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https://www.readbyqxmd.com/read/29781070/antiplatelet-therapy-for-patients-undergoing-coronary-artery-bypass-surgery
#1
Christine M DeStephan, David J Schneider
Considerable variation in the use and duration of antiplatelet medications during the perioperative and postoperative care of patients undergoing coronary artery bypass grafting (CABG) reflects limited studies focused directly on these patients as well as variation in the results reported. In this review we will highlight the incidence and mechanisms of graft closure as well as the evidence in support of antiplatelet therapy that is balanced by the impact of antiplatelet therapy on the risk of bleeding to provide recommendations for the use of antiplatelet therapy in patients undergoing CABG...
May 21, 2018: Kardiologia Polska
https://www.readbyqxmd.com/read/29773988/microglia-p2y-13-receptors-prevent-astrocyte-proliferation-mediated-by-p2y-1-receptors
#2
Clara Quintas, Nuno Vale, Jorge Gonçalves, Glória Queiroz
Cerebral inflammation is a common feature of several neurodegenerative diseases that requires a fine interplay between astrocytes and microglia to acquire appropriate phenotypes for an efficient response to neuronal damage. During brain inflammation, ATP is massively released into the extracellular medium and converted into ADP. Both nucleotides acting on P2 receptors, modulate astrogliosis through mechanisms involving microglia-astrocytes communication. In previous studies, primary cultures of astrocytes and co-cultures of astrocytes and microglia were used to investigate the influence of microglia on astroglial proliferation induced by ADPβS, a stable ADP analog...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29765331/high-ph-sensitive-store-operated-ca-2-entry-mediated-by-ca-2-release-activated-ca-2-channels-in-rat-odontoblasts
#3
Maki Kimura, Koichi Nishi, Asuka Higashikawa, Sadao Ohyama, Kaoru Sakurai, Masakazu Tazaki, Yoshiyuki Shibukawa
Odontoblasts play a crucial role in dentin formation and sensory transduction following the application of stimuli to the dentin surface. Various exogenous and endogenous stimuli elicit an increase in the intracellular free calcium concentration ([Ca2+ ]i ) in odontoblasts, which is mediated by Ca2+ release from intracellular Ca2+ stores and/or Ca2+ influx from the extracellular medium. In a previous study, we demonstrated that the depletion of Ca2+ stores in odontoblasts activated store-operated Ca2+ entry (SOCE), a Ca2+ influx pathway...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29725296/the-p2y-12-receptor-antagonist-ticagrelor-reduces-lysosomal-ph-and-autofluorescence-in-retinal-pigmented-epithelial-cells-from-the-abca4-mouse-model-of-retinal-degeneration
#4
Wennan Lu, Néstor M Gómez, Jason C Lim, Sonia Guha, Ann O'Brien-Jenkins, Erin E Coffey, Keith E Campagno, Stuart A McCaughey, Alan M Laties, Leif G Carlsson, Claire H Mitchell
The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE) cells, and may be related to early stages of age-related macular degeneration. While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4-/- mouse model of Stargardt's disease, an early onset retinal degeneration...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29660366/tools-and-drugs-for-uracil-nucleotide-activated-p2y-receptors
#5
REVIEW
Muhammad Rafehi, Christa E Müller
P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y1 , P2Y2 , P2Y4 , P2Y6 , P2Y11 , P2Y12 , P2Y13 , and P2Y14 , which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y2 (UTP, also ATP and dinucleotides), P2Y4 (UTP), P2Y6 (UDP), and P2Y14 (UDP, UDP-glucose, UDP-galactose)...
April 13, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29628327/reversible-orally-available-adp-receptor-p2y-12-antagonists-part-i-hit-to-lead-process
#6
Imadul Islam, Shendong Yuan, Robert G Wei, Wei Xu, Michael Morrissey, Raju Mohan, Dewan Zheng, Andrea DiMella, Laura Dunning, Michael Snider, Babu Subramanyam, Jih-Lie Tseng, Judi A Bryant, Brad O Buckman
A hit to lead process to identify reversible, orally available ADP receptor (P2Y12 ) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (KB  = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed...
March 31, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29575062/restored-response-to-adp-downstream-of-purinergic-p2y-12-receptor-in-apheresis-platelets-after-pathogen-reducing-xenon-flash-treatment
#7
Hideki Abe, Takaaki Abe, Masayuki Shiba, Masahiro Satake
BACKGROUND: Our previous study revealed that pathogen-reducing filtered xenon flash-treated platelets (fXe-PLTs) showed sustained aggregation in response to adenosine diphosphate (ADP), but apheresis-collected PLTs (Aph-PLTs) showed reversible aggregation. STUDY DESIGN AND METHODS: Aph-PLTs, fXe-PLTs, and freshly prepared PLTs (PRP-PLTs) from whole blood were used to investigate the following responses to ADP: concentration response and effects of ADP receptor antagonists on aggregation, the cytosolic calcium (Ca2+ ) flux downstream of P2Y1 receptor signaling, and phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and signaling intermediate protein Akt downstream of the P2Y12 receptor...
March 25, 2018: Transfusion
https://www.readbyqxmd.com/read/29574692/p2y-12-receptor-modulation-of-adp-evoked-intracellular-ca-2-signalling-in-thp-1-human-monocytic-cells
#8
J J Micklewright, J A Layhadi, S J Fountain
BACKGROUND AND PURPOSE: The Gi-coupled, ADP-activated P2Y12 receptor is well characterised as playing a key role in platelet activation via crosstalk with P2Y1 in ADP-evoked intracellular Ca2+ response. There is limited knowledge on the role of P2Y12 in ADP-evoked Ca2+ responses in other blood cells. Here we investigate the role of P2Y12 receptor activation in modulation of ADP-evoked Ca2+ responses in human THP-1 monocytic cells. EXPERIMENTAL APPROACH: A combination of intracellular Ca2+ measurements, RT-PCR, immunocytochemistry, leukocyte isolation and siRNA-mediated gene knockdown were used to identify the role of P2Y12 receptor activation...
March 25, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29574630/p2y-12-but-not-p2y-13-purinergic-receptor-controls-postnatal-rat-retinogenesis-in-vivo
#9
Luana de Almeida-Pereira, Marinna Garcia Repossi, Camila Feitosa Magalhães, Rafael de Freitas Azevedo, Juliana da Cruz Corrêa-Velloso, Henning Ulrich, Ana Lúcia Marques Ventura, Lucianne Fragel-Madeira
Adenine nucleotides through P2Y1 receptor stimulation are known to control retinal progenitor cell (RPC) proliferation by modulating expression of the p57KIP2 , a cell cycle regulator. However, the role of Gi protein-coupled P2Y12 and P2Y13 receptors also activated by adenine nucleotides in RPC proliferation is still unknown. Gene expression of the purinergic P2Y12 subtype was detected in rat retina during early postnatal days (P0 to P5), while expression levels of P2Y13 were low. Immunohistochemistry assays performed with rat retina on P3 revealed P2Y12 receptor expression in both Ki-67-positive cells in the neuroblastic layer and Ki-67-negative cells in the ganglion cell layer and inner nuclear layer...
March 25, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29456511/p2y-12-receptors-in-tumorigenesis-and-metastasis
#10
REVIEW
Patrizia Ballerini, Melania Dovizio, Annalisa Bruno, Stefania Tacconelli, Paola Patrignani
Platelets, beyond their role in hemostasis and thrombosis, may sustain tumorigenesis and metastasis. These effects may occur via direct interaction of platelets with cancer and stromal cells and by the release of several platelet products. Platelets and tumor cells release several bioactive molecules among which a great amount of adenosine triphosphate (ATP) and adenosine diphosphate (ADP). ADP is also formed extracellularly from ATP breakdown by the ecto-nucleoside-triphosphate-diphosphohydrolases. Under ATP and ADP stimulation the purinergic P2Y1 receptor (R) initiates platelet activation followed by the ADP-P2Y12 R-mediated amplification...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29451832/circulating-progenitor-cells-and-their-interaction-with-platelets-in-patients-with-an-acute-coronary-syndrome
#11
Prokopia T Tatsidou, Vasileios G Chantzichristos, Maria E Tsoumani, Sofia Sidiropoulou, Ioannis V Ntalas, John A Goudevenos, Konstantinos Stellos, Alexandros D Tselepis
CD34+ cells expressing KDR (CD34+ /KDR+ ) represent a small proportion of circulating progenitor cells that have the capacity to interact with platelets and to differentiate into mature endothelial cells, thus contributing to vascular homeostasis and regeneration as well as to re-endothelialization. We investigated the levels of CD34+ and CD34+ /KDR+ progenitor cells as well as their interaction with platelets in acute coronary syndrome (ACS) patients before the initiation (baseline) of their treatment with a P2Y12 receptor antagonist, and at 5-days post-treatment (follow-up)...
February 16, 2018: Platelets
https://www.readbyqxmd.com/read/29447780/nonprimary-pci-at-hospitals-without-cardiac-surgery-on-site-consistent-outcomes-for-all
#12
Matthew J Czarny, Julie M Miller, Daniel Q Naiman, Chao-Wei Hwang, Rani K Hasan, Cynthia C Lemmon, Thomas Aversano
BACKGROUND: The CPORT-E trial showed the noninferiority of nonprimary percutaneous coronary intervention (PCI) at hospitals without cardiac surgery on-site (SoS) compared with hospitals with SoS for 6-week mortality and 9-month major adverse cardiac events (MACE). However, target vessel revascularization (TVR) was increased at non-SoS hospitals. Therefore, we aimed to determine the consistency of the CPORT-E trial findings across the spectrum of enrolled patients. METHODS: Post hoc subgroup analyses of 6-week mortality and 9-month MACE, defined as the composite of death, Q-wave myocardial infarction, or TVR, were performed...
March 2018: American Heart Journal
https://www.readbyqxmd.com/read/29447773/percutaneous-coronary-intervention-and-antiplatelet-therapy-in-patients-with-atrial-fibrillation-receiving-apixaban-or-warfarin-insights-from-the-aristotle-trial
#13
David Kopin, W Schuyler Jones, Matthew W Sherwood, Daniel M Wojdyla, Lars Wallentin, Basil S Lewis, Freek W A Verheugt, Dragos Vinereanu, M Cecilia Bahit, Sigrun Halvorsen, Kurt Huber, Alexander Parkhomenko, Christopher B Granger, Renato D Lopes, John H Alexander
BACKGROUND: We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial. METHODS: Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are reported. Of the 18,201 trial participants, 316 (1.7%) underwent PCI (152 in apixaban group, 164 in warfarin group). RESULTS: At the time of PCI, 84% (267) were on study drug (either apixaban or warfarin)...
March 2018: American Heart Journal
https://www.readbyqxmd.com/read/29393654/trpv4-stimulation-releases-atp-via-pannexin-channels-in-human-pulmonary-fibroblasts
#14
Mozibur Rahman, Rui Sun, Subhendu Mukherjee, Bernd Nilius, Luke J Janssen
We previously described several ionic conductances in human pulmonary fibroblasts (HPFs), including one activated by two structurally distinct TRPV4-channel agonists: 4α-phorbol-12,13-didecanoate (4αPDD) and GSK1016790A. However, the TRPV4-activated current exhibited peculiar properties: it developed slowly over many minutes, exhibited reversal potentials that could vary by tens of millivolts even within a given cell, and was not easily reversed by subsequent addition of two distinct TRPV4-selective blockers (RN-1734 or HC-067047)...
February 2, 2018: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29365273/p2y-receptor-regulation-of-k2p-channels-that-facilitate-k-secretion-by-human-mammary-epithelial-cells
#15
Yotesawee Srisomboon, Nathan A Zaidman, Peter J Maniak, Chatsri Deachapunya, Scott M O'Grady
The objective of this study was to determine the molecular identity of ion channels involved in K+ secretion by the mammary epithelium and to examine their regulation by purinoceptor agonists. Apical membrane voltage clamp experiments were performed on human mammary epithelial cells where the basolateral membrane was exposed to the pore-forming antibiotic amphotericin B dissolved in a solution with intracellular-like ionic composition. Addition of the Na+ channel inhibitor benzamil reduced the basal current, consistent with inhibition of Na+ uptake across the apical membrane whereas the KCa 3...
January 24, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#16
B R Branchford, T J Stalker, L Law, G Acevedo, S Sather, C Brzezinski, K M Wilson, K Minson, A B Lee-Sherick, P Davizon-Castillo, C Ng, W Zhang, K B Neeves, S R Lentz, X Wang, S V Frye, H Shelton Earp, D DeRyckere, L F Brass, D K Graham, J A Di Paola
Essentials Signaling by Gas6 through Tyro3/Axl/Mer receptors is essential for stable platelet aggregation. UNC2025 is a small molecule inhibitor of the Mer tyrosine kinase. UNC2025 decreases platelet activation in vitro and thrombus formation in vivo. UNC2025's anti-platelet effect is synergistic with inhibition of the ADP receptor, P2Y12 . SUMMARY: Background Growth arrest-specific protein 6 signals through the TAM (TYRO-3-AXL-MERTK) receptor family, mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αII b β3 integrin...
February 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28982722/differences-in-relative-and-absolute-effectiveness-of-oral-p2y-12-inhibition-in-men-and-women-a-meta-analysis-and-modelling-study
#17
Kuan Ken Lee, Nicky Welton, Anoop S Shah, Philip D Adamson, Sofia Dias, Atul Anand, David E Newby, Nicholas L Mills, David A McAllister
OBJECTIVE: To estimate the absolute treatment effects of newer P2Y12 inhibitors (ticagrelor and prasugrel) compared with clopidogrel in men and women with acute coronary syndrome (ACS). METHODS: We searched Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for randomised controlled trials of oral P2Y12 inhibitors for acute stroke or ACS. Age-specific and sex-specific mortality was obtained for all patients admitted to hospital with myocardial infarction in Scotland from 2006 to 2010 (prior to introduction of prasugrel or ticagrelor)...
October 5, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28362883/use-of-aspirin-and-p2y12-response-assays-in-detecting-reversal-of-platelet-inhibition-with-platelet-transfusion-in-patients-with-traumatic-brain-injury-on-antiplatelet-therapy
#18
Phillip A Choi, Phillip V Parry, Joshua S Bauer, Benjamin E Zusman, David M Panczykowski, Ava M Puccio, David O Okonkwo
BACKGROUND: At present, guidelines are lacking on platelet transfusion in patients with a traumatic intracranial bleed and history of antiplatelet therapy. The aspirin and P2Y 12 response unit (ARU and PRU, respectively) assays detect the effect of aspirin and P2Y 12 inhibitors in the cardiac population. OBJECTIVE: To describe the reversal of platelet inhibition after platelet transfusion using the ARU and PRU assays in patients with traumatic brain injury. METHODS: Between 2010 and 2015, we conducted a prospective comparative cohort study of patients presenting with a positive head computed tomography and a history of antiplatelet therapy...
January 1, 2017: Neurosurgery
https://www.readbyqxmd.com/read/28174191/augmentation-of-muscle-blood-flow-by-ultrasound-cavitation-is-mediated-by-atp-and-purinergic-signaling
#19
J Todd Belcik, Brian P Davidson, Aris Xie, Melinda D Wu, Mrinal Yadava, Yue Qi, Sherry Liang, Chae Ryung Chon, Azzdine Y Ammi, Joshua Field, Leanne Harmann, William M Chilian, Joel Linden, Jonathan R Lindner
BACKGROUND: Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. METHODS: Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1...
March 28, 2017: Circulation
https://www.readbyqxmd.com/read/27682519/influence-of-p2x-receptors-on-renal-medullary-circulation-is-not-altered-by-angiotensin-ii-pretreatment
#20
Marta Kuczeriszka, Leszek Dobrowolski, Agnieszka Walkowska, Janusz Sadowski
BACKGROUND: Purine P2X and P2Y receptors (P2-R) are involved in control of renal circulation, especially in the medulla, wherein they appear to interact with angiotensin II (Ang II). Our experimental approach enabled examination of interaction with Ang II per se, in the absence of blood pressure elevation. In this whole-kidney functional study we focused on the influence of P2X1-R on perfusion of the renal medulla. METHODS: Acute experiments were conducted with normal rats, untreated or subjected to two weeks' infusion of Ang II (osmotic minipumps)...
December 2016: Pharmacological Reports: PR
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