基于Nrf2/ARE通路的黎药-高良姜改善IR药效物质基础及机制研究

The discovery of natural regulator of nuclear factor erythroid 2-related factor 2 (Nrf2) / antioxidant response element (ARE) pathways is an effective way to improve the development of insulin resistance (IR). Project group early found the extract of Li medicine - Alpinia officinarum Hance significantly improved the IR and determined the total diphenylheptanes as an effective site. Diphenylheptanes (DHs) in this site may play an active role in the improvement of IR by activating Nrf2. Therefore, We proposed that DHs are the material basis of Alpinia officinarum Hance to improve IR and may play an effect on Nrf2/ARE pathway. Based on the previous work, this project intends to systematically separation and identification of DHs of the effective site and in vitro evaluation of DHs to improve IR and activation of Nrf2/ARE by comprehensively using research methods such as traditional Chinese medicine chemistry, pharmacology and molecular biology. Furthermore, Preferred active DHs are prepared in sufficient amounts and systematically evaluated them in improving IR in vivo. And the molecular mechanism is illustrated by which the active ingredient exerts its effect by activating the Nrf2/ARE pathway. Through the implementation of this project, we will basically clarify the substance basis and mechanism of the efficacy of Alpinia officinarum Hance in improving IR. It provides scientific basis for its in-depth research and development and lays scientific foundations for the formation of drugs with independent intellectual property rights.

核因子E2相关因子2（Nrf2）/抗氧化反应元件（ARE）通路天然调控剂的发现是改善胰岛素抵抗（IR）药物研发的有效途径。课题组前期发现黎药-高良姜提取物改善IR作用显著，并确定总二苯庚烷为有效部位，该部位富含的二苯庚烷类成分（DHs）可能通过激活Nrf2发挥改善IR作用。因此，课题组提出DHs是高良姜改善IR的物质基础且可能作用于Nrf2/ARE通路发挥功效。本项目拟在前期工作基础上，综合运用中药化学、药理学、分子生物学等研究方法，实现有效部位中DHs的系统分离与结构鉴定；体外评价所得成分改善IR及激活Nrf2/ARE的作用；优选活性优的DHs，足量制备；完成优选成分体内改善IR作用的系统评估，并阐释活性成分通过激活Nrf2/ARE通路发挥功效的分子机制。通过本项目的实施，基本阐明高良姜改善IR的药效物质基础和作用机制，为其深入研发提供科学依据，为形成具自主知识产权的药物奠定科学基础。

从中药或民族药物中寻找高效、低毒的 Nrf2/ARE 通路的激活剂对改善胰岛素抵抗药物的发现具有重要意义。课题组前期发现黎药-高良姜提取物改IR作用显著，并确定总二苯庚烷为有效部位，该部位富含的二苯庚烷类成分（DHs）可能通过激活Nrf2发挥改善IR作用。本项目采用现代色谱技术对高良姜中DHs进行了系统的分离和制备，并采用核磁共振和质谱等技术对其结构进行解析；在体外试验中对得到的DHs改善IR 和激活 Nrf2/ARE 的作用进行评价和活性优选，对于活性较强的DHs成分进行足量制备；在体内试验中应用胰岛素抵抗模型db/db小鼠，考察优选化合物对其血液生化指标、脏器病变的影响，评价其改善 IR 的功效；接着采用一系列分子生物学方法探明DHs成分调控 Nrf2/ARE 通路改善 IR 的作用机制。经过系统研究，本项目已明确高良姜中DHs成分对IR的治疗改善作用，并阐明高良姜改善 IR 的药效物质基础和高良姜DHs成分调控Nrf2/ARE通路改善IR的分子机制，为高良姜的深入研发提供科学依据，为形成具自主知识产权的药物奠定科学基础。