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Marine Natural Products for Human Health Care
Published in Hafiz Ansar Rasul Suleria, Megh R. Goyal, Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
Significant discoveries have resulted in drugs from marine organisms against CVD [279]. Activation of thrombin receptor plays a key role in arterial thrombosis and atherosclerosis [45]. Atherosclerosis begins with damage of endothelium and ensuing deposition of fats, cholesterol, platelets, cellular waste products, calcium, and other substances on the arterial wall [272]. Studies show that halichlorine from sponge (Halichondria okadai) inhibits the vascular cell adhesion molecule 1 expression [162]. Two polysaccharides isolated from sea cucumber (a fucosylated chondroitin sulfate and a sulfated fucan) showed anti-thrombic activity [143, 199].
The Acute Phase Response: An Overview
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Irving Kushner, Andrzej Mackiewicz
Other cofactors have been studied less extensively. Insulin has been found to modulate APP production, interacting with cytokines and dexamethasone in a complex fashion.68,69 Thrombin had a synergistic effect on the induction of plasminogen-activator inhibitor type 1 by TGFβ,49 a finding of considerable interest since thrombin receptors have been identified on eukaryotic cells.70 Finally, histamine was found to potentiate the induction of C3 by IL-6 in mouse hepatocytes,71 a somewhat surprising finding in view of the downregulatory effect of histamine on IL-6 binding in Hep G2 cells.72
Laboratory coagulation assays
Published in John Edward Boland, David W. M. Muller, Interventional Cardiology and Cardiac Catheterisation, 2019
The tests available in the Multiplate system are: ADPtest. Measures platelet aggregation in the presence of adenosine diphosphate (ADP). Sensitive to ADP receptor defects and P2Y12 inhibitors such as clopiodgrel and prasugrel.ADPtest HS. A high-sensitivity measure of the ADP P2Y12 pathway through addition of prostaglandin E2.ASPItest. Measures platelet aggregation in the presence of arachidonic acid. Sensitive to aspirin.TRAPtest. Measures platelet aggregation in the presence of a thrombin receptor activating peptide (platelet PAR1 thrombin receptor). Antiplatelet agents such as aspirin and clopidogrel have little effect on this assay.COLtest. Measures platelet aggregation in the presence of collagen. Sensitive to collagen receptor defects.RISTOtest high and low. Measures platelet aggregation/agglutination in the presence of high and low concentrations of ristocetin. Used to diagnose von Willebrand disease.
Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation
Published in Expert Opinion on Therapeutic Targets, 2023
Yanjie Huang, Xueru Zhao, Qiushuang Zhang, Xiaoqing Yang, Gailing Hou, Chaoqun Peng, Mengzhen Jia, Li Zhou, Tatsuo Yamamoto, Jian Zheng
Protease-activated receptors consist of four members (PAR-1, −2, −3, and −4) [48]. PAR-1 and PAR-2 are the most abundant receptors and have been shown to be expressed in kidney vascular and tubular cells. PAR-1, also known as thrombin receptor, is the main receptor for thrombin. It is abundantly expressed in the kidneys of humans and rodents [49]. Under pathological conditions, thrombin can participate in the proliferation and inflammation of kidney cells in various kidney diseases by activating PAR-1 [50]. In 2019, it was demonstrated that high concentrations of thrombin could increase the expression level of PAR-1 [51]. In vivo, compared with those in wild-type mice, PAR-1 deficiency remarkably reduced the formation of glomerular crescent lesions, T cell and macrophage infiltration, and fibrin deposition [50,52], indicating that PAR-1 was involved in the formation of glomerular crescents. Vorapaxar can selectively antagonize PAR-1 and was approved by both the Food and Drug Administration and the European Medicines Agency as an add-on therapy for secondary prevention in patients with a history of acute myocardial infarction or peripheral artery disease. It can inhibit thrombin-induced platelet activation and has been approved for cardiovascular diseases by reducing thrombotic cardiovascular events [53,54]. Currently, it has been reported to reduce fibrosis and protect renal function during unilateral ureteral obstruction and acute kidney injury -to-chronic kidney disease [49]; however, its function in CrGN has not yet been reported.
An optimized agonist peptide of protease-activated receptor 4 and its use in a validated platelet-aggregation assay
Published in Platelets, 2022
Jing Yang, Claudio Mapelli, Zhaoqing Wang, Chi Shing Sum, Ji Hua, R. Michael Lawrence, Yan Ni, Dietmar A. Seiffert
In the past two decades, platelet thrombin receptors have become new targets for pharmaceutical research [1,2]. Human platelets express two distinct G-protein coupled thrombin receptors: protease-activated receptor-1 (PAR1) and protease-activated receptor-4 (PAR4) [3,4]. PAR1 and PAR4 mediate early and late-stage thrombin actions on human platelets, respectively, and thus are believed to differ in their roles in hemostasis and thrombosis [2,5,6]. In 2014, an orally active PAR1 antagonist, vorapaxar, was approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. However, similar to other current antiplatelet agents, vorapaxar treatment caused an increased risk of bleeding, thereby limiting its clinical utility [7,8,9]. There remains a critical need to discover and develop new antiplatelet agents that can achieve efficacy with a reduced bleeding risk compared with currently marketed antiplatelet agents.
New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans
Published in Platelets, 2022
Samira Merali, Zhaoqing Wang, Charles Frost, Mario Callejo, Michael Hedrick, Lester Hui, Stephanie Meadows Shropshire, Ke Xu, Michel Bouvier, Mary M. DeSouza, Jing Yang
Thrombin, the most potent platelet activator, may play a major role in atherothrombosis. Thrombin activates human platelets via proteolytic cleavage of two distinct G-protein-coupled receptors called protease-activated receptor 1 and 4 (PAR1 and PAR4) [4]. The high-affinity thrombin receptor PAR1 is the target of the antiplatelet agent vorapaxar, which has efficacy in reducing thrombotic events in patients with a history of myocardial infarction or with peripheral arterial disease [5]. In patients with history of myocardial infarction, vorapaxar showed 20% reduction in the combined endpoint of cardiovascular death, myocardial infarction, or stroke compared with placebo [6]. However, vorapaxar increased the risk of bleeding, including intracranial hemorrhage and fatal bleeding [5,6]. Vorapaxar, when added to standard of care in patients with acute coronary syndrome, was associated with increased bleeding risk while failing to provide additional benefit on the primary efficacy endpoint of recurrent ischemic cardiovascular events [7]. To identify an agent that could further improve clinical outcome without added bleeding risk, we sought to target PAR4, a low-affinity thrombin receptor believed to mediate a late stage of platelet activation, contributing to occlusive thrombus formation but playing a lesser role in primary hemostasis [8].