XJ-8, a natural compound isolated from Sanguis draxonis, inhibits platelet function and thrombosis by targeting MAP3K3.
BACKGROUND
Vascular injury initiates rapid platelet activation, which is critical for haemostasis, while it also causes fatal thrombotic diseases, such as myocardial infarction or ischemic stroke.


OBJECTIVES
To study the inhibitory effects and underlying mechanisms of XJ-8, a natural compound isolated from Sanguis draxonis, on platelet activation and thrombosis.


METHODS
The regulatory effects of XJ-8 on the dense granule release, thromboxane A2 (TxA2 ) synthesis, α-granule release, activation of integrin αIIbβ3, and aggregation of platelets induced by multiple agonists were investigated in in vitro experiments. The effects of XJ-8 on bleeding time and FeCl3 -induced carotid artery thrombosis were also evaluated in in vivo experiments. Furthermore, we investigated the underlying mechanisms by which XJ-8 exerted its pharmacological effects.


RESULTS
XJ-8 not only significantly inhibited the dense granule release, TxA2 synthesis, and aggregation of platelets induced by multiple agonists, but also exerted extending effects on bleeding time and therapeutic effects on thrombotic disease. In addition, XJ-8 selectively and moderately inhibited the activity of mitogen-activated protein kinase kinase kinase 3 (MAP3K3) and the activation of signalling pathways downstream MAP3K3, which play important roles in platelet activation.


CONCLUSION
XJ-8 can inhibit platelet function and thrombosis by targeting MAP3K3 and has potential to be developed into a novel therapeutic agent for the treatment of thrombotic diseases.
['Zhu|Zhixiang|Z|https://orcid.org/0000-0002-7476-309X', 'Wang|Lili|L|', 'Guo|Ran|R|', 'Pang|Daoran|D|', 'Wang|Wenxuan|W|', 'Wu|Yan|Y|', 'Wei|Ning|N|', 'Li|Jun|J|', 'Tu|Pengfei|P|']
thrombosis MAP3K3 dense granule release platelet aggregation thromboxane A2 synthesis