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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/28432078/effect-of-4-5-6-7-8-tetrahydro-5-5-8-8-tetramethyl-2-naphthalenyl-carbamoyl-benzoic-acid-am80-on-alveolar-regeneration-in-adiponectin-deficient-mice-showing-a-chronic-obstructive-pulmonary-disease-like-pathophysiology
#1
Hitomi Sakai, Michiko Horiguchi, Tomomi Akita, Chihiro Ozawa, Mai Hirokawa, Yuki Oiso, Harumi Kumagai, Yoshito Takeda, Isao Tachibana, Norikazu Maeda, Chikamasa Yamashita
Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease that causes widespread and irreversible alveolar collapse. Although COPD occurs worldwide, only symptomatic therapy is currently available. The objective of the present study was the development of therapeutic agents to eradicate COPD. Therefore, we focused on 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (Am80), which is a derivative of all-trans retinoic acid. We evaluated the effects of Am80 on alveolar repair in a novel COPD model of adiponectin-deficient mice...
April 21, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28428223/glutamatergic-mechanisms-involved-in-bladder-overactivity-and-pudendal-neuromodulation-in-cats
#2
Jamie Uy, Michelle Yu, Xuewen Jiang, Cameron Jones, Bing Shen, Jicheng Wang, James R Roppolo, William C de Groat, Changfeng Tai
The involvement of ionotropic glutamate receptors in bladder overactivity and pudendal neuromodulation was determined in α-chloralose anesthetized cats by intravenously administering MK801 (a NMDA receptor antagonist) or CP465022 (an AMPA receptor antagonist). Infusion of 0.5% acetic acid (AA) into the bladder produced bladder overactivity. In the first group of 5 cats, bladder capacity was significantly (p<0.05) reduced to 55.3±10.0% of saline control by AA irritation. Pudendal nerve stimulation (PNS) significantly (p<0...
April 20, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28416568/pharmacological-and-toxicological-properties-of-the-potent-oral-%C3%AE-secretase-modulator-bpn-15606
#3
Steven L Wagner, Kevin D Rynearson, Steven K Duddy, Can Zhang, Phuong D Nguyen, Ann Becker, Uyen Vo, Deborah Masliah, Louise Monte, Justin B Klee, Corinne M Echmalian, Weiming Xia, Luisa Quinti, Graham Johnson, Jiunn H Lin, Doo Y Kim, William C Mobley, Robert A Rissman, Rudolph E Tanzi
Alzheimer's disease is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42 amino acid amyloid β peptide, as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance are postulated to initiate and drive the AD pathological process. We initially introduced a novel class of bridged aromatics referred to as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides...
April 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28411257/relief-of-pain-depressed-behavior-in-rats-by-activation-of-d1-like-dopamine-receptors
#4
Matthew F Lazenka, Kelen C Freitas, Sydney Henck, S Stevens Negus
Clinically significant pain often includes depression of both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study compared effects of indirect and direct dopamine agonists in a preclinical assay of pain-depressed operant responding. Male Sprague-Dawley rats with chronic indwelling microelectrodes in the medial forebrain bundle were trained in an intracranial self-stimulation (ICSS) procedure to press a lever for pulses of electrical brain stimulation...
April 14, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28404691/exemestane-and-its-active-metabolite-17-hydroexemestane-induce-udp-glucuronosyltransferase-ugt-2b17-expression-in-breast-cancer-cells
#5
Apichaya Chanawong, Peter Ian Mackenzie, Ross A McKinnon, Dong Gui Hu, Robyn Meech
Exemestane (EXE) is an aromatase inhibitor indicated for endocrine therapy of breast cancer in post-menopausal women. The primary active metabolite of EXE, 17-hydroexemestane (17-HE), is inactivated via glucuronidation, mainly by UGT2B17. UGT2B17 also has a primary role in inactivation of endogenous androgens testosterone and dihydrotestosterone (DHT) and may play an important role in regulation of breast and prostate tumour intracrinology. We recently reported that UGT2B17 could be induced by both estrogenic and androgenic ligands in breast cancer cells via binding of the estrogen receptor alpha (ERα) or the androgen receptor (AR) to a complex regulatory unit in the proximal UGT2B17 promoter...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28404690/pharmacologic-characterization-of-valbenazine-nbi-98854-and-its-metabolites
#6
Dimitri E Grigoriadis, Evan Smith, Sam R J Hoare, Ajay Madan, Haig Bozigian
The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is being developed for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)-α-dihydrotetrabenazine (R,R,R-DHTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand binding studies were conducted to assess and compare valbenazine, tetrabenazine and their respective metabolites in their abilities to selectively and potently inhibit [(3)H]-DHTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28404689/methoxyluteolin-inhibits-neuropeptide-stimulated-tnf-cxcl8-and-vegf-release-via-mtor-activation-from-human-mast-cells
#7
Arti B Patel, Theoharis C Theoharides
Mast cells (MC) are critical for allergic reactions, but are also important in inflammatory processes. Stimulation by neuropeptides, such as substance P (SP) and neurotensin (NT) leads to release of pre-formed molecules stored in numerous MC secretory granules and newly-synthesized pro-inflammatory mediators, including tumor necrosis factor (TNF), interleukin 8 (CXCL8) and vascular endothelial growth factor (VEGF). Here, we investigate the role of mammalian target of rapamycin (mTOR) signaling in the stimulation of cultured human LAD2 MC by NT or SP, and the inhibitory effect of the natural flavonoids 3',4',5,7-tetrahydroxyflavone (luteolin) and its novel structural analog 3 ',4',5,7-tetramethoxyluteolin (methoxyluteolin)...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28404688/brain-disposition-of-cis-para-methyl-4-methylaminorex-cis-4-4-dmar-and-its-potential-metabolites-after-acute-and-chronic-treatment-in-rats-correlation-with-central-behavioral-effects
#8
Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Angelo Di Clemente, Federico Moro, Renzo Bagnati, Marco Gobbi, Luigi Cervo
Para-methyl-4-methylaminorex (4,4'-DMAR) is a phenethylamine derivative with psychostimulant activity, whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated an HPLC-MS/MS method to measure the compound's concentrations in plasma, and applied it to describe the pharmacokinetic properties after single dose in rats. In this study we investigated the brain disposition and metabolism of cis-4,4'-DMAR after intraperitoneal injection, and its central behavioral effects...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28404687/selective-calcium-dependent-inhibition-of-atp-gated-p2x3-receptors-by-bisphosphonates-induced-endogenous-atp-analogue-apppi
#9
Yevheniia Ishchenko, Anastasia Shakirzyanova, Raisa Giniatullina, Andrei Skorinkin, Geneviev Bart, Petri Turhanen, Jorma Maatta, Jukka Monkkonen, Rashid Giniatullin
Pain is the most unbearable symptom accompanying primary bone cancers and bone metastases. Bone resorptive disorders are often associated with hypercalcemia contributing to the pathological process. Nitrogen-containing bisphosphonates (NBP) are efficiently used to treat bone-cancers and metastases. NBP, apart from their toxic effect on cancer cells, also provide analgesia via poorly understood mechanisms. We have previously shown, that NBP, by inhibiting the mevalonate pathway, induced the formation of the novel ATP-analogues such as ApppI which can potentially be involved in NBP analgesia...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28404686/propofol-anesthesia-is-reduced-in-phospholipase-c-related-inactive-protein-type-1-knockout-mice
#10
Yoshikazu Nikaido, Tomonori Furukawa, Shuji Shimoyama, Junko Yamada, Keisuke Migita, Kohei Koga, Tetsuya Kushikata, Kazuyoshi Hirota, Takashi Kanematsu, Masato Hirata, Shinya Ueno
The GABA type A receptor (GABAA-R) is a major target of intravenous anesthetics. Phospholipase C-related inactive protein type-1 (PRIP-1) is important in GABAA-R phosphorylation and membrane trafficking. In this study, we investigated the role of PRIP-1 in general anesthetic action. The anesthetic effects of propofol, etomidate, and pentobarbital were evaluated in wild-type and PRIP-1 knockout (PRIP-1 KO) mice by measuring the latency and duration of loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR)...
April 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28389526/regulation-of-ugt2b4-and-ugt2b7-by-mirnas-in-liver-cancer-cells
#11
Dhilushi Wijayakumara, Peter Ian Mackenzie, Ross A McKinnon, Dong Gui Hu, Robyn Meech
The transcriptional regulation of UGT2B4 and UGT2B7 has been well studied using liver cancer cell lines and recently post-transcriptional regulation of these two UGTs by miR-216b-5p was reported. The present study describes novel miRNA-mediated regulation of UGT2B4 and UGT2B7 in liver cancer cells. Bioinformatic analyses identified a putative miR-3664-3p binding site in the UGT2B7 3'-UTR, and binding sites for both miR-135a-5p and miR-410-3p in the UGT2B4 3'-UTR. These sites were functionally characterized using miRNA mimics and reporter constructs...
April 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28385952/dieldrin-augments-mtor-signaling-and-inhibits-lysosomal-acidification-in-the-adult-zebrafish-heart-danio-rerio
#12
Logan Slade, Andrew Cowie, Chris J Martynuik, Petra C Kienesberger, Thomas Pulinilkunnil
Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiological studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been adequately addressed to date given that these chemicals are detectable in human serum and are environmentally persistent, thus individuals may show latent adverse effects in the cardiovasculature system due to chronic, low dose exposure over time...
April 6, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28360334/a-genomic-dna-reporter-screen-identifies-squalene-synthase-inhibitors-which-act-cooperatively-with-statins-to-upregulate-the-low-density-lipoprotein-receptor
#13
Alastair G Kerr, Lawrence C S Tam, Ashley B Hale, Milena Cioroch, Gillian Douglas, Sarina Agkatsev, Olivia Hibbit, Joseph Mason, James Holt-Martyn, Carole J R Bataille, Graham M Wynne, Keith M Channon, Angela J Russell, Richard Wade-Martins
Hypercholesterolaemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering LDL-cholesterol using a statin can reduce the risk of having a cardiovascular event by ~30%. However, despite the success of statins, some patient populations are unable to lower their LDL-cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for heterozygous familial hypercholesterolaemia (heFH) patients who may require additional upregulation of the Low-Density Lipoprotein Receptor (LDLR) to reduce LDL-cholesterol levels below those achievable with maximal dosing of statins...
March 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28360333/detailed-characterization-of-the-in-vitro-pharmacological-and-pharmacokinetic-properties-of-n-2-hydroxybenzyl-2-5-dimethoxy-4-cyanophenylethylamine-25cn-nboh-a-highly-selective-and-brain-penetrant-5-ht2a-receptor-agonist
#14
Anders A Jensen, John D McCorvy, Sebastian Leth Petersen, Christoffer Bundgaard, Gudrun Liebscher, Terry P Kenakin, Hans Brauner-Osborne, Jan Kehler, Jesper L Kristensen
Therapeutic interest in augmentation of 5-hydroxytryptamine2A (5-HT2A) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT2 receptor agonist 2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT2A, 5- HT2B and 5-HT2C receptors and investigated the pharmacokinetic properties of the compound...
March 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28356494/soluble-epoxide-hydrolase-pharmacological-inhibition-decreases-alveolar-bone-loss-by-modulating-host-inflammatory-response-rank-related-signaling-er-stress-and-apoptosis
#15
Carlos A Trindade da Silva, Ahmed Bettaieb, Marcelo H Napimoga, Kin Sing Stephen Lee, Bora Inceoglu, Carlos Ueira-Vieira, Donald Bruun, Sumanta K Goswami, Fawaz G Haj, Bruce D Hammock
Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) enzymes, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) in a mouse model of periodontitis induced by infection with A...
March 29, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28351853/pharmaceutical-characterization-of-tropomyosin-receptor-kinase-b-agonistic-antibodies-on-human-ips-cell-derived-neurons
#16
Stefanie Traub, Heiko Stahl, Holger Rosenbrock, Eric Simon, Lore Florin, Lisa Hospach, Stefan Hoerer, Ralf Heilker
Brain-derived neurotrophic factor (BDNF) is a central modulator of neuronal development and synaptic plasticity in the central nervous system (CNS). This renders the BDNF-modulated tropomyosin receptor kinase B (TrkB) a promising drug target to treat synaptic dysfunctions. Using GRowth factor-driven expansion and INhibition of NotCH during maturation, the so-called GRINCH neurons were derived from human induced pluripotent stem (hiPS) cells. These GRINCH neurons were employed as model cells for pharmacological profiling of two TrkB-agonistic antibodies, hereafter referred to as AB2 and AB20...
March 28, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28348059/the-glycolytic-enzyme-pfkfb3-is-involved-in-estrogen-mediated-angiogenesis-via-gper1
#17
Annalisa Trenti, Serena Tedesco, Carlotta Boscaro, Nicola Ferri, Andrea Cignarella, Lucia Trevisi, Chiara Bolego
The endogenous estrogen 17β-estradiol (E2) is a key factor in promoting endothelial healing and angiogenesis. Recently, proangiogenic signals including vascular endothelial growth factor and others have been shown to converge onto endothelial cell metabolism. Because inhibition of the glycolytic enzyme activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) reduces pathological angiogenesis and estrogen receptor (ER) signaling stimulates glucose uptake and glycolysis by inducing PFKFB3 in breast cancer, we hypothesized that E2 triggers angiogenesis in endothelial cells via rapid ER signaling that requires PFKFB3 as a downstream effector...
March 27, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28348058/edema-and-nociception-induced-by-philodryas-patagoniensis-venom-in-mice-a-pharmacological-evaluation-with-implications-for-the-accident-treatment
#18
Priscila H Lopes, Marisa M T Rocha, Alexandre K Kuniyoshi, Fernanda V Portaro, Luis R C Goncalves
We have investigated the mechanisms involved in the genesis of edema and nociception induced by the Philodryas patagoniensis venom (PpV) injected into mice footpad. The PpV induced dose-related edema and nociceptive effects. Pre-treatment of mice with cyclooxygenase inhibitor (indomethacin), but not with cyclooxygenase 2 inhibitor (celecoxib) markedly inhibited both effects. Pre-treatments with H1 receptor antagonist (promethazine) or with dual histamine-serotonin inhibitor (cyproheptadine) failed in inhibiting both effects...
March 27, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28336575/pharmacologic-profile-of-naloxegol-a-peripherally-acting-%C3%A2%C2%B5-opioid-receptor-antagonist-for-the-treatment-of-opioid-induced-constipation
#19
Eike Floettmann, Khanh Bui, Mark Sostek, Kemal Payza, Michael Eldon
Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol...
March 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28302862/arresting-the-development-of-addiction-the-role-of-%C3%AE-arrestin2-in-drug-abuse
#20
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
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