Inhibition of collagen-induced platelet aggregation by Sanggenon N via the Ca²⁺ signaling pathway

Cudrania tricuspidata (C. tricuspidata), a medicinal plant widely employed throughout Asia in ethnomedicine, has various bioactive properties, including antidiabetic, antiobesity, antitumor, and anti-inflammatory activities. In addition, the C. tricuspidata root extract reportedly inhibits platelet aggregation. Therefore, we focused on the active substances present in the C. tricuspidata extract. Sanggenon N (SN) is a flavonoid found in the root bark of C. tricuspidata. In the present study, we examined the inhibitory effects of SN on platelet aggregation, phosphoproteins, thromboxane A 2 generation, and integrin IIb3 activity. SN inhibited collagen-induced human platelet aggregation in a dosedependent manner without cytotoxicity. Furthermore, SN suppressed Ca 2+ mobilization and influx through associated signaling molecules, such as inositol 1, 4, 5-triphosphate receptor I (Ser 1756 ), and extracellular signal-regulated kinase. In addition, SN inhibited thromboxane A 2 generation and associated signaling molecules, including cytosolic phospholipase A 2 and mitogen-activated protein kinase p38. Finally, SN could inhibit integrin (IIb/ 3 ) activity by regulating vasodilator-stimulated phosphoprotein and Akt. Collectively, SN possesses potent antiplatelet effects and is a potential therapeutic drug candidate to prevent platelet-related thrombosis and cardiovascular disease.