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Journal of Pharmacology and Experimental Therapeutics

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https://www.readbyqxmd.com/read/28096456/antibody-conjugated-dna-based-nanocarriers-intercalated-with-doxorubicin-eliminate-myofibroblasts-in-explants-of-human-lens-tissue
#1
Jacquelyn Gerhart, Marvin Greenbaum, Lou Casta, Anthony Clemente, Keith Mathers, Robert Getts, Mindy George-Weinstein
Posterior capsule opacification (PCO) occurs in some adults and most children following cataract surgery. The fibrotic form of PCO arises, in part, from migratory, contractile myofibroblasts that deform the lens capsule and impair vision. In short-term cultures of human anterior lens tissue, myofibroblasts emerge from Myo/Nog cells that are identified with the G8 monoclonal antibody and by their expression of the MyoD transcription factor and bone morphogenetic protein inhibitor noggin. In this study, we tested the hypothesis that targeted depletion of Myo/Nog cells with the G8 mAb conjugated to three-dimensional DNA nanocarriers intercalated with Doxorubicin (G8:3DNA:Dox) would prevent the accumulation of myofibroblasts in long-term, serum and growth factor free cultures of human lens tissue obtained by capsulorhexis...
January 17, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28087785/thermolytic-degradation-of-synthetic-cannabinoids-chemical-exposures-and-pharmacological-consequences
#2
Brian F Thomas, Timothy W Lefever, Ricardo A Cortes, Alexander L Kovach, Anderson O Cox, Purvi R Patel, Gerald T Pollard, Julie A Marusich, Richard A Kevin, Thomas F Gamage, Jenny L Wiley
Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal "Spice" for smoking or as bulk compound for mixing with a solvent and inhalation via electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here we show that heating synthetic cannabinoids containing tetramethylcyclopropyl-ring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds...
January 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28087784/interactions-between-zinc-and-allosteric-modulators-of-the-glycine-receptor
#3
Garrett L Cornelison, Anna W Daszkowski, Natasha C Pflanz, S John Mihic
The glycine receptor is a pentameric ligand-gated ion channel involved in fast inhibitory neurotransmission in the central nervous system. Zinc is an allosteric modulator of glycine receptor function, enhancing the effects of glycine at nM to low μM concentrations, and inhibiting its effects at higher concentrations. Low nM concentrations of contaminating zinc in electrophysiological buffers are capable of synergistically enhancing receptor modulation by other compounds such as ethanol. This suggests that, unless accounted for, previous studies of glycine receptor modulation were measuring the effects of modulator plus co-modulation by zinc on receptor function...
January 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28062526/regulation-of-chemokine-signal-integration-by-activator-of-g-protein-signaling-4-ags4
#4
William G Robichaux, Melissa Branham-O'Connor, Il-Young Hwang, Ali Vural, John H Kehrl, Joe B Blumer
Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gαi-GDP free of Gβγ. We previously demonstrated that the AGS4-Gαi interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gαi module to the receptor analogous to canonical Gαβγ heterotrimer. Here, we demonstrate that the AGS4-Gαi complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal...
January 6, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28057840/delineating-the-role-of-various-factors-in-renal-disposition-of-digoxin-through-application-of-physiologically-based-kidney-model-to-renal-impairment-populations
#5
Daniel Scotcher, Christopher R Jones, Aleksandra Galetin, Amin Rostami-Hodjegan
Development of sub-models of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, the advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology (Rowland Yeo et al...
January 5, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28057839/niacin-promotes-cardiac-healing-after-myocardial-infarction-through-activation-of-the-myeloid-prostaglandin-d2-receptor-subtype-1
#6
Deping Kong, Juanjuan Li, Yujun Shen, Guihu Liu, Shengkai Zuo, Bo Tao, Yong Ji, Ankang Lu, Michael Lazarus, Richard M Breyer, Ying Yu
Niacin is a well-established drug used to lower cholesterol and prevent cardiovascular disease (CVD) events. However, niacin also causes cutaneous flushing side effects due to release of the proresolution mediator prostaglandin (PG) D2. Recent randomized clinical trials have demonstrated that addition of niacin with laropiprant (a PGD2 receptor subtype 1 [DP1] blocker) to statin-based therapies does not significantly decrease the risk of CVD events but increases the risk of serious adverse events. Here, we tested whether, and how, niacin beneficial effects in vivo myocardial ischemia requires the activation of the PGD2/DP1 axis...
January 5, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28039330/dissecting-the-influence-of-two-structural-substituents-on-the-differential-neurotoxic-effects-of-methamphetamine-and-mephedrone-on-dopamine-nerve-endings-with-the-use-of-4-methylmethamphetamine-and-methcathinone
#7
John H Anneken, Mariana Angoa-Perez, Girish C Sati, David Crich, Donald M Kuhn
Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. While MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared to METH. The addition of a β-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, 2 analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH...
December 30, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28035009/inhibition-of-leukotriene-b4-action-mitigates-intracerebral-hemorrhage-associated-pathological-events-in-mice
#8
Masanori Hijioka, Junpei Anan, Hayato Ishibashi, Yuki Kurauchi, Akinori Hisatsune, Takahiro Seki, Tomoaki Koga, Takehiko Yokomizo, Takao Shimizu, Hiroshi Katsuki
Infiltration of neutrophils has been suggested to play an important role in the pathogenesis of intracerebral hemorrhage (ICH) for which effective therapeutic interventions remain unavailable. In the present study we focused on leukotriene B4 (LTB4) as a potent chemotactic factor for neutrophils, to address its contribution to the pathological events associated with ICH. ICH with hematoma expansion into the internal capsule that resulted in severe sensorimotor dysfunction was induced by injection of collagenase in mouse striatum...
December 29, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28035008/regulator-of-g-protein-signaling-6-protects-the-heart-from-ischemic-injury
#9
Boyd R Rorabaugh, Bandana Chakravarti, Nathaniel W Mabe, Sarah L Seeley, Albert D Bui, Jianqi Yang, Stephanie W Watts, Richard R Neubig, Rory A Fisher
Gαi-coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In the present study, we investigated the impact of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6-/-) and wildtype (RGS6+/+) mice were subjected to 30 min ischemia and 2 hr reperfusion on a Langendorff heart apparatus...
December 29, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28035007/inhibition-of-factor-xia-reduces-the-frequency-of-cerebral-microembolic-signals-derived-from-carotid-arterial-thrombosis-in-rabbits
#10
Xinkang Wang, Stan Kurowsk, Weizhen Wu, Gino A Castriota, Xueping Zhou, Lin Chu, Kenneth P Ellsworth, Scott Edmondson, Donald Chu, Amjad Ali, Patrick Andre, Dietmar Seiffert, Mark Erion, David E Gutstein, Zhu Chen
Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Since its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study utilized a potent and selective small molecule inhibitor of FXIa, Compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl3 injury of the carotid artery in male New Zealand White rabbits. Ascending doses of Compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler...
December 29, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28035006/factor-xiia-as-a-novel-target-for-thrombosis-target-engagement-requirement-and-efficacy-in-a-rabbit-model-of-microembolic-signals
#11
Christopher M Barbieri, Xinkang Wang, Weizhen Wu, Xueping Zhou, Aimie M Ogawa, Kim O'Neill, Donald Chu, Gino Castriota, Dietmar A Seiffert, David E Gutstein, Zhu Chen
Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear is the level of enzyme occupancy of FXIIa needed for efficacy, and impact of FXIIa inhibition on cerebral embolism. A selective FXIIa inhibitor, recombinant human albumin-tagged mutant Infestin4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable to the original wild-type HA-Infestin4 (rHA-WT-inf) (human FXIIa KI = 0.07 and 0.12 nM, respectively), with markedly improved selectivity against FXa and plasmin...
December 29, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28028124/characterising-gemcitabine-effects-administered-as-single-agent-or-combined-with-carboplatin-in-mice-pancreatic-and-ovarian-cancer-xenografts-a-semi-mechanistic-pharmacokinetic-pharmacodynamics-tumour-growth-response-model
#12
Maria Garcia-Cremades, Celine Pitou, Philip W Iversen, Inaki F Troconiz
In this work, a semi-mechanistic tumour growth response model for gemcitabine in pancreatic (administered as single agent) and ovarian (given as single agent and in combination with carboplatin) cancer in mice was developed. Tumour profiles were obtained from nude mice, previously inoculated with KP4, ASPC1, MIA PACA2, PANC1 (pancreas), A2780 or SKOV3xluc (ovarian) cell lines, and then treated with different dosing schedules of gemcitabine and/or carboplatin. Data were fitted using the population approach with NONMEM 7...
December 27, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28011874/activation-of-nrf2-reduces-uva-mediated-mmp-1-upregulation-via-mapk-ap-1-signaling-cascades-the-photoprotective-effects-of-sulforaphane-and-hispidulin
#13
Anyamanee Chaiprasongsuk, Jinaphat Lohakul, Kitipong Soontrapa, Somponnat Sampattavanich, Pravit Akarasereenont, Uraiwan Panich
Ultraviolet A (UVA) irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds which can activate Nrf2, a transcription factor regulating antioxidant gene expression, should therefore serve as effective anti-photoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of MAPK/AP-1 signaling using human keratinocyte cell line (HaCaT)...
December 23, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27986860/quantification-of-ono-2952-occupancy-of-translocator-protein-18kda-in-conscious-monkey-brain-using-positron-emission-tomography
#14
Katsukuni Mitsui, Noriko Morimoto, Tomohiro Niwa, Yoshiyuki Yamaura, Hiroyuki Ohba, Hideo Tsukada, Seishi Katsumata
We have previously shown that ONO-2952, a novel translocator protein 18kDa (TSPO) antagonist, inhibits stress-induced neurosteroids accumulation and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with (11)C-PBR28 as ligand for translational research to clinical application. PET scans were performed following single and repeated oral administration of ONO-2952 at several dose levels for each animal with sequential arterial blood sampling...
December 16, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27980039/intracellular-calcium-mobilization-in-response-to-ion-channel-regulators-via-a-calcium-induced-calcium-release-mechanism
#15
Terry Petrou, Hervor L Olsen, Christopher Thrasivoulou, John R Masters, Jonathan F Ashmore, Aamir Ahmed
Free intracellular calcium ([Ca2+]i), in addition to being an important second messenger, is a key regulator of many cellular processes including cell membrane potential, proliferation and apoptosis. In many cases, the mobilization of [Ca2+]i is controlled by intracellular store activation and calcium influx. We have investigated the effect of several ion channel modulators, which have been used to treat a range of human diseases, on [Ca2+]i release, by ratiometric calcium imaging. We show that six such modulators (Amiodarone (Ami), Dofetilide (Dof), Furosemide (Fur), Minoxidil (Min), Loxapine (Lox), and Nicorandil (Nic)) initiate release of [Ca2+]i in prostate and breast cancer cell lines, PC3 and MCF7, respectively...
December 15, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27965369/pharmacological-characterization-of-a-novel-beta3-adrenergic-agonist-vibegron-evaluation-of-anti-muscarinic-receptor-selectivity-for-optimal-combination-therapy-for-overactive-bladder
#16
Jerry Di Salvo, Hiroshi Nagabukuro, Alexandra Wickham, Catherine Abbadie, Julie A DeMartino, Aileen Fitzmaurice, Loise Gichuru, Alison Kulick, Marcie J Donnelly, Nina Jochnowitz, Amanda Hurley, Antonio Pereira, Anthony Sanfiz, Gregory Veronin, Katherine Villa, John Woods, Beata Zamlynny, Emanuel Zycband, Gino M Salituro, Tara Frenkl, Ann E Weber, Scott D Edmondson, Mary Struthers
Although the physiological role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of β3-adrenergic receptors (β3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel β3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of β3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full β3AR agonist across species and it dose-dependently increased bladder capacity, decreased micturition pressure and increased bladder compliance in rhesus monkeys...
December 13, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27927913/two-janus-cannabinoids-that-are-both-cb2-agonists-and-cb1-antagonists
#17
Amey Dhopeshwarkar, Natalia Murataeva, Alex Makriyannis, Alex Straiker, Ken P Mackie
The cannabinoid signaling system includes two G protein coupled receptors, CB1 and CB2. These receptors are widely distributed throughout the body and have each been implicated in many physiologically important processes. Though the cannabinoid signaling system has therapeutic potential, a persistent hurdle has remained the development of receptor-selective ligands. Because CB1 and CB2 are involved in diverse processes, it would be advantageous develop ligands that differentially engaging CB1 and CB2. We now report that GW405833 and AM1710, described as selective CB2 agonists, can antagonize CB1 receptor signaling...
December 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27934627/characterization-and-prediction-of-cardiovascular-effects-of-fingolimod-and-siponimod-using-a-systems-pharmacology-modelling-approach
#18
Nelleke Snelder, Bart A Ploeger, Olivier Luttringer, Dean F Rigel, Randy L Webb, David Feldman, Fumin Fu, Michael Beil, Liang Jin, Donald R Stanski, Meindert Danhof
Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once daily fingolimod (0, 0.1, 0.3, 1, 3 and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats...
December 1, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27856936/reveglucosidase-alfa-bmn-701-an-igf-2-tagged-rhacid-%C3%AE-glucosidase-improves-respiratory-functional-parameters-in-a-murine-model-of-pompe-disease
#19
Jeff Peng, Jill Dalton, Mark Butt, Kristin Tracy, Derek Kennedy, Peter Haroldsen, Rhea Cahayag, Stephen Zoog, Charles A O'Neill, Laurie Tsuruda
Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701), is an insulin-like growth factor 2 (IGF2) tagged rhGAA that enhances rhGAA cellular uptake via a glycosylation independent IGF2-binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). These studies evaluated the effects of reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA as well as changes in respiratory function and glycogen clearance in respiratory related tissue in a Pompe mouse model (GAA(tm1Rabn))...
November 16, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27821710/exploration-of-%C3%AE-1-antitrypsin-treatment-protocol-for-islet-transplantation-dosing-plan-and-route-of-administration
#20
Boris M Baranovski, Eyal Ozeri, Galit Shahaf, David E Ochayon, Ronen Schuster, Nofar Bahar, Noa Kalay, Pablo Cal, Mark I Mizrahi, Omer Nisim, Pnina Strauss, Eran Schenker, Eli C Lewis
Life-long weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Since the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related injury. Islet-grafted mice were treated with hAAT (Glassia™; i...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
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