岭南中药毛冬青萜类成分分离鉴定与成药性机理

Cardio-vascular disease (CVD) has became the first cause of death and of the serious worldwide public health problem, is also threat to the people’s health and social development of our country in recent years. The roots of Ilex pubescens have been widely used as a traditional Chinese herbal medicine for treatment of cardiocerebral and cardiovascular diseases, such as acute myocardial infarction, coronary arterial disease and thromboangiitisobliterans. However, the bioactivities and pharmacological effects and the pharmacokinetic characteristics of Ilex pubescens remain to be elucidated. Our previous studies revealed that hemiterene glucosides from I.pubescens possess potent anti-platelet aggregation activities, triterpene saponins exhibit potent anti-inflammatory and analgesic effects as well as the underlying mechanisms might be associated with inhibition of the elevated expression of COX-2 protein and the overproduction of the proinflammatory cytokines. Accordingly, terpenoids will be isolated by using various column chromatographic technologies and characterized by physical and chemical properties as well as spectroscopic. We will investigate the anti-inflammatory and anti- thrombus effect as well as the mechanisms of terpenoids. Also the mechanisms of absorption, distribution, metabolism and elimination will be investigateed through ADME model. The study of the project will provide substantial scientific supports for developing the safety and effective new anti-CVD agents.

缺血性冠状动脉粥样硬化性心脏病、脑卒中和周围血管病等心脑血管疾病是导致人类死亡的主要病因。岭南中药毛冬青在临床上广泛应用于治疗冠心病、急性心肌梗死、血栓闭塞性脉管炎等疾病，但是，其药效物质基础以及作用机理尚不清晰。我们在前期研究中发现，萜类化合物是毛冬青的主要成分，其中酰化半萜苷具有强大的抗血小板聚集活性，三萜皂苷具有良好的抗炎镇痛活性，初步的研究机理表明三萜皂苷能够选择性的抑制环氧酶-2，以及调整前炎症性细胞因子和抗炎性细胞因子的平衡。因此，本项目拟在前期工作基础上，采用多种色谱方法和波谱技术集中对毛冬青中萜类成分进行分离纯化和结构鉴定，以抗炎和抗血栓为活性指标对萜类成分进行药效学及作用机理评价，采用ADME评价模型对其药代动力学特征及调控机制进行研究，从而系统研究毛冬青中萜类成分的分子结构、作用机制和药代动力学特征，为毛冬青萜类成分在抗炎症性血管疾病药物研究开发中奠定成药性基础。

缺血性冠状动脉粥样硬化性心脏病、脑卒中和周围血管疾病等心脑血管疾病是导致人类死亡的主要病因。岭南中药毛冬青在临床广泛应用于治疗冠心病、急性心肌梗死、血栓闭塞性脉管炎等疾病，但是，其药效物质基础以及作用机理尚不清楚。本项目采用多种色谱方法和波谱技术集中对毛冬青中萜类成分进行分离纯化和结构鉴定，最终从毛冬青根部位分离得到66个化合物，包括40个三萜皂苷类化合物，其中有19个新化合物。以抗炎和心肌细胞保护作用为活性指标对醇提取物和单体化合物进行药效学及作用机理评价，结果表明部分三萜皂苷能明显抑制一氧化氮合成酶和环氧酶-2蛋白的表达，从而表现出较好的抗炎活性。同时，三萜皂苷类成分IP-8和IP-27可以激活PI3K/Akt信号通路，进而促进GSK-3βSer9位磷酸化，该结果预示三萜皂苷类成分可能通过作用线粒体膜蛋白来调控线粒体膜开放，苯丙素类成分pubescenosides B能与Keap1共价结合，进而激活Nrf2/HO-1信号通路，可以促进Nrf2入核，并且诱导下游信号HO-1表达，从而达到心肌保护的目的。采用血药浓度法研究了三萜皂苷类成分ilexpublesnin T在大鼠体内的吸收、分布、代谢和排泄规律。为毛冬青萜类成分在抗炎症性血管疾病药物研究开发中奠定了成药性基础。