Metabolomics Coupled with Proteomics Advancing Drug Discovery toward More Agile Development of Targeted Combination Therapies
Metabolomics Coupled with Proteomics Advancing Drug Discovery toward More Agile Development of Targeted Combination Therapies
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DOI：
10.1074/mcp.m112.021683
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发表时间：
2013-05-01
影响因子：
7
通讯作者：
Meng, Xiangcai
中科院分区：
文献类型：
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作者：
Wang, Xijun;Zhang, Aihua;Meng, Xiangcai
为了提高疗效和减少传统中药的副作用，医生经常处方植物物种和/或矿物质的组合，称为配方。不幸的是，大多数这些化合物的工作机制很难确定，因此仍然未知。为了解决目前的生物医学方法的基础上的配方的好处，我们分析了茵陈蒿汤，一个经典的配方，已被证明是临床有效的治疗肝损伤综合征的组成部分。茵陈蒿汤的三个主要成分是青蒿，栀子（Gardenia jasminoids Ellis）和大黄（Rheum Palmatum L.），其主要活性成分分别为6，7-二甲基七叶苷（D）、京尼平苷（G）和大黄酸（R）。为了确定该配方功效的潜在机制，我们使用免疫组织化学、生物化学、代谢组学和蛋白质组学对DGR化合物的治疗效果进行了系统分析。在这里，我们报告说，DGR组合发挥更强大的治疗效果比任何一个或两个三个单独的化合物击中多个目标，在大鼠模型的肝损伤。因此，DGR协同地引起代谢生物标志物的增强的动态变化，通过靶蛋白调节分子网络，具有协同/累加效应，并且激活内在和外在途径。
To enhance the therapeutic efficacy and reduce the adverse effects of traditional Chinese medicine, practitioners often prescribe combinations of plant species and/or minerals, called formulae. Unfortunately, the working mechanisms of most of these compounds are difficult to determine and thus remain unknown. In an attempt to address the benefits of formulae based on current biomedical approaches, we analyzed the components of Yinchenhao Tang, a classical formula that has been shown to be clinically effective for treating hepatic injury syndrome. The three principal components of Yinchenhao Tang are Artemisia annua L., Gardenia jasminoids Ellis, and Rheum Palmatum L., whose major active ingredients are 6,7-dimethylesculetin (D), geniposide (G), and rhein (R), respectively. To determine the mechanisms underlying the efficacy of this formula, we conducted a systematic analysis of the therapeutic effects of the DGR compound using immunohistochemistry, biochemistry, metabolomics, and proteomics. Here, we report that the DGR combination exerts a more robust therapeutic effect than any one or two of the three individual compounds by hitting multiple targets in a rat model of hepatic injury. Thus, DGR synergistically causes intensified dynamic changes in metabolic biomarkers, regulates molecular networks through target proteins, has a synergistic/additive effect, and activates both intrinsic and extrinsic pathways.