaume, Philippe Lluel, Murielle Meen, Frederique Lemaux, Vasso Terzidou, Phillip R Bennett, Jean-Pierre Gotteland
Preterm birth is the major challenge in obstetrics affecting ~10% of pregnancies. Pan-prostaglandin synthesis inhibitors (NSAID) prevent preterm labor and prolong pregnancy but raise concerns about fetal renal and cardiovascular safety. We conducted preclinical studies examining the tocolytic effect and fetal safety of the oral prodrug candidate OBE022 and its parent OBE002, both potent and highly selective antagonist of the contractile PGF2α prostaglandin receptor (FP). Efficacy of OBE022 and OBE002, alone and in combination with other tocolytics, was assessed in human tissues and pregnant animal models for inhibition of uterine contraction and delay of parturition...
May 18, 2018: Journal of Pharmacology and Experimental Therapeutics
Amreen Mughal, Chengwen Sun, Stephen T O'Rourke
Apelin increases coronary blood flow, cardiac contractility and cardiac output. Based on these favorable hemodynamic effects, apelin and apelin-like analogs are being developed for treating heart failure and related disorders; however, the molecular mechanisms underlying apelin-induced coronary vasodilation are unknown. This study aimed to elucidate the signaling pathways by which apelin causes smooth muscle relaxation in coronary arteries. Receptors for apelin (APJ receptors) were expressed in coronary arteries, as determined by Western blot and PCR analyses...
May 17, 2018: Journal of Pharmacology and Experimental Therapeutics
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