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Chuan-Guo Guo, Lijia Chen, Esther W Chan, Ka Shing Cheung, Takaaki Isshiki, Ian C K Wong, Wai K Leung
BACKGROUND: Ticagrelor and prasugrel are third-generation oral P2Y12 receptor antagonists with rapid onset and pronounced platelet inhibition. However, higher overall bleeding rates have been reported for these agents when compared with clopidogrel. AIM: To compare the risk of gastrointestinal bleeding (GIB) among users of third-generation P2Y12 inhibitors with clopidogrel. METHODS: We systematically searched for published randomised controlled trials of ticagrelor or prasugrel versus clopidogrel until September 2018...
December 2, 2018: Alimentary Pharmacology & Therapeutics
Nikolaos Spinthakis, Mohamed Farag, Ying X Gue, Manivannan Srinivasan, David M Wellsted, Diana A Gorog
Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y12 inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown. Blood taken from patients pre- and post-aspirin (n = 20) and on aspirin alone and on dual antiplatelet therapy comprising aspirin plus clopidogrel (n = 20), ticagrelor (n = 20) or cangrelor (n = 20), was tested using the Global Thrombosis Test. The number of "rebleeds" or drops (D) after early platelet-rich thrombus formation (occlusion time, OT), and before final lasting occlusion, was used as an inverse measure of thrombus stability...
November 24, 2018: Thrombosis Research
Elena Smolensky Koganov, Alan D Michelson, Ivan B Yanachkov, Milka I Yanachkova, George E Wright, Karin Przyklenk, Andrew L Frelinger
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
November 29, 2018: Scientific Reports
Laurie Erb, Lucas T Woods, Mahmoud G Khalafalla, Gary A Weisman
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by three major histopathological markers: amyloid-β (Aβ) plaques, neurofibrillary tangles and gliosis in the central nervous system (CNS). It is now accepted that neuroinflammatory events in the CNS play a crucial role in the development of AD. This review focuses on neuroinflammatory signaling mediated by purinergic receptors (P1 adenosine receptors, P2X ATP-gated ion channels and G protein-coupled P2Y nucleotide receptors) and how therapeutic modulation of purinergic signaling influences disease progression in AD patients and animal models of AD...
November 22, 2018: Brain Research Bulletin
Magdalena Boncler, Joanna Wzorek, Nina Wolska, Dawid Polak, Cezary Watala, Marcin Rozalski
Several adenosine receptor (AR) agonists have been shown in the past to possess anti-platelet potential; however, the adjunctive role of AR agonists in anti-platelet therapy with the use of P2Y12 receptor inhibitors has not been elucidated so far. This in vitro aggregation-based study investigates whether the inhibition of platelet function mediated by cangrelor or prasugrel metabolite can be potentiated by AR agonists. It evaluates the effect of non-selective (2-chloroadenosine), A2A -selective (UK 432097, MRE 0094, PSB 0777) and A2B -selective AR agonists (BAY 60-6583) on platelet function in relation to their toxicity, specificity towards adenosine receptor subtypes, structure and solubility...
November 21, 2018: Vascular Pharmacology
Byeongjae Chun, Bradley D Stewart, Darin D Vaughan, Adam D Bachstetter, Peter M Kekenes-Huskey
KEY POINTS SUMMARY: • A computational model of P2X channel activation in microglia was developed that includes downfield Ca2+ dependent signaling pathways. • This model provides quantitative insights into how diverse signaling pathways in microglia converge to control microglial function. ABSTRACT: Microglia function is orchestrated through highly-coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adeno- sine triphosphate (ATP), transient increases in intracellular Ca2+ driven through the activation of purinergic receptors, P2X and P2Y, are sufficient to promote cytokine synthesis...
November 21, 2018: Journal of Physiology
Anna Lisa Giuliani, Alba Clara Sarti, Francesco Di Virgilio
Extracellular nucleotides, mainly ATP, but also ADP, UTP, UDP and UDP-sugars, adenosine, and adenine base participate in the "purinergic signalling" pathway, an ubiquitous system of cell-to-cell communication. Fundamental pathophysiological processes such as tissue homeostasis, wound healing, neurodegeneration, immunity, inflammation and cancer are modulated by purinergic signalling. Nucleotides can be released from cells via unspecific or specific mechanisms. A non-regulated nucleotide release can occur from damaged or dying cells, whereas exocytotic granules, plasma membrane-derived microvesicles, membrane channels (connexins, pannexins, calcium homeostasis modulator (CALHM) channels and P2X7 receptor) or specific ATP binding cassette (ABC) transporters are involved in the controlled release...
November 12, 2018: Immunology Letters
Cédric Garcia, Agnès Maurel-Ribes, Michel Nauze, Du N'Guyen, Laurent O Martinez, Bernard Payrastre, Jean-Michel Sénard, Céline Galés, Véronique Pons
P2Y12 receptor (P2Y12 -R) is one of the major targets for drug inhibiting platelet aggregation in the treatment/prevention of arterial thrombosis. However, the clinical use of P2Y12 -R antagonists faces some limitations, such as a delayed onset of action (clopidogrel) or adverse effect profile (ticagrelor, cangrelor), justifying the development of a new generation of P2Y12 -R antagonists with a better clinical benefit-risk balance. Although the recent concept of biased agonism offers the possibility to alleviate undesirable adverse effects while preserving therapeutic outcomes, it has never been explored at P2Y12 -R...
November 7, 2018: Cellular and Molecular Life Sciences: CMLS
Liyanage Manosika Buddhini Perera, Akiko Sekiguchi, Akihiko Uchiyama, Akihito Uehara, Chisako Fujiwara, Sahori Yamazaki, Yoko Yokoyama, Sachiko Ogino, Ryoko Torii, Mari Hosoi, Osamu Ishikawa, Sei-Ichiro Motegi
Tissue injury/hypoxia and oxidative stress induced-extracellular ATP can act as a damage-associated molecular pattern molecules (DAMPs), which initiates inflammatory response. Objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release, and extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptors expressions between normal and SSc fibroblasts...
November 4, 2018: Journal of Investigative Dermatology
Hongliu Sun, Luyu Ma, Yurong Zhang, Xiaohong Pan, Chaoyun Wang, Jinjin Zhang, Xiuli Zhang, Hongwei Sun, Qiaoyun Wang, Wei Zhu
Previous studies suggested that the thrombospondin-1/transforming growth factor-β1 (TSP-1/TGF-β1) pathway might be critical in synaptogenesis during development and that the purinergic P2 receptor family could regulate synaptogenesis by modulating TSP-1 signaling. However, it is unclear whether this pathway plays a role in synaptogenesis during epileptic progression. This study was designed to investigate this question by analyzing the dynamic changes and effects of TSP-1 levels on the density of synaptic markers that are related to epileptic seizure activity...
2018: Frontiers in Cellular Neuroscience
S Zhang, D Ye, L Ma, Y Ren, R T Dirksen, X Liu
Human dental pulp stem cells (hDPSCs) reside in postnatal dental pulp and exhibit the potential to differentiate into odontoblasts as well as neurons. However, the intercellular signaling niches necessary for hDPSC survival and self-renewal remain largely unknown. The objective of this study is to demonstrate the existence of intercellular purinergic signaling in hDPSCs and to assess the impact of purinergic signaling on hDPSC survival and proliferation. hDPSCs were isolated from extracted third molars and cultured in minimum essential medium...
November 1, 2018: Journal of Dental Research
Marek Cieślak, Andrzej Wojtczak
Etiology of the Alzheimer's disease (AD) is not fully understood. Different pathological processes are considered, such as amyloid deposition, tau protein phosphorylation, oxidative stress (OS), metal ion disregulation, or chronic neuroinflammation. Purinergic signaling is involved in all these processes, suggesting the importance of nucleotide receptors (P2X and P2Y) and adenosine receptors (A1, A2A, A2B, A3) present on the CNS cells. Ecto-purines, ecto-pyrimidines, and enzymes participating in their metabolism are present in the inter-cellular spaces...
October 25, 2018: Purinergic Signalling
Laurent Bonello, Dominick J Angiolillo, Daniel Aradi, Dirk Sibbing
Because of its high prevalence, chronic kidney disease (CKD) remains a major health hazard throughout the world. Patients with CKD have a high prevalence and incidence of acute coronary syndromes (ACS). Despite decades of improved care, their higher risk profile persists and cardiovascular diseases remain their leading cause of death. Along with the reduction of glomerular filtration rate, several physiological processes are impacted and participate in the pathophysiology of ischemic and bleeding events. CKD is associated with an accelerated and severe course of atherothrombotic disease, and this relates to a modified vascular milieu with alterations on the level of the coagulation cascade and platelet aggregation...
October 9, 2018: Circulation
M J Whitley, D M Henke, A Ghazi, M Nieman, Michelle Stoller, L M Simon, E Chen, J Vesci, M Holinstat, S E McKenzie, C A Shaw, L C Edelstein, Paul F Bray
BACKGROUND: F2RL3 encodes protease-activated receptor 4 (PAR4) and harbors an A/G SNP (rs773902) with racially dimorphic allelic frequencies. This SNP mediates an alanine to threonine substitution at residue 120 that alters platelet PAR4 activation by the artificial PAR4-activation peptide, AYPGKF. OBJECTIVES: We determined the functional effect of rs773902 on stimulation by a physiological agonist, thrombin, and on antiplatelet antagonist activity. METHODS: Healthy human donors were screened and genotyped for rs773902...
October 22, 2018: Journal of Thrombosis and Haemostasis: JTH
Miho Sugioka, Yasuhiko Saito
In the nervous system, adenosine 5'-trisphosphate (ATP) functions as a neurotransmitter and binds to ionotropic P2X receptors and metabotropic P2Y receptors. Although ATP receptors are expressed in the prepositus hypoglossi nucleus (PHN), which is a brainstem structure involved in controlling horizontal gaze, it is unclear whether ATP indeed affects the activity of PHN neurons. In this study, we investigated the effects of ATP on spontaneous firing of PHN neurons using whole-cell recordings in rat brainstem slices...
October 19, 2018: European Journal of Neuroscience
Julian Merz, Philipp Albrecht, Sunaina von Garlen, Ibrahim Ahmed, Daniel Dimanski, Dennis Wolf, Ingo Hilgendorf, Carmen Härdtner, Katja Grotius, Florian Willecke, Timo Heidt, Heiko Bugger, Natalie Hoppe, Ulrich Kintscher, Constantin von Zur Mühlen, Marco Idzko, Christoph Bode, Andreas Zirlik, Peter Stachon
Sterile inflammation of visceral fat, provoked by dying adipocytes, links the metabolic syndrome to cardiovascular disease. Danger-associated molecular patterns, such as adenosine triphosphate (ATP), are released by activated or dying cells and orchestrate leukocyte infiltration and inflammation via the purinergic receptor P2Y2 . The gene expression of ATP receptor P2Y2 did not change in several tissues in the course of obesity, but was increased within epididymal fat. Adipose tissue from P2Y 2 -/- mice consuming high-fat diet (HFD) contained less crown-like structures with a reduced frequency of adipose tissue macrophages (ATMs)...
October 18, 2018: Basic Research in Cardiology
Yuichiro Fukumoto, Kenji F Tanaka, Bijay Parajuli, Keisuke Shibata, Hideyuki Yoshioka, Kazuya Kanemaru, Christian Gachet, Kazuhiro Ikenaka, Schuichi Koizumi, Hiroyuki Kinouchi
Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y1 receptors (P2Y1 R) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2Y1 R in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2Y1 R to provide neuroprotective effects following ischemic stress...
October 18, 2018: Journal of Cerebral Blood Flow and Metabolism
Seema B Ali, Jeremy J O Turner, Samuel J Fountain
White adipocytes are key regulators of metabolic homeostasis, which release stored energy as free fatty acids via lipolysis. Adipocytes possess both basal and stimulated lipolytic capacity, but limited information exists regarding the molecular mechanisms that regulate basal lipolysis. Here, we describe a mechanism whereby autocrine purinergic signaling and constitutive P2Y2 receptor activation suppresses basal lipolysis in primary human in vitro differentiated adipocytes. We found that human adipocytes possess cytoplasmic calcium tone due to ATP secretion and constitutive P2Y2 receptor activation...
October 17, 2018: Journal of Cell Science
Cai Liu, Yifan Zhang, Weili Chen, Youming Lu, Wei Li, Yongqiang Liu, Xiaojuan Lai, Yanchun Gong, Xuefang Liu, Yongguo Li, Xiaoyan Chen, Xuening Li, Hongbin Sun, Jin Yang, Dafang Zhong
BACKGROUND AND OBJECTIVES: Vicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel...
October 13, 2018: European Journal of Pharmaceutical Sciences
Piotr Sirko, Jonathan E Gale, Jonathan F Ashmore
Intercellular Ca2+ waves are increases in cytoplasmic Ca2+ levels that propagate between cells Periodic Ca2+ waves have been linked to gene regulation and are thought to play a crucial role in the development of our hearing epithelium the organ of Corti and the acquisition of hearing We have observed regular periodic intercellular Ca2+ waves in supporting cells of an ex vivo preparation of the adult mouse organ of Corti, the waves were found to propagate independently of extracellular ATP and were inhibited by the gap junction blockers 1-octanol and carbenoxolone...
October 15, 2018: Journal of Physiology
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