Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China.
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, and Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China; Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an 712046, Shaanxi Province, China.
J Pharm Biomed Anal. 2020 Jan 5;177:112837. doi: 10.1016/j.jpba.2019.112837. Epub 2019 Aug 26.
The ambiguity of dose-effect relationship of many traditional Chinese medicines (TCMs) has always influenced their rational use in TCM clinic. Rhubarb, a preferred representative of cathartic TCM, is currently widely used that results in a diversity of its dosage. The aim of this study was to use an integrated metabolomics strategy to simultaneously reveal dose-effect relationship and therapeutic mechanisms of different efficacy of rhubarb in constipation rats. Six doses of rhubarb (0.135, 0.27, 0.81, 1.35, 4.05, and 8.1 g/kg) were examined to elucidate the laxative and fire-purging effects by pathological sections and UPLC-Q-TOF/MS. The results showed that there existed serious lesions in the stomach and colon of model rats. And conditions were basically improved to some extent in rhubarb-treated groups. Through relative distance calculation based on metabolomics score plots, it suggested that the effective dose threshold (EC-EC range) of rhubarb was from 0.31 to 4.5 g/kg (corresponding to 3.44-50.00 g in the clinic) in rat serum and 0.29-2.1 g/kg (corresponding to 3.22-23.33 g in the clinic) in feces. Then, 33 potential biomarkers were identified in total. Functional pathway analysis revealed that the alterations of these biomarkers were associated with 15 metabolic pathways, mainly including arachidonic acid metabolism, glycerophospholipid metabolism, steroid biosynthesis, primary bile acid biosynthesis and sphingolipid metabolism. Of note, different doses of rhubarb could alleviate endogenous disorders to varying degrees through regulating multiple perturbed pathways to the normal state, which might be in a dose-dependent manner and involved in therapeutic mechanisms. To sum up, integrated serum and fecal metabolomics obtained that rhubarb ranging from 0.31 to 2.1 g/kg is safe and effective for constipation treatment. Also, our findings showed that the robust metabolomics techniques would be promising to be more accurately used in the dose-effect studies of complex TCM, and to clarify syndrome pathogenesis and action mechanisms in Chinese medicine.
大黄作为泻下类中药的代表，目前临床应用广泛，导致其剂量多样化。本研究采用整合代谢组学策略，同时揭示不同剂量大黄治疗便秘大鼠的量效关系和作用机制。考察了 6 个剂量的大黄（0.135、0.27、0.81、1.35、4.05 和 8.1 g/kg），通过病理切片和 UPLC-Q-TOF/MS 阐明泻下和泻火作用。结果表明，模型大鼠胃和结肠存在严重病变，大黄处理组的情况在一定程度上有所改善。基于代谢组学得分图的相对距离计算表明，大黄在大鼠血清中的有效剂量阈值（EC-EC 范围）为 0.31-4.5 g/kg（对应临床剂量 3.44-50.00 g），在粪便中的有效剂量阈值为 0.29-2.1 g/kg（对应临床剂量 3.22-23.33 g）。然后，共鉴定出 33 个潜在生物标志物。功能途径分析表明，这些生物标志物的变化与 15 条代谢途径有关，主要包括花生四烯酸代谢、甘油磷脂代谢、类固醇生物合成、初级胆汁酸生物合成和鞘脂代谢。值得注意的是，不同剂量的大黄可以通过调节多个受干扰的途径恢复正常状态，从而在一定程度上缓解内源性紊乱，这可能与剂量依赖有关，并涉及治疗机制。总之，整合血清和粪便代谢组学研究表明，大黄剂量在 0.31-2.1 g/kg 范围内治疗便秘安全有效。本研究还表明，强大的代谢组学技术有望更准确地应用于复杂中药的量效研究，阐明中医证候发病机制和作用机制。
