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Journal of Pharmacology and Experimental Therapeutics

Marta Quadri, Deniz Bagdas, Wisam Toma, Clare Stokes, Nicole A Horenstein, M Imad Damaj, Roger L Papke
Chronic pain and inflammatory diseases are regulated by complex mechanisms that involve the α7 nicotinic acetylcholine receptor (nAChR), making this subtype a promising drug target for anti-inflammatory therapies. Recent evidence suggests that the potential way to address treatment of pain and inflammation in non-neuronal cells may rely on metabotropic-like rather than ionotropic activation of the α7 receptor subtype. Among the compounds that are able to selectively promote α7 metabotropic function are some that can be classified as silent agonists...
August 15, 2018: Journal of Pharmacology and Experimental Therapeutics
Sarah R Mikelman, Bipasha Guptaroy, Kyle C Schmitt, Kymry T Jones, Juan Zhen, Maarten E A Reith, Margaret E Gnegy
The selective estrogen receptor modulator tamoxifen increases extracellular dopamine in vivo and act as a neuroprotectant in models of dopamine neurotoxicity. We investigated the effect of tamoxifen on dopamine transporter (DAT)-mediated dopamine uptake, dopamine efflux, and [3 H]WIN 35,428 binding in rat striatal tissue. Tamoxifen dose dependently blocks dopamine uptake (54% reduction at 10 μM) and amphetamine-stimulated efflux (59% reduction at 10 μM) in synaptosomes. It also produces a small but significant reduction in [3 H] WIN35,428 binding in striatal membranes, indicating a weak interaction with the substrate binding site in the DAT...
August 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Fabio Henrique Silva, Kleber Yotsumoto Fertrin, Eduardo Costa Alexandre, Fabiano Beraldi Calmasini, Carla Fernanda Franco-Penteado, Fernando Ferreira Costa
Paroxysmal nocturnal hemoglobinuria (PNH) patients display exaggerated intravascular hemolysis and esophageal disorders. Since excess hemoglobin in the plasma causes reduced nitric oxide (NO) bioavailability and oxidative stress, we hypothesized that esopagheal contraction may be impaired by intravascular hemolysis. This study aimed to analyze the alterations of the esophagus contractile mechanisms in a murine model of exaggerated intravascular hemolysis induced by phenylhydrazine (PHZ). For comparative purposes, sickle cell disease (SCD) mice were also studied, a less severe intravascular hemolysis model...
August 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Jean M Bidlack, Brian I Knapp, Daniel R Deaver, Margarita Plotnikava, Derrick Arnelle, Angela M Wonsey, May Fenn Toh, Sokhom S Pin, Mark N Namchuk
A combination of buprenorphine (BUP) and samidorphan (SAM) at a 1:1 fixed dose ratio (mg/mg), is being investigated as an adjunctive treatment for major depressive disorder (BUP/SAM, ALKS 5461). Both [3 H]BUP and [3 H]SAM bound to the mu, kappa and delta opioid receptors (MOR, KOR and DOR, respectively) with Kd values of 3 nM or less. [3 H]BUP dissociated slower from the MOR than [3 H]SAM did. In the [35 S]GTPγS assay, BUP was a partial agonist at the MOR, KOR and DOR. SAM was an antagonist at the MOR and a partial agonist at the KOR and DOR...
August 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Gabriela M Bertollotto, Mariana G de Oliveira, Eduardo C Alexandre, Fabiano B Calmasini, Gabriela R Passos, Edson Antunes, Fabiola Z Monica
The biological effect of cyclic adenosine- and guanosine- monophosphate (cAMP and cGMP) is terminated by phosphodiesterases and multidrug resistance proteins type 4 and 5, which pump cyclic nucleotides out of the cell. Therefore, this study is aimed to characterize by means of functional assay, protein expression and cyclic nucleotides quantification the role of MRPs inhibitor, MK 571 in bladder, prostate and urethra from male mice. The cumulative addition of MK 571 (1-30 µM) produced only small relaxations (~25%) in all studied tissues...
August 14, 2018: Journal of Pharmacology and Experimental Therapeutics
Abubakr H Mossa, Monica Velasquez Flores, Hieu Nguyen, Philippe Cammisotto, Lysanne Campeau
Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs, and controls an array of molecular responses in the urothelium through activation of its receptor GPR91. Mirabegron, a β3-adrenergic receptor (β3-AR) agonist used to treat overactive bladder syndrome, increases intracellular cyclic AMP (cAMP) in the detrusor smooth muscle cells (SMCs), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium...
August 13, 2018: Journal of Pharmacology and Experimental Therapeutics
John M Haynes, James N Selby, Isaiah Pl Abad, Teresa Vandekolk, Joan K Ho, Wai-Ling Lieuw, Katie Leach, Judith Savige, Sheetal Saini, Craig Fisher, Sharon Ricardo
Renal podocyte survival depends upon the dynamic regulation of a complex cell architecture that links glomerular basement membrane to integrins, ion channels and receptors. Alport syndrome is a heritable chronic kidney disease where mutations in α3, α4 or α5 collagen genes promote podocyte death. In rodent models of renal failure, activation of the calcium sensing receptor (CaSR) can protect podocytes from stress related death. In this study we assess CaSR function in podocyte-like cells from induced-pluripotent stem cells derived from two patients with Alport Syndrome (AS1 & AS2), a renal disease free individual (NHMC) and an immortalized podocyte-like (HIP) cell line...
August 13, 2018: Journal of Pharmacology and Experimental Therapeutics
Brigitte Grouix, Francois Sarra-Bournet, Martin Leduc, Jean-Christophe Simard, Kathy Hince, Lilianne Geerts, Alexandra Blais, Liette Gervais, Alexandre Laverdure, Alexandra Felton, Jonathan Richard, Jugurtha Ouboudinar, William Gagnon, Francois Leblond, Pierre Laurin, Lyne Gagnon
Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We have previously shown that PBI-4050 is a dual GPR40 agonist/GPR84 antagonist exerting anti-fibrotic, anti-inflammatory and anti-proliferative actions. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The anti-fibrotic effect of PBI-4050 was evaluated in carbon tetrachloride and in bile duct ligation-induced liver fibrosis rodent models...
August 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Wanghui Jing, Ane Nunes, Ted Farzaneh, Mahyar Khazaeli, Wei Ling Lau, Nosratola D Vaziri
Chronic kidney disease (CKD) causes anemia and impairs intestinal iron absorption. However, use of the phosphate binder, ferric citrate (FC), increases body iron stores and hemoglobin levels in CKD patients. By intensifying oxidative stress and inflammation iron overload can accelerate CKD progression. Present study explored the route of absorption and tissue distribution of iron with FC administration and its effect on renal function, histology and inflammatory, oxidative and fibrosis pathways in CKD rats...
August 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Elizabeth Brigham, Tom Johnston, Carl Brown, Jonathon Holt, Susan Fox, Michael Hill, Patrick Howson, Jonathan Brotchie, Jack Nguyen
Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and non-human primates have demonstrated that the NMDA antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic-pharmacodynamic (PK/PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing...
August 7, 2018: Journal of Pharmacology and Experimental Therapeutics
Vivaswath S Ayyar, Siddharth Sukumaran, Debra C DuBois, Richard R Almon, William J Jusko
Corticosteroids (CS) regulate the expression of numerous genes at the mRNA and protein levels. The time-course of CS pharmacogenomics and proteomics were examined in livers obtained from adrenalectomized rats given a 50 mg/kg bolus dose of methylprednisolone. Microarrays and mass-spectrometry based proteomics were employed to quantify hepatic transcript and protein dynamics. A total of 163 differentially expressed mRNA and their corresponding proteins (163 genes) were clustered into two dominant groups. The temporal profiles of most proteins were delayed compared to its mRNA, attributable to synthesis delays and slower degradation kinetics...
August 7, 2018: Journal of Pharmacology and Experimental Therapeutics
Erifili Hatziagelaki, Maria Adamaki, Irene Tsilioni, George Dimitriadis, Theoharis C Theoharides
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms. A significant percentage of ME/CFS patients remains undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient...
August 3, 2018: Journal of Pharmacology and Experimental Therapeutics
Sheik Pran Babu Sardar Pasha, Kamakshi Sishtla, Rania S Sulaiman, Bomina Park, Trupti Shetty, Fenil Shah, Melissa L Fishel, James H Wikel, Mark R Kelley, Timothy W Corson
Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-κB and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1's function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity...
August 3, 2018: Journal of Pharmacology and Experimental Therapeutics
Martin L Marro, Andrew W Patterson, Lac Lee, Lin Deng, Aimee Reynolds, Xianglin Ren, Laura Axford, Anup Patnaik, Micah Hollis-Symynkywicz, Nigel Casson, Dominique Custeau, Lisa Ames, Sally Loi, Lihe Zhang, Toshiyuki Honda, Jutta Blank, Tyler Harrison, Julien P N Papillon, Lawrence Hamann, Jovita Marcinkeviciene, Jean B Regard
Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based, inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis...
August 3, 2018: Journal of Pharmacology and Experimental Therapeutics
Daniel P Heruth, Katherine Shortt, Nini Zhang, Ding-You Li, Li Q Zhang, Shui Q Ye
Acetaminophen is commonly used to reduce pain and fever. Unfortunately, overdose of acetaminophen is a leading cause of acute liver injury and failure in many developed countries. The majority of acetaminophen is safely metabolized in the liver and excreted in the urine; however a small percentage is converted to the highly reactive N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is inactivated by glutathione S-transferases, but at toxic levels, excess NAPQI forms reactive protein adducts that lead to hepatotoxicity...
August 3, 2018: Journal of Pharmacology and Experimental Therapeutics
Andrea Guidarelli, Mara Fiorani, Orazio Cantoni
Arsenite is an established human carcinogen inducing cyto- and genotoxic effects through poorly defined mechanisms involving the formation of reactive oxygen species (ROS) and deregulated Ca2+ homeostasis. We used variants of the U937 cell line to address the central issue of the mechanism whereby arsenite affects Ca2+ homeostasis. We found that a 6 h exposure to the metalloid (2.5 μM), while not associated to an immediate or delayed toxicity, causes a significant increase in the intracellular Ca2+ concentration ([Ca2+ ]i ) through a mechanism characterized by the following components: i) it was not affected by ROS produced under the same conditions; ii) a small amount of Ca2+ was mobilized from the inositol-1,4,5-trisphosphate receptor (IP3 R)...
August 1, 2018: Journal of Pharmacology and Experimental Therapeutics
Jack H Taylor, Nancy A Schulte, Jeffrey A French, Myron L Toews
A clade of New World monkeys (NWM) exhibits considerable diversity in both oxytocin ligand (OT) and receptor (OTR) structure. Most notable is the variant Pro8-OT, with proline instead of leucine at the eighth position (Pro8-OT), resulting in a rigid bend in the peptide backbone. A higher proportion of species that express Pro8-OT also engage in biparental care and social monogamy. When marmosets (genus Callithrix), a biparental and monogamous Pro8-OT NWM species, are administered the ancestral Leu8-OT, there is no change in social behavior compared to saline treatment...
August 1, 2018: Journal of Pharmacology and Experimental Therapeutics
Steven E Trasino, Xiao-Han Tang, Maria M Shevchuk, Mary E Choi, Lorraine J Gudas
Vitamin A (VA) and its derivatives, known as retinoids, play critical roles in renal development through retinoic acid receptor β2 (RARβ2). Disruptions in VA signaling pathways are associated with the onset of diabetic nephropathy (DN). Despite the known role of RARβ2 in renal development, the effects of selective agonists for RARβ2 in a high fat diet (HFD) model of DN are unknown. Here we examined whether AC261066 (AC261), a highly selective agonist for RARβ2, exhibited therapeutic effects in a HFD model of DN in C57BL/6 mice...
July 27, 2018: Journal of Pharmacology and Experimental Therapeutics
Carrie Bowman Dalley, Barbara Wroblewska, Barry B Wolfe, Jarda T Wroblewski
Glioma refers to malignant central nervous system tumors that have histological characteristics in common with glial cells. The most prevalent type, glioblastoma multiforme, is associated with a poor prognosis and few treatment options. Based on reports of aberrant expression of mGluR1 mRNA in glioma, evidence that melanoma growth is directly influenced by mGluR1, and characterization of β-arrestin dependent pro-survival signaling by this receptor, this study investigates the hypothesis that glioma cell lines aberrantly express mGluR1 and depend on mGluR1 mediated signaling to maintain viability and proliferation...
July 27, 2018: Journal of Pharmacology and Experimental Therapeutics
Herana Kamal Seneviratne, Craig W Hendrix, Edward J Fuchs, Namandje N Bumpus
Efforts to prevent HIV infection via pre-exposure prophylaxis (PrEP) include the development of anti-HIV drugs as microbicides for topical application to the mucosal sites of infection; however, while understanding the distribution profiles of these drugs in target mucosal tissues is of critical importance to guiding their optimization, data in this regard are largely lacking. With this in mind, we developed a Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI MSI) approach to visualize tenofovir (TFV), an HIV nucleotide analog reverse-transcriptase inhibitor under investigation for use as a topical microbicide, and its active metabolite TFV-diphosphate (TFV-DP) in colorectal biopsies obtained from healthy volunteers who received TFV-containing enemas...
July 23, 2018: Journal of Pharmacology and Experimental Therapeutics
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