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Journal of Pharmacology and Experimental Therapeutics

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https://read.qxmd.com/read/30765424/acetylcholine-inhibits-platelet-activation
#1
John A Bennett, Sara K Ture, Rachel A Schmidt, Michael A Mastrangelo, Scott J Cameron, Lara E Terry, David I Yule, Craig N Morrell, Charles J Lowenstein
Platelets are key mediators of thrombosis. Many agonists of platelet activation are known, but there are fewer identified endogenous inhibitors of platelets, such as prostacyclin and nitric oxide (NO). Acetylcholinesterase inhibitors such as donepezil can cause bleeding in patients, but the underlying mechanisms are not well understood. We hypothesized that acetylcholine is an endogenous inhibitor of platelets. We measured the effect of acetylcholine or analogues of acetylcholine upon human platelet activation ex vivo...
February 14, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30760494/targeting-thioredoxin-reductase-by-ibrutinib-promotes-apoptosis-of-smmc-7721-cells
#2
Xiao Han, Junmin Zhang, Danfeng Shi, Yueting Wu, Ruijuan Liu, Tianyu Liu, Jianqiang Xu, Xiaojun Yao, Jianguo Fang
Ibrutinib (IBT), the first-in-class inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated clinical activity against various B-cell malignancies. IBT is the second agent approved by U.S. Food and Drug Administration via Breakthrough Therapy Designation. Aside from its therapeutic mechanism through BTK inhibition, IBT has other target sites reported for cancer therapy, leading us to investigate whether IBT has unreported targets. Our study revealed that IBT can inhibit the growth of SMMC-7721 cells through irreversible inhibition of mammalian thioredoxin reductase (TrxR) enzymes, which are components of the thioredoxin (Trx) system...
February 13, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30745416/rla8-a-new-and-highly-effective-quadruple-ppars-%C3%AE-%C3%AE-%C3%AE-and-gpr40-agonist-to-reverse-nonalcoholic-steatohepatitis-and-fibrosis
#3
Menghua Li, Wei Chen, Lili Wang, Jialin Sun, Lei Zhou, Yucong Shi, Chuhan Wang, Bohua Zhong, Weiguo Shi, Zhongwu Guo
Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, thereby a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-α/γ/δ and G-protein-coupled receptor 40 (GPR40), as a NASH drug candidate...
February 11, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30745415/targeting-dopamine-d2-adenosine-a2a-and-glutamate-mglu5-receptors-to-reduce-repetitive-behaviors-in-deer-mice
#4
Mark H Lewis, Christopher Primiani, Amber M Muehlmann
Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurological disorders. Our work has identified that hypofunctioning of the indirect basal ganglia pathway is associated with the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D2, adenosine A2A, and glutamate mGlu5 receptors...
February 11, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30737357/nanotechnology-and-immunotherapy-in-ovarian-cancer-tracing-new-landscapes
#5
Bruna Corradetti, Simone Pisano, Robert Steven Conlan, Mauro Ferrari
Ovarian cancer (OC) is the seventh most common cancer in women worldwide. Standard therapeutic treatments involve debulking surgery combined with platinum-based chemotherapies. Of the patients with advanced stage cancer that initially respond to current treatments 50%-75% relapse. Immunotherapy-based approaches aimed at boosting anti-tumor immunity have recently emerged as promising tools to challenge tumor progression. Treatments with inhibitors of immune checkpoint molecules have shown impressive results in other types of tumors...
February 8, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30733244/mechanism-based-pharmacokinetic-pharmacodynamic-model-describing-dextroamphetamine-exposure-and-striatal-dopamine-response-in-rats-and-non-human-primates-following-a-single-intravenous-dose-of-dextroamphetamine
#6
Marcel van Gaalen, Christina Schlumbohm, Joost Folgering, Saugat Adhikari, Chandrali Bhattacharya, Douglas Steinbach, Robert E Stratford
Acute CNS exposure to dextroamphetamine (D-amphetamine) elicits a multitude of effects, including dual action on the dopamine transporter (DAT) to increase extracellular dopamine, and induction of a negative feedback response to limit the dopamine increase. A semi-mechanistic pharmacokinetic and pharmacodynamic (PK/PD) model based on consideration of these multiple effects was developed. Integrated pharmacokinetics of D-amphetamine in plasma, brain extracellular fluid (ECF) via microdialysis, and cerebrospinal fluid (CSF) were characterized using a population approach...
February 7, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30728250/contractile-effects-of-serotonin-in-the-rat-cauda-epididymis-expression-and-functional-characterization-of-5-ht-receptors
#7
Andre Mueller, Luiz R A Kiguti, Erick J R Silva, Andre S Pupo
Serotonin (5-HT) exerts multiple central and peripheral functions. High concentrations of 5-HT have been found in the epididymis, a ductal organ that plays pivotal roles in sperm transport and maturation. The contraction of the epididymal smooth muscle is essential for sperm transport and emission during ejaculation. The contributions of the epididymal 5-HT system to these events are poorly understood. Here, we assessed the contractile function of 5-HT in the rat cauda epididymis (CE), pharmacologically targeting the receptor(s) and the reuptake mechanism involved in this system...
February 6, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30728249/initial-characterization-of-transgenic-mice-overexpressing-human-histamine-h2-receptors
#8
Ulrich Gergs, Guenther Bernhardt, Igor Buchwalow, Hanna Edler, Janine Froeba, Max Keller, Uwe Kirchhefer, Friderike Koehler, Natascha Misslinger, Hartmut Wache, Joachim Neumann
In an integrative approach, we studied the role of H2 receptors in the mouse heart. We noted that histamine, added cumulatively to the organ bath, failed to affect the force of contraction in left atrial preparations and did not change spontaneous heart rate in right atrial preparations from wild type mice. By contrast, in the same preparations from mice that overexpressed the human H2 receptor in a cardiac specific way, histamine exerted concentration and time dependent positive inotropic and positive chronotropic effects...
February 6, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30728248/long-term-engraftment-of-human-cardiomyocytes-combined-with-biodegradable-microparticles-induces-heart-repair
#9
Laura Saludas, Elisa Garbayo, Manuel Mazo, Beatriz Pelacho, Gloria Abizanda, Olalla Iglesias Garcia, Angel Raya, Felipe Prosper, Maria J Blanco-Prieto
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are a promising cell source for cardiac repair after myocardial infarction (MI) as they offer several advantages, such as potential to remuscularize infarcted tissue, integration in the host myocardium and paracrine therapeutic effects. However, cell delivery issues have limited their potential application in clinical practice, showing poor survival and engraftment after transplantation. In this work, we hypothesized that the combination of hiPSC-CMs with microparticles (MPs) could enhance the long-term cell survival and retention in the heart and consequently improve cardiac repair...
February 6, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30709867/a-novel-angiotensin-1-7-glycosylated-mas-receptor-agonist-for-treating-vascular-cognitive-impairment-and-inflammation-related-memory-dysfunction
#10
Meredith Hay, Robin Polt, Michael L Heien, Todd W Vanderah, Tally M Largen-Milnes, Kathleen E Rodgers, Torsten Falk, Mitchell J Bartlett, Kristian Doyle, John Konhilas
A growing body of evidence indicates that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate the progression of neurodegenerative diseases such as vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias (ADRD). There is an urgent clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension and diabetes...
February 1, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30709866/proximal-tubule-%C3%AE-2-adrenergic-receptor-mediates-formoterol-induced-recovery-of-mitochondrial-and-renal-function-after-ischemia-reperfusion-injury
#11
Robert B Cameron, Whitney S Gibbs, Siennah R Miller, Tess V Dupre, Judit K Megyesi, Craig Cano Beeson, Rick G Schnellmann
Acute kidney injury (AKI) is the rapid loss of renal function following an insult and renal proximal tubule cells (RPTC) are central to the pathogenesis of AKI. The β2 adrenergic receptor (β2AR) agonist formoterol accelerates recovery of renal function in mice following ischemia-reperfusion injury (IRI) with associated rescue of mitochondrial proteins. However, the cell type responsible for this recovery remains unknown. The role of RPTC in formoterol-induced recovery of renal function was assessed in a proximal tubule-specific knockout of the β2AR (γGT-Cre:ADRB2Flox/Flox)...
February 1, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30692148/facilitation-of-chemotaxis-activity-of-mesenchymal-stem-cells-via-stromal-cell-derived-factor-1-and-its-receptor-may-promote-ectopic-ossification-of-human-spinal-ligaments
#12
Shunfu Chin, Ken-Ichi Furukawa, Keigo Kurotaki, Shunpei Nagasaki, Kanichiro Wada, Gentaro Kumagai, Shigeru Motomura, Yasuyuki Ishibashi
Mesenchymal stem cells (MSCs) have been utilized to elucidate the pathogenesis of numerous diseases. Our recent study showed that MSCs may conduce to the ossification of spinal ligaments. Stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) regulate MSC migration. Moreover, their expression is elevated in sites of damage and remodeling in pathological states. We explored the possible role of the SDF-1/CXCR4 axis in chemotactic behavior of MSCs in ossification of spinal ligaments. Specimens of thoracic vertebra ossified ligamentum flavum (OLF) and non-OLF plaques were received from patients whom we had performed spine surgery...
January 28, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30683666/polymeric-nanogel-based-treatment-regimen-for-enhanced-efficacy-and-sequential-administration-of-synergistic-drug-combination-in-pancreatic-cancer
#13
Kruti S Soni, Divya Thomas, Thomas Caffrey, Kamiya Mehla, Fan Lei, Kelly A O'Connell, Satish Sagar, Subodh M Lele, Michael A Hollingsworth, Prakash Radhakrishnan, Tatiana K Bronich
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of Cisplatin (CDDP) and Gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and non-targeted delivery. More than 80% of the PDAC aberrantly expresses Sialyl Tn (STn) antigen due to the loss of function of COSMC, a specific chaperone for the activity of core 1 β3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen specific antibody (TKH2 mAb) for the targeted treatment of PDAC...
January 25, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30674560/pharmacokinetic-pharmacodynamic-modeling-of-brain-dopamine-levels-based-on-dopamine-transporter-occupancy-after-administration-of-methylphenidate-in-rats
#14
Ryosuke Shimizu, Naotaka Horiguchi, Koji Yano, Masashi Sakuramoto, Naoki Kanegawa, Shunji Shinohara, Shuichi Ohnishi
Dopamine exerts various effects including movement coordination and reward. It is useful to understand the quantitative relationship between drug pharmacokinetics and target engagement such as the change of occupancy and dopamine level in brain for the proper treatment of dopamine-related diseases. This study was aimed at developing a pharmacokinetic-pharmacodynamic (PK-PD) model based on dopamine transporter (DAT) occupancies that could describe changes in extracellular dopamine levels in brain after administration of methylphenidate (DAT inhibitor) to rats...
January 23, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30670480/impact-of-cea-targeting-nanoparticles-for-drug-delivery-in-colorectal-cancer
#15
Ana Rita Sousa, Maria Jose Oliveira, Bruno Sarmento
Colorectal cancer (CRC) is one of the most common cause of cancer-related death in the world, mainly due to distant metastasis events. Developing targeted strategies to treat and follow individuals in more developed stages is needed. The carcinoembryonic antigen (CEA) is a cell surface-overexpressed glycoprotein in most CRC patients and the evaluation of its serum levels is recommended in the clinics. These reasons motivated the production of CEA-targeted nanotechnologies for monitorization of CRC progression, but only a few reports its usage for drug delivery...
January 22, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30670479/squalene-adenosine-nanoparticles-ligands-of-adenosine-receptors-or-adenosine-prodrug
#16
Marie Rouquette, Sinda Lepetre-Mouelhi, Ophelie Dufrancais, Xue Yang, Julie Mougin, Gregory Pieters, Sebastien Garcia-Argote, Adriaan P IJzerman, Patrick Couvreur
Adenosine receptors (ARs) represent key drug targets in many human pathologies, including cardiovascular, neurological and inflammatory diseases. To overcome the very rapid metabolization of adenosine, metabolically stable ARs agonists and antagonists were developed. However, few of these molecules have reached the market due to efficacy and safety issues. Conjugation of adenosine to squalene to form squalene-adenosine nanoparticles (SQAd NPs) dramatically improved the pharmacological efficacy of adenosine, especially for neuroprotection in stroke and spinal cord injury...
January 22, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30655298/differential-free-intracellular-calcium-release-by-class-ii-antiarrhythmics-in-cancer-cell-lines
#17
Marta Reyes-Corral, Naja M Sorensen, Christopher Thrasivoulou, Prokar Dasgupta, Jonathan F Ashmore, Aamir Ahmed
Class II antiarrhythmics or β-blockers are anti-sympathetic nervous system agents and act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca2+ i ), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed, β-blockers (atenolol, metoprolol, propranolol, and sotalol) on Ca2+ i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines)...
January 17, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30643015/pharmacologic-characterization-of-ald1910-a-potent-humanized-monoclonal-antibody-against-the-pituitary-adenylate-cyclase-activating-peptide
#18
Cristina Moldovan Loomis, Benjamin Dutzar, Ethan W Ojala, Lee Hendrix, Charlie Karasek, Michelle Scalley-Kim, Jenny Mulligan, Pei Fan, Jens Billgren, Vanessa Rubin, Heidi Boshaw, Gayle Kwon, Sam Marzolf, Erica Stewart, David Jurchen, Susan M Pederson, Lisa Perrino McCulloch, Brian Baker, Roger K Cady, John A Latham, Dan Allison, Leon F Garcia-Martinez
Migraine is a debilitating disease that affects almost 15% of the population worldwide and is the first cause of disability in people under 50 years of age, yet its etiology and pathophysiology remain incompletely understood. Recently, small molecules and therapeutic antibodies that block the calcitonin gene-related peptide (CGRP) signaling pathway have reduced migraine occurrence and aborted acute attacks of migraine in clinical trials and provide prevention in patiens with episodic and chronic migraine. Heterogeneity is present within each diagnosis and a patient's response to treatment, suggesting migraine as a final common pathway potentially activated by multiple mechanisms, e...
January 14, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30635474/ferroptosis-as-a-novel-therapeutic-target-for-friedreich-s-ataxia
#19
M Grazia Cotticelli, Shujuan Xia, Daniel Lin, Taehee Lee, Leila Terrab, Peter Wipf, Donna Huryn, Robert Wilson
Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, and hypertrophic cardiomyopathy. In most cases, the disorder is caused by GAA repeat expansions in the first introns of both alleles of the FXN gene, resulting in decreased expression of the encoded protein, frataxin. Frataxin localizes to the mitochondrial matrix and is required for iron-sulfur-cluster biosynthesis. Decreased expression of frataxin is associated with mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress...
January 11, 2019: Journal of Pharmacology and Experimental Therapeutics
https://read.qxmd.com/read/30635473/therapeutic-opportunities-in-neuroblastoma-using-nanotechnology
#20
Carlos Rodriguez-Nogales, Rosa Noguera, Couvreur Patrick, Maria J J Blanco-Prieto
Neuroblastoma is the most common extracranial solid tumor that preferentially occurs in preschoolers. Its characteristic aggressiveness and heterogeneous clinical behavior is especially visible in relapsed or refractory cases and hampers the therapeutic success. Although the introduction of novel antitumor agents such as dinutuximab, isotretinoin, irinotecan or I-131-MIBG has increased survival, the situation in high-risk neuroblastoma is still dismal. Moreover, treatment is particularly aggressive in these patients, leading to short- and long-term toxicities...
January 11, 2019: Journal of Pharmacology and Experimental Therapeutics
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