orin Hydrate (3,five,7,two ,four -pentahydroxyflavone) is a polyphenol compound that has been extensively studied for various pharmacological activities in several human disorders, with slight unwanted side effects. Morin hydrate crucially inhibits platelet activation by way of inhibition from the PLC2-PKC cascade and subsequent suppression of Akt and MAPK activation. Moreover, morin hydrate substantially enhanced the occlusion time of thrombotic platelet plug formation but didn’t have an ADAM8 Compound effect on the bleeding time in mice [94]. five.six. Shear Stress-Induced Platelet Aggregation SIPA, which happens below abnormally high shear anxiety, plays a crucial role in the improvement of arterial thrombotic ailments. Of note, SIPA is often a promising target to overcome bleeding considering that SIPA happens only below pathological conditions. In isolated human platelets, protocatechuic acid (PCA) decreased SIPA. Antithrombotic effects of PCA have been confirmed in vivo inside a rat arterial thrombosis model, exactly where PCA drastically delayed the arterial occlusion induced by FeCl3 . Of note, PCA didn’t enhance bleeding instances in a rat tail transection model [95]. The effects of paeoniflorin showed inhibition of SIPA and considerably prevented arterial thrombosis in vivo devoid of prolonging bleeding time or blood clotting time in rats [96]. Cyanidin-3-glucoside inhibits human platelet activation, aggrega-Int. J. Mol. Sci. 2021, 22,7 oftion, and secretion and downregulates the collagen-GPVI signaling pathway and thrombus formation (each venous and arterial shear stresses) with out prolonging the bleeding time in mice [97]. Delphinidin-3-glucoside lowered thrombus growth in human and murine blood in perfusion chambers at both low and higher shear rates, and no considerable difference in tail bleeding occasions was observed [98]. The antiplatelet action of tetramethylpyrazine was selective by inhibiting the platelet thrombus formation under higher shear prices [99]. Thrombosis, chronic inflammation, and fibrosis are in the finish of your pathological interactions of 5-HT1 Receptor list activated endothelium, neutrophils, and platelets [100]. Either pure or food-derived polyphenols happen to be reported to lower endothelial dysfunction and endothelial cell activation in vitro, ex vivo, and in animal models of endothelial dysfunction by decreasing oxidant production. Consequently, polyphenols reduce the interaction of platelets with activated endothelial cells by increasing the availability of nitric oxide, thus stopping platelet aggregation [101]. The impact of every bioactive compound on bleeding time is described in Table 1. The examples presented above exert their antiplatelet activities through the additive, cooperative, or synergic action from the bioactive compounds present in plants’ or fruits’ extracts (Figure 1).Figure 1. Antiplatelet targets of bioactive compounds with no bleeding danger. In red lines: inhibition, black arrows: activation. DHM: dihydromyricetin, PCA: protocatechuic acid. SQL: tripeptide H-Ser-Gln-Leu-OH.Int. J. Mol. Sci. 2021, 22,8 ofTable 1. Antiplatelet compounds without rising bleeding timepound Natural Sources Myricetin (from Syzygium cumini leaf) Syzygium cumini (L.) As quercitrin (3-rhamnoside) in numerous fruit and vegetables: apples, honey, raspberries, onions, red grapes, cherries, citrus fruits Effects and Proposed Mechanisms Inhibition of aggregation induced by collagen or TRAP-6 Inhibition of fibrinogen binding and alpha-granule secretion induced by CRP The mechanism entails PDI inhibition Impaired CRP-induced