基于多维筛选和代谢组学的决明子治疗代谢综合征药效物质及整合作用机制研究

代谢综合征是一组以肥胖、高血糖、血脂代谢异常为主要临床特征的常见慢性综合性疾病，严重影响生活质量、威胁人类健康。决明子具清肝、润肠、通便之功效，是治疗高血脂等代谢性疾病的常用中药。其临床功效确切，使用广泛，但治疗代谢综合征的药效物质基础及整合作用机制尚不明确。本项目拟融合多学科技术手段以“组合拳”策略系统辨识决明子的药效物质组：以血糖、血脂相关的酶为切入点，基于三酶杂化纳米花微反应器-毛细管电泳系统快速辨识酶抑制剂；进一步，基于高速逆流色谱组分敲除技术，结合多种细胞模型评价药效，综合生物信息学整合分析，阐释酶抑制剂活性贡献度，系统获得药效物质组并体外验证。此外，基于非靶向和靶向代谢组学技术系统揭示决明子药效成分群多成分多靶点治疗代谢综合征的作用机制。本项目以期阐释决明子治疗代谢综合征的科学内涵，为决明子的新药创制提供科学依据，为中药药效物质基础及整合作用机制研究提供新思路。

Metabolomic syndrome is common chronic comprehensive diseases characterized by dyslipidemia, insulin resistance, abdominal fat, hypertriglyceridemia etc. It has seriously affected the quality of people’s life and threatened human’s health. Cassiae Semen is a commonly used traditional Chinese medicines with the effect of clearing liver, moistening intestine and relieving constipation. It has been widely used for the treatment of metabolic diseases such as hyperlipidemia with definite clinic effect. However, the effective components and integrated mechanism of Cassiae Semen for the treatment of metabolomic syndrome remain unclear. In this study, we propose a “combination punch” strategy with multi-discipling methods which aiming to resolve the major scientific issue of systematic identification of effective components in traditional Chinese medicines. The strategy starts with developing a fast and efficient three enzyme nanoflower microreactor-electrophoresis-mass spectrometry method to screen α-glucosidase, lipase and α-amylase inhibitors. And then, the contribution of enzyme inhibitors to the whole efficiency is explored with “knocked-out” strategy based on high speed counter-current chromatography and in vitro metabolomic syndrome mode. At last, artificial neural network analysis is applied to acquire the true effective components systematically with in vivo mode validation. In all, the effective components are screened through multi-index and multi-dimension aspect. Furthermore, non-targeted and targeted metabolimics are applied to reveal the effective components combination mechanism of Cassiae Semen for the treatment of metabolomic syndrome. This project would be helpful for the clinical application of Cassiae Semen and new drug development to cure metabolimic syndrome. Moreover, it may provide new idea for investigation of the effective components and mechanism of traditional Chinese medicines.