背景:黄芪葛根汤(HGD),其中包括黄芪(AR)和葛根(PR),在中国广泛用于治疗血栓。然而,其在血栓形成治疗中的协同作用机制尚不清楚.
目标:PR给药后,据报道,其主要成分的血浆暴露量较低。在这方面,本研究就黄芪多糖(APS)对葛根素(PUE)口服给药的影响而言,研究了AR对PR抗血栓疗效的影响。
方法:为了评估HGD的协同作用,通过腹腔注射角叉菜胶建立血栓小鼠模型。治疗后,进行了组织病理学观察,和尾部血栓长度的比例,以及血浆APTT,PT,INR,和FIB水平,被检测到。分子对接用于评估可以抑制HMGB1/NF-κB/NLRP3通路的PR成分。还比较了PR和HGD组之间PR成分在大鼠中的药代动力学。此外,APS对溶解度的影响,肠道吸收,并对PUE的药代动力学进行了评价。此外,评估了APS对PUE抗血栓疗效的影响.
结果:在小鼠中,AR增强了PR的抗血栓作用。这种改善的PR效应与异黄酮诱导的HMGB1/NF-κB/NLRP3途径的下调有关。HGD组分相容性产生的协同效应主要是通过改善PR异黄酮的血浆暴露来实现的。具体来说,APS通过自组装纳米粒子的形成增强PUE的水溶性,增加其肠道吸收和口服生物利用度,which,反过来,抑制HMGB1/NF-κB/NLRP3通路,从而提高其抗血栓作用。
结论:我们的发现表明APS改善了PUE的血浆暴露,增强其对HMGB1/NF-κB/NLRP3通路的抑制作用。该机制是HGD相容性在血栓形成治疗中的协同作用的关键方面。
BACKGROUND: Huangqi Gegen decoction (HGD), which comprises Astragali Radix (AR) and Puerariae Radix (PR), is widely used to treat thrombosis in China. However, the mechanism underlying its synergistic effect in thrombosis treatment remains unclear.
OBJECTIVE: Following PR administration, low plasma exposure was reported for its primary ingredients. In this regard, this study examined the effect of AR on PR\'s antithrombotic efficacy with respect to the impact of Astragalus Polysaccharide (APS) on the oral delivery of Puerarin (PUE).
METHODS: To evaluate the synergistic effect of HGD, a thrombus mice model was established via intraperitoneal injection of carrageenan. After treatment, histopathological observations were made, and the proportion of thrombus length in the tail, as well as the plasma APTT, PT, INR, and FIB levels, were detected. Molecular docking was employed to assess the PR ingredients that could inhibit the HMGB1/NF-κB/NLRP3 pathway. The Pharmacokinetics of PR ingredients in rats were also compared between the PR and HGD groups. Moreover, the effect of APS on the solubility, intestinal absorption, and pharmacokinetics of PUE was evaluated. Furthermore, the impact of APS on the antithrombotic efficacy of PUE was assessed.
RESULTS: In mice, AR enhanced the antithrombotic effect of PR. This improved PR effect was associated with isoflavones-induced downregulation of the HMGB1/NF-κB/NLRP3 pathway. The synergistic effect resulting from the compatibility of HGD components was primarily achieved by improving the plasma exposure of PR isoflavones. Specifically, APS enhanced PUE\'s water solubility through the formation of self-assembly Nanoparticles, increasing its intestinal absorption and oral bioavailability, which, in turn, suppressed the HMGB1/NF-κB/NLRP3 pathway, thus improving its antithrombotic effect.
CONCLUSIONS: Our findings revealed that APS improved PUE\'s plasma exposure, enhancing its inhibitory effect on the HMGB1/NF-κB/NLRP3 pathway. This mechanism presents a key aspect of the synergistic effect of HGD compatibility in thrombosis treatment.