Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P2Y(12) receptor antagonists have become a mainstay for the treatment of CVD (cardiovascular diseases). However, they have rarely been evaluated under pathophysiological conditions apart from arterial diseases. We hypothesized interactions between prasugrel and enhanced vWF (von Willebrand Factor) release in a model of systemic inflammation, and compared the pharmacodynamic effects of prasugrel against placebo on agonist-induced platelet aggregation and shear-induced platelet plug formation. A total of 20 healthy male volunteers were enrolled in a double-blind placebo-controlled two-way crossover trial. Each volunteer received either placebo or a 60 mg loading dose of prasugrel 2 h before endotoxin or placebo infusion. Platelet inhibition was measured with MEA (multiple electrode aggregometry), the PFA-100 system and the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay. Prasugrel blunted various platelet aggregation pathways, including those induced by ADP (-81%), AA (arachidonic acid) (-60%), ristocetin (-75%; P<0.001 for all) and, to a lesser degree, collagen or TRAP (thrombin-receptor-activating peptide). Prasugrel decreased shear-induced platelet plug formation, but vWF release during endotoxaemia partly antagonized the inhibitory effect of prasugrel as measured with the PFA-100 system. Endotoxaemia acutely decreased ristocetin and TRAP-induced platelet aggregation, and enhanced ristocetin-induced aggregation after 24 h. Strong in vivo blockade of P2Y(12) inhibits a broad spectrum of platelet aggregation pathways. However, vWF release may reduce prasugrel's effects under high-shear conditions.
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PMID:Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial. 2264 40

Previously, we reported that post-translational modifications (PTMs) of MAGI1, including S741 phosphorylation and K931 de-SUMOylation, both of which are regulated by p90RSK activation, lead to endothelial cell (EC) activation. However, roles for p90RSK and MAGI1-PTMs in regulating EC permeability remain unclear despite MAGI1 being a junctional molecule. Here, we show that thrombin (Thb)-induced EC permeability, detected by the electric cell-substrate impedance sensing (ECIS) based system, was decreased by overexpression of dominant negative p90RSK or a MAGI1-S741A phosphorylation mutant, but was accelerated by overexpression of p90RSK, siRNA-mediated knockdown of magi1, or the MAGI1-K931R SUMOylation mutant. MAGI1 depletion also increased the mRNA and protein expression of the large tumor suppressor kinases 1 and 2 (LATS1/2), which inhibited YAP/TAZ activity and increased EC permeability. Because the endothelial barrier is a critical mediator of tumor hypoxia, we also evaluated the role of p90RSK activation in tumor vessel leakiness by using a relatively low dose of the p90RSK specific inhibitor, FMK-MEA. FMK-MEA significantly inhibited tumor vessel leakiness at a dose that does not affect morphology and growth of tumor vessels in vivo. These results provide novel insights into crucial roles for p90RSK-mediated MAGI1 PTMs and the Hippo pathway in EC permeability, as well as p90RSK activation in tumor vessel leakiness.
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PMID:p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway. 3330 25