经典方剂二至丸补益肝肾的生物学基础研究

The Classical prescriptions in Chinese medicine are the collection of herbal medicine prescriptions, the efficiency of these prescriptions were confirmed by the longterm clinical practice，it’s an important treatment method in traditional Chinese medicine. Each of the prescription contains multiple effective components, which be able to regulate multiple targets through molecular network. Especially, it applies secondary effect via neuro-endocrine pathway. Erzhi pill is one of this class of prescription to tonify the liver-kidney in clinic. Our study is based on the analysis of the chemical compounds; preliminary experiments examined estrogen effect and clinic verified effect of Erzhi pill. We proposed that its estrogen effect is the biological foundation of tonifying liver and kidney. The genomic and non genomic outcome of the estrogen effect will examine on cell lines from target organs of Erzhi pill, such as adrenal gland, prostate, breast, bone, brain and liver. In vivo, the effects of Erzhi pill will examine by using mice models include SAMP6 (Osteoporosis model), SAMP8 (Dementia model), Ovariectomized rat and AR, ER, LDLR,ApoE knockout mice, which mimic the “liver-kidney yin deficiency” degenerative disease. Then the biological mechanism of Erzhi pill will be clinical verified by random clinical trials, which performs through recruiting voluntary “liver-kidney yin deficiency” pre-menopause women with hypertension or osteoporosis. Finally, the biological evidence of Erzhi pill will elucidate to enhance its precision in treating chronic disease and provide scientific foundation of treatment of different disease with the same classical prescription in traditional Chinese medicine theory.

经典方剂是中医治疗疾病的主要手段，其不仅通过多成分、多靶点直接调节靶器官分子网络，也经由神经内分泌间接调节人体网络。本研究以补益肝肾经方二至丸为研究对象，在明确其化学物质、雌雄激素活性及临床疗效工作基础上，围绕 “二至丸类雌雄激素样作用途径是其补益肝肾的生物学基础”假说。采用雌雄性激素直接或间接经由神经内分泌作用的靶器官肾上腺、前列腺、乳腺、骨、脑、肝脏等相关细胞，研究二至丸入血化学成分雌雄激素基因组和非基因组效应；采用在体类似肝肾阴虚证的自然快速老化的SAMP6骨松小鼠、SAMP8痴呆小鼠、去势大鼠以及基因（AR、ER、LDLR、ApoE）敲除小鼠等动物模型，研究二至丸补益肝肾的生物学基础；选择肝肾阴虚型围绝经期高血压或骨质疏松症受试者验证其科学性。整合基础和临床研究结果阐明二至丸治疗肝肾阴虚疾病的生物学基础，提高其治疗慢性病的精准性，也为中医“异病同治”提供科学依据。

经典方剂是中医治疗疾病的主要手段，其不仅通过多成分、多靶点直接调节靶器官分子网络，也经由神经内分泌间接调节人体网络。本课题围绕“二至丸类雌雄激素样作用途径是其补益肝肾的主要生物学基础”的假设，集成中药化学、药物代谢、中药药理学、化学生物学、分子生物学及生物信息学、临床等研究手段，探索二至丸雌雄激素样作用，以及直接或间接经由神经内分泌网络调节相应雌雄激素靶器官，从而达到治疗相应病证。完成二至丸中墨旱莲、女贞子成分分离鉴定、入血成分的定性及药代动力学、二至丸多成分鉴定与真伪鉴别、以及女贞子多成分鉴定与酒蒸炮制前后化学成分转化等研究，首先明确其化学物质基础。随后确认二至丸及入血成分的雌雄激素样活性，阐明了其治疗与雌雄激素相关的骨质疏松、前列腺增生、脂代谢异常、妊娠障碍小鼠子宫内膜容受性及便秘等机制。围绕 “二至丸类雌雄激素样作用途径是其补益肝肾的生物学基础”假说，阐释二至丸补益肝肾的生物学基础。最后完成了二至丸治疗围绝经期综合征、绝经期妇女阴道萎缩（VVA）的RCT临床研究、以及辅助治疗围绝经期和绝经期女性高血压的临床研究。. 整合基础和临床研究结果最终揭示二至丸治疗肝肾阴虚的药效物质和生物学基础，阐明二至丸治疗肝肾阴虚疾病的生物学基础，提高其治疗慢性病的精准性，为临床二至丸治疗慢性病的精准使用提供科学依据；阐明肝肾阴虚证候部分生物学基础，为中医证候生物学基础研究提供研究思路和方法；验证中医“异病同治”理论的科学性。. 共发表标注课题论文24篇，其中SCI收录论文20篇；申请发明专利14项，已授权3项；培养毕业硕、博研究生10名。