upregulation of P2Y12 in platelet

Ticlopidine exerts its anti-platelet effects mainly by antagonizing platelet p2y12 receptors. Previously, a few studies have shown that ticlopidine can induce liver injury, but the exact mechanism of hepatotoxicity remains unclear. Oxidative stress, metabolic disorders, hepatocyte apoptosis, lipid peroxidation, and inflammatory responses can all lead to hepatic liver damage, which can cause hepatotoxicity. In this study, in order to deeply explore the potential molecular mechanisms of ticlopidine -induced hepatotoxicity, we used zebrafish as a model organism to comprehensively evaluate the hepatotoxicity of ticlopidine and its associated mechanism...

Lipid-lowering agents and antiplatelet drugs are guideline-recommended standard treatment for secondary prevention of acute thrombotic events in patients with increased cardiovascular risk. Aspirin is the most frequently used antiplatelet drug, either alone or in combination with other antiplatelet agents (P2Y12 inhibitors), while statins are first-line treatment of hypercholesterolemia. The well-established mode of action of aspirin is inhibition of platelet-dependent thromboxane formation. In addition, aspirin also improves endothelial oxygen defense via enhanced NO formation and inhibits thrombin formation...

Purinergic 2Y12 (P2Y12) receptor antagonists are used as platelet aggregation inhibitors. Long non-coding RNAs (lncRNAs) play an important role in neuropathological events. Satellite glial cells (SGCs) in the superior cervical ganglia (SCGs) encircle the somata of neurons. This study explored if the upregulated P2Y12 receptor in SCGs was relevant to lncRNA uc.48+ during myocardial ischemia (MI). The results showed that upregulation of P2Y12 receptor was accompanied by increased expression of uc.48+ in the SCGs of MI rats which displayed abnormal changes in cervical sympathetic nerve activity, blood pressure, heart rate, electrocardiograms and cardiac tissue structure...

The pathological conditions caused by blood platelet activation constitute a fundamental core in the pathogenesis of Acute Coronary Syndrome (ACS). The hyperactivity of platelets in ACS is well-documented, but there is still little research into the molecular basis of phenotypic changes in platelet functionality. To expand the knowledge of this phenomenon, we analyzed the disturbances in the expression of several key platelet receptors and the aspect of regulating potential abnormalities. Platelet surface receptors are responsible for maintaining the hemostatic balance, platelet interaction with immune cells, and support of the coagulation cascade leading to occlusion of the vessel lumen...

BACKGROUND: Platelets from septic patients exhibit increased reactivity. However, the underlying mechanism of sepsis-induced platelet hyperactivity is still not completely understood. OBJECTIVE: P2Y12 is a central receptor for platelet activation. In this study, we investigated the role of platelet P2Y12 in platelet hyperactivity during sepsis. METHODS: We measured platelet P2Y12 expression and aggregation in response to ADP in septic patients and cecal ligation and puncture (CLP)-treated mice...

BACKGROUND AND PURPOSE: P2Y12 receptors regulate different forms of pain and inflammation. In this study, we investigated the participation of P2Y12 receptors in an animal model of migraine. EXPERIMENTAL APPROACH: We tested the effect of the centrally administered selective P2Y12 antagonist PSB-0739 and P2Y12 receptor gene (P2ry12-/- ) deficiency in acute nitroglycerin-treated mice. Additionally, platelet depletion was used to investigate the role of platelet P2Y12 receptors during migraine-like pain...

The reactivity of platelets, which play a key role in the pathogenesis of atherothrombosis, is tightly regulated. The integral membrane protein tetherin/bone marrow stromal antigen-2 (BST-2) regulates membrane organization, altering both lipid and protein distribution within the plasma membrane. Because membrane microdomains have an established role in platelet receptor biology, we sought to characterize the physiological relevance of tetherin/BST-2 in those cells. To characterize the potential importance of tetherin/BST-2 to platelet function, we used tetherin/BST-2-/- murine platelets...

This study probed the differential utilization of P2Y1 and P2Y12 receptors in mobilizing CD62P (P-selectin) from intracellular granules following activation of human platelets with adenosine 5'-diphosphate (ADP, 100 µmol·L-1 ) Platelet-rich plasma (PRP) was prepared from the blood of adult humans. CD62P was measured by flow cytometry following activation of PRP with ADP in the absence and presence of the selective antagonists of P2Y1 and P2Y12 receptors, MRS2500 and PSB0739 (both 0.155-10 µmol·L-1 ), respectively...

Inhibition of either P2Y12 receptor or the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome provides cardioprotective effects. Here, we investigate whether direct NLRP3 inflammasome inhibition exerts additive effects on myocardial protection induced by the P2Y12 receptor antagonist Ticagrelor. Ticagrelor (150 mg/kg) was orally administered to rats for three consecutive days. Then, isolated hearts underwent an ischemia/reperfusion (30 min ischemia/60 min reperfusion; IR) protocol...

Changes in circulating cell populations may promote ischemic events that occur soon after discontinuation of P2Y12 -inhibition. The aim of the study was to track the course of thrombopoietic and erythropoietic cells in patients with coronary artery diseases (CAD) after planned and physician-driven cessation of chronic P2Y12 -inhibition (clopidogrel 75 mg OD, or prasugrel 10 mg OD, or ticagrelor 90 mg BID). Cell fractions were determined in 62 patients at baseline (the last day of P2Y12 -inhibitor intake), on day-10, day-30, and day-180 thereafter...

The ADP receptor P2Y12 , the thromboxane A2 receptor (TXA2 R) and the C-type lectin-like receptor 2 (CLEC-2) mediate platelet activation by different mechanisms. Only little is known about the expression of the receptors in human megakaryopoiesis. Our study aimed to establish a flow cytometry (FC) method for the measurement of P2Y12 , TXA2 R, and CLEC-2 on platelets of healthy donors and to monitor receptor expression in ex vivo megakaryopoiesis. We determined mean fluorescence intensity (MFI) values of FITC, PE, or APC labeled antibodies binding to the receptors on platelets of 90 healthy donors...

BACKGROUND: Reticulated platelets (RP) are the youngest circulating platelets in blood. An increased amount of this subpopulation is associated with higher cardiovascular risk and mortality. OBJECTIVES: It is unknown to what extent intrinsic properties of RP contribute to their hyperreactive features. This study is the first providing a multifactorial approach based on ultrastructural, transcriptional, and functional analysis of RP compared to non-RP sorted by flow cytometry...

The disorders of hemostasis and coagulation were believed to be the main contributors to the pathogenesis of pulmonary thromboembolism (PTE), and platelets are the basic factors regulating hemostasis and coagulation and play important roles in the process of thrombosis. This study investigated the proteome of human umbilical vein endothelial cells (HUVECs) with platelet endothelial aggregation receptor-1 (PEAR1) knockdown using the isobaric tags for relative and absolute quantitation (iTRAQ) method and analyzed the role of differential abundance proteins (DAPs) in the regulation of platelets aggregation...

Platelet hyperaggregation and hypercoagulation are associated with increase of thrombogenic risk, especially in patients with type 2 diabetes (T2D). High activity of P2Y12 receptor is found in T2D patients, exposing such patients to a prothrombotic condition. P2Y12 is a promising target for antiplatelet, but due to P2Y12 receptor constitutive activation, the clinical practical phenomena such as "clopidogrel resistance" are commonly occurring. In this study, we investigate the role of lncRNA on platelet activation...

Platelets have been demonstrated to be vital in cancer epithelial-mesenchymal transition (EMT), an important step in metastasis. Markers of EMT are associated with chemotherapy resistance. However, the association between the development of chemoresistance, EMT, and the contribution of platelets to the process, is still unclear. Here we report that platelets regulate the expression of (1) human equilibrative nucleoside transporter 1 (hENT1) and (2) cytidine deaminase (CDD), markers of gemcitabine resistance in pancreatic cancer...

We investigated whether platelets prime colon cancer cells for metastasis and whether pharmacological inhibition of platelet function may prevent it. Coculturing HT29 human colon carcinoma cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of E-cadherin and upregulation of Twist1, enhanced cell mobility and a proaggregatory action on platelets. These changes were prevented by different antiplatelet agents, aspirin[an inhibitor of cyclooxygenase(COX)-1], DG-041[an antagonist of prostaglandin(PG)E2 EP3 receptor] and ticagrelor (a P2Y12 receptor antagonist)...

Diabetes is an established risk factor for ischemic stroke, but the associated molecular mechanisms remain to be fully elucidated. This study investigated the role of plasma and platelet microRNAs and their targeting proteins in the activation of platelets and their association with the occurrence of ischemic stroke in patients with type 2 diabetes mellitus (T2DM). Results showed that the expressions of platelet and plasma miR-144 and miR-223 were significantly altered in T2DM patients with or without ischemic stroke compared to that in healthy controls, but these changes were more significant in T2DM patients with ischemic stroke...

Platelet membrane receptor glycoprotein IIb/IIIa (gpiibiiia) is a receptor detected on platelets. Adenosine diphosphate (ADP) activates gpiibiiia and P2Y12, causing platelet aggregation and thrombus stabilization during blood loss. Chitosan biomaterials were found to promote surface induced hemostasis and were capable of activating blood coagulation cascades by enhancing platelet aggregation. Our current findings show that the activation of the gpiibiiia complex and the major ADP receptor P2Y12 is required for platelet aggregation to reach hemostasis following the adherence of various concentrations of chitosan biomaterials [7% N,O-carboxymethylchitosan (NO-CMC) with 0...

OBJECTIVE: In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). APPROACH AND RESULTS: Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion...

In this study the role of P2Y12 receptors (P2Y12R) was explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y12R, the majority of P2Y12R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor antagonist PSB-0739 was most potent upon intrathecal application...