Yang Liu,Chunling Wang,Pengfei Wei,Chengzhi Yang,Xiaoyu Cheng,Yinlong Zhang,Guangjun Nie
The severe bleeding complications of long-term antiplatelet therapy limit its broader application in the treatment or prevention of thrombosis-associated diseases. This risk is particularly serious when facing emergency surgeries where rapid restoration of normal platelet function is required. Timely reversal of the effects of antiplatelet agents becomes crucial in such scenarios. Despite the widespread use of clopidogrel and prasugrel for their potent antiplatelet activity, the absence of specific and effective reversal agents remains a notable challenge. The pharmacological activity of clopidogrel and prasugrel is mediated by sulfhydryl-containing active metabolites, which form disulfide bonds with P2Y 12 receptors on the surface of platelets to inhibit their aggregation. Taking advantage of this action mechanism of these “irreversible” antiplatelet drugs, click chemistry-functionalized mesoporous silica (SiO 2 -Mal) nanotraps are fabricated to capture the antiplatelet drugs' active metabolites and restore hemostasis. Subsequently, a comprehensive assessment of the effectiveness and safety of the SiO 2 -Mal nanotraps is conducted using mouse, rabbit, and pig animal models, highlighting their potential application as a functional reversal agent for clinically relevant thienopyridine antiplatelet drugs, believed until now to be irreversible in their inhibition of platelet activity.
Bo Wei,Guo Cheng,Qianqian Bi,Cheng Lu,Qihang Sun,Li Li,Ningting Chen,Miner Hu,Haoran Lu,Xuancheng Xu,Genxiang Mao,Shu Wan,Zhechun Hu,Yan Gu,Jiaxin Zheng,Li Zhao,Xiao Z. Shen,Xiaoli Liu,Peng Shi
Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
危险品化学品经营许可证（带存储）