基于化学物质组和代谢组学方法探讨菊三七属降糖植物效应物质基础与作用机理的异同

Recently, some species in plants of Gynura Cass attract many attentions for their use for the prevention and treatment of diabetes mellitus in China. In previous phytochemical reports, the wide presence of flavonoids, terpenes and phenolics was reported among these plants. A variety of research efforts in the past were focused on evaluating total extracts through pharmacological methods or isolating single constituents for single-targeted in vitro bioassay. However, they disregarded the combinatorial role and integrative therapeutic effects of multiple active compounds. The exact composition of hypoglycemic components in Gynura plants is remained to be resolved. In this work, we propose a hypothesis that bioactive components accounting for the similar anti-diabetic efficacy of these Gynura species could be discovered from a combination of their mutual constituents (flavonoids, terpenes and phenolics), by applying a metabolomics strategy to profile the metabolites in typical T2DM mice using HPLC-TOF/MS coupled to partial least square-discriminant analysis. Moreover, the nontargeted metabolomics profiling will reveal the effect of these chemical combinations, with diverse perturbed metabolites being correlated with antidiabetic activities, to discover the novel mechanism of action and related biomarkers. This work helps to offer evidence-based data to answer the key questions of which are real bioactive components for Gynura Cass. plants that could been used for diabetes treatment.

近年来，菊三七属的多种植物在民间被广泛食用，用于防治糖尿病效果显著。前期化学成分的比较研究提示，黄酮、萜类和酚酸类化合物为该属降糖植物的共有显效成分，而药效研究尚停留在单个植物宏观提取物的降糖评价或单一化合物的简单靶点活性筛选，忽略了该属内不同物种间共有显效成分的异同比较和统一评价，造成该属植物降糖药效成分未能全面准确理解。本项目拟以菊三七属中已被证实具有降糖效果的四种植物为研究对象，采用组合比较和代谢组学相结合的研究方法，对其共有显效成分开展针对2型糖尿病模型动物的生物学活性评价，通过对生物样品代谢物的动态分析，结合糖尿病相关生理生化指标，利用多变量相关分析，从中筛选与抗糖尿病疗效密切关联的代谢物靶标和代谢轮廓，并以此为指导追寻与显效成分变化的关联性，解析其确切有效成分（群）及作用机制。同时，项目将考察肝毒性PAs成分在该属植物内的分布规律，并进行体内毒性评价，为其安全利用提供科学依据。

菊三七属的植物多具有降糖效果，黄酮、酚酸和萜类化合物是该属植物普遍存在的化学成分，这些成分是否发挥了抗糖尿病疗效？其效应背后的作用机制也值得深入探究。.本项目在全国范围内收集了菊三七属10个不同种植物资源，基于形态学特性和生物学性状对它们进行了物种鉴别；基于叶绿体基因组进行了系统发育分析，探讨了该属植物不同物种间的亲缘关系。项目还对菊三七属植物普遍所含的共性化学成分——总黄酮、总酚酸和总萜类成分进行了分析比较，完成了菊三七属内不同植物间该些化学物质组成的异同比较；在整体动物水平开展了菊三七属4种代表性植物（红凤菜、白子菜、平卧菊三七、灵菊七）不同化学物质组（总黄酮、总酚酸、总萜）治疗糖尿病生物学活性的统一评价，发现各化学物质组均具有一定的降糖、减重调脂以及抗炎效果，红凤菜总萜对糖尿病小鼠生理各项异常的整体改善作用最为全面。我们结合相关生化指标，采用组合比较和代谢组学相结合的研究方法，进一步构建了菊三七属植物治疗糖尿病的代谢谱轮廓并从中筛选了与抗糖尿病疗效密切关联的代谢物靶标，推测ABC膜转运蛋白调控和花生四烯酸代谢通路是菊三七属植物发挥抗糖尿病疗效的关键通路。.本项目通过探讨菊三七属内不同植物不同化学物质组之间抗糖尿病活性的差异，尝试解决了目前该属植物降糖药效物质基础不明确的问题，并对其可能的作用机制进行了阐释。此外，项目还考察了潜在肝毒性吡咯里西定生物碱成分在该属植物内的分布情况，针对菊三七等代表性植物进行了体内安全性的初步评价，为该属植物安全利用提供了科学依据。