基于网络药理学探讨藏药久如尼埃日布对血性血隆病及多血症“异病同治”的作用机制

Both Xuelong syndrome and Duoxue disease in Tibetan medicine belong to blood system diseases with high morbidity rates and acute conditions in the Tibetan Plateau，which have the same pathogenesis that is the disorder of "blood" and "long" resulted in bad blood increasing. And the "same treatment for different diseases" is one of the Tibetan medicine treatment means. Our previous studies (funded by the National Science Foundation No.30750006) indicated that: Tibetan classical prescription Jiuruniairibu (Ershiwuwei Yuganzi Wan) could effectively cure Xuelong syndrome with "blood" and Duoxue disease, and the expression of HIF-1 gene, which could regulate EPO and other target genes, was the important biological basis for regulating "blood" and "long". Consequently, the project proposes the hypothesis that "according to affecting HIF-1/ROS/EPO network target path, Tibetan medicine Jiuruniairibu could regulate the disorder of Xuelong syndrome with 'blood' and Duoxue disease, in order to achieve the purpose of the 'same treatment for different diseases'". Taking the micro molecules of ROS, HIF, EPO and so on as a breakthrough point, a target network model of Xuelong syndrome with "blood" and Duoxue disease could be established through searching in TCMSP, OMIM and other databases. Then to analysis the relation between the genes-pathways-diseases, the molecular regulation mechanism of the "same treatment for different diseases" by Jiuruniairibu would be explored, for reveling the scientific connotation of the mechanism of the regulation of "blood" and "long" and the same treatment for Xuelong syndrome with "blood" and Duoxue disease.

藏医血性血隆病和多血症均属于青藏高原地区患病率高、危害严重的血液系统相关疾病，二者病因病机均为“血”“隆”紊乱致坏血增多。“异病同治”是藏医临床治疗手段之一，本课题组前期研究表明（国家自然基金No.30750006）：藏医经典方久如尼埃日布（二十五味余甘子丸）能有效治疗藏医血性血隆病及多血症；HIF-1基因表达调控EPO等靶基因是调节血、隆的重要生物学基础。故本课题提出“藏药久如尼埃日布通过影响HIF-1/ROS/EPO网络靶标通路对血性血隆病和多血症的血、隆紊乱起整体调节作用，达到‘异病同治’目的”的假说，以ROS、HIF、EPO等小分子为切入点，通过搜索TCMSP、OMIM等数据库，构建血性血隆病及多血症相关的靶标网络模型，分析基因-通路-疾病之间的关联，探究藏药久如尼埃日布“异病同治”的分子调控机制，揭示久如尼埃日布调节“血”“隆”机制及对血性血隆病、多血症“异病同治”的科学内涵。

藏医血性血隆病（血瘀性高血压）和多血症均为“血”“隆”紊乱致坏血增多所致疾病，藏医临床以经典方久如尼埃日布（二十五味余甘子丸）能有效治疗藏医血性血隆病及多血症。本研究以网络药理学研究方法，预测到二十五味余甘子治疗两种疾病的共同靶点有TGFB1、HIF1A等36个，治疗两种疾病共同相关通路Type II diabetes mellitus、Tyrosine metabolism等22条，构建了血性血隆病及多血症相关的靶标网络模型，分析了基因-通路-疾病之间的关联。发现二十五味余甘子丸治疗血性血隆病和多血症的化合物以具有抗氧化、增强免疫力、保护心血管等作用为主，相关的靶点主要有以下几类：参与调节血脂血糖有P49841（GSK3B）等，参与抗氧化反应有P11766（ADHX）等，参与机体免疫调节有P63000（RAC1）等，及P00734（F2）参与调节凝血系统、与血栓形成风险增加相关。病机相关的通路主要有：参与代谢系统有Type II diabetes mellitus等，免疫系统有Complement and coagulation cascades等，参与内分泌系统有PPAR signaling pathway等，参与体内信息处理有Neuroactive ligand-receptor interaction等，得到藏药二十五味余甘子丸可能是通过调节体内氧化应激、代谢系统、免疫系统、循环系统及内分泌，并改善体内的炎性反应等途径，对血性血隆病和多血症都具有临床治疗作用。在此研究基础上，本项目尚开展了藏医治疗血隆病（高血压）的临床用药规律，针对血性血隆病与多血症的共同关键病因—坏血对治药物（由临床研究发现）-石榴子进行临床用药规律及药性研究，并研究了血性血隆病与多血症的常见并发症-萨滞布病的临床用药规律分析等，探讨了以血液病变为主的血性血隆病及多血症及萨滞布病在治疗药物方面的相关性。