青钱柳抗2型糖尿病三萜类成分及AMPK/mTOR信号通路介导的作用机制研究

Type 2 diabetes mellitus (T2DM) has become a serious global public health problem, and the currently available anti-type 2 diabetes mellitus (anti-T2DM) drugs still can not meet the needs of clinical treatment. Traditional Chinese medicine (TCM) has accumulated rich experience in the prevention and treatment of T2DM. Cyclocarya paliurus is one of an important TCM commonly used in the treatment of T2DM since long, but its active components showing beneficial effects during this disease as well as their mechanism of action are still not clear. In our previous work, a series of compounds, including eight rare 3,4-seco-dammarane triterpenoids, were isolated from the leaves of C. paliurus (Batal.) Iljinskaja. Among them, some new triterpenoids could significantly activate the AMPK by inhibiting the mTOR signaling pathway. AMPK/mTOR signaling pathway is amongst the key pathways, playing a central sensor role for regulation of energy metabolism at cellular level, which plays critical roles in the occurrence, prevention and treatment of metabolic diseases such as, T2DM and obesity. It has become an important target for the development of anti-T2DM drugs. This project intends to the systematic investigation of triterpenoids from C. paliurus, evaluating their bioactivities on AMPK/mTOR signaling pathway and their molecular mechanism as well leading to discovery of novel lead compounds having good selectivity and lower side effect. We believe that this project will provide innovative approach for research and discovery of anti-T2DM lead compounds from C. paliurus showing good selectivity thus minimizing the side effects, and provide a substance and theory basis for treatment of T2DM

2型糖尿病(T2DM)已成为全球性严重的公共卫生问题，现有的抗T2DM药物仍然不能满足临床治疗的需求。中医药防治糖尿病已经积累了丰富的经验，民间中药青钱柳防治T2DM效果显著，但其活性成分和作用机制仍不明确。本课题组前期对青钱柳的化学成分进行了系统研究，从中分离并鉴定了一系列化合物，包括13个三萜类成分，其中8个新化合物均为罕见的3,4-裂环达玛烷型三萜类化合物。并发现部分新三萜类成分可显著激活AMPK/mTOR信号通路，该通路是细胞能量代谢的关键感受器，是抗T2DM药物研发的重要靶点。基于此，我们拟用该通路进一步对青钱柳叶中的三萜类成分进行深入研究和活性筛选，评价其激活AMPK、抑制mTOR信号通路的生物活性，揭示具体的分子作用机制和靶蛋白。以期从青钱柳中寻找和发现选择性好、毒副作用小的抗T2DM先导化合物，为青钱柳防治T2DM奠定物质理论基础。

随着社会发展和科技的进步，人们生活方式以及膳食结构发生了重大改变，肥胖、糖尿病等代谢性疾病在世界范围内呈现广泛流行趋势，严重危害着人类的健康。特别是2型糖尿病(T2DM)已成为全球性严重的公共卫生问题，现有的抗T2DM药物仍然不能满足临床治疗的需求。中医药防治糖尿病已经积累了丰富的经验，民间中药青钱柳防治T2DM效果显著，但其活性成分和作用机制仍不明确。本课题组对青钱柳的化学成分，特别是三萜类成分进行了系统研究，从中分离，并通过波谱学分析、X-射线单晶衍射分析方法鉴定了61个化合物，包括35个三萜类成分，其中个35三萜类化合物（包括25个3,4-开环的达玛烷型四环三萜，6个齐墩果烷型五环三萜，4个乌苏烷型五环三萜，1个β-粘霉烯醇三萜）；7个黄酮及其苷类衍生物；4个绿原酸类化合物；5个紫罗兰酮类化合物；4个苯丙酸衍生物；此外，还有萘酮、酰胺类生物碱、β-谷甾醇及β-胡萝卜苷。所分离化合物中新化合物共26个，包括新3,4开环达玛烷型四环三萜类化合物22个，新的黄酮苷类化合物1个，新的绿原酸类化合物2个，新的桂皮酸苷衍生物1个。此外，还有12个化合物首次从该植物中发现。并发现部分新三萜类成分可显著激活AMPK/mTOR信号通路，该通路是细胞能量代谢的关键感受器，是抗T2DM药物研发的重要靶点。基于此，我们拟用该通路进一步对青钱柳叶中的三萜类成分进行深入研究和活性筛选，评价其激活AMPK、抑制mTOR信号通路的生物活性，揭示具体的分子作用机制和靶蛋白。以期从青钱柳中寻找和发现选择性好、毒副作用小的抗T2DM先导化合物，为青钱柳防治T2DM奠定物质理论基础。