%A Gaspar,Renato Simões %A da Silva,Samira Abdalla %A Stapleton,Jennifer %A Fontelles,João Lucas de Lima %A Sousa,Hiran Reis %A Chagas,Vinicyus Teles %A Alsufyani,Shuruq %A Trostchansky,Andrés %A Gibbins,Jonathan M. %A Paes,Antonio Marcus de Andrade %D 2020 %J Frontiers in Pharmacology %C %F %G English %K Syzygium cumini,antithrombotic agents,Platelet,Oxidation-Reduction,Platelet Aggregation Inhibitors,Flavonoid,Myricetin,PDI = protein disulfide isomerase %Q %R 10.3389/fphar.2019.01678 %W %L %M %P %7 %8 2020-January-31 %9 Original Research %+ Renato Simões Gaspar,Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading,United Kingdom,renatosgaspar@gmail.com %+ Renato Simões Gaspar,Laboratory of Experimental Physiology, Department of Physiological Sciences, Federal University of Maranhão,Brazil,renatosgaspar@gmail.com %+ Antonio Marcus de Andrade Paes,Laboratory of Experimental Physiology, Department of Physiological Sciences, Federal University of Maranhão,Brazil,renatosgaspar@gmail.com %# %! Myricetin inhibits PDI and ERp5 %* %< %T Myricetin, the Main Flavonoid in Syzygium cumini Leaf, Is a Novel Inhibitor of Platelet Thiol Isomerases PDI and ERp5 %U https://www.frontiersin.org/articles/10.3389/fphar.2019.01678 %V 10 %0 JOURNAL ARTICLE %@ 1663-9812 %X BackgroundFlavonoids have been characterized as a prominent class of compounds to treat thrombotic diseases through the inhibition of thiol isomerases. Syzygium cumini is a flavonoid-rich medicinal plant that contains myricetin and gallic acid. Little is known about the potential antiplatelet properties of S. cumini and its constituent flavonoids.ObjectiveTo evaluate the antiplatelet effects and mechanism of action of a polyphenol-rich extract (PESc) from S. cumini leaf and its most prevalent polyphenols, myricetin and gallic acid.MethodsPESc, myricetin, and gallic acid were incubated with platelet-rich plasma and washed platelets to assess platelet aggregation and activation. In vitro platelet adhesion and thrombus formation as well as in vivo bleeding time were performed. Finally, myricetin was incubated with recombinant thiol isomerases to assess its potential to bind and inhibit these, while molecular docking studies predicted possible binding sites.ResultsPESc decreased platelet activation and aggregation induced by different agonists. Myricetin exerted potent antiplatelet effects, whereas gallic acid did not. Myricetin reduced the ability of platelets to spread on collagen, form thrombi in vitro without affecting hemostasis in vivo. Fluorescence quenching studies suggested myricetin binds to different thiol isomerases with similar affinity, despite inhibiting only protein disulfide isomerase (PDI) and ERp5 reductase activities. Finally, molecular docking studies suggested myricetin formed non-covalent bonds with PDI and ERp5.ConclusionsPESc and its most abundant flavonoid myricetin strongly inhibit platelet function. Additionally, myricetin is a novel inhibitor of ERp5 and PDI, unveiling a new therapeutic perspective for the treatment of thrombotic disorders.