附子“毒与效”的多维评价与整合分析研究

The project selects Fuzi (the lateral roots of Aconitum carmichaelii Debx.), a common traditional Chinese medicine with great toxicity, good efficacy, and close toxicity-efficacy relationship, as the research object. The applicant first proposes the research thought of multidimensional evaluation and integrated research on "toxicity and efficacy" of traditional Chinese medicines. Focusing on the same targets of the toxicity and efficacy of Fuzi, the project will establish animal models of combination of diseases and syndromes, target organ models in vitro, and models of target cells, stem cells, and zebra fish. By using modern chemistry and biology techniques, the project will not only study the multiple toxic-pharmacodynamic material bases of Fuzi, but also research the toxic-pharmacodynamic effects, as well as the efficacy-enhancing and toxicity-reducing principles of different chemical portions, different components, and different prescription compatibilities of Fuzi, for different disease status and different levels (including integral, organismal, cellular, molecular levels). Meanwhile, in this project, the high content screening (HCS) and omics methods will be used to research the action targets, intensity, and process, together with the relationships of “time-efficacy-toxicity” and “quality-efficacy-toxicity” of Fuzi. In addition, systematic toxicology and network pharmacology methods will be applied to construct the network of “components-targets-activities” and “components-targets-toxicities” of Fuzi. These results are expected to illuminate the internal mechanisms of “heart failure therapy and cardiotoxicity”, “rheumatic arthralgia therapy and neurotoxicity”, and “pregnant diseases therapy and embryotoxicity” of Fuzi, and reveal the scientific intension of the integration of toxicity and efficacy, which can provide scientific basis for safe and rational use of Fuzi clinically.

本项目选择毒性大、效果好、毒效关系密切的常用中药附子作为研究对象，首次提出中药“毒效”多维评价与整合分析的研究思路，围绕附子毒效共同的靶部位，建立病证结合模型、离体靶器官模型和靶细胞、干细胞、斑马鱼模型；应用化学生物学技术，研究附子的多重“毒效”物质基础，研究附子不同组分、不同成分、不同配伍组合对机体不同病证状态、不同层面（整体、器官、细胞、分子）的毒效作用和增效减毒原理；应用高内涵、组学方法，研究附子的作用靶点、作用强度、作用环节和“时-效-毒”与“量-效-毒”的时空关系；应用系统毒理学、网络药理学方法，构建附子“成分-靶点-活性”网络和“成分-靶点-毒性”网络，阐明附子“治疗心衰与心脏毒性”、“治疗风湿痹痛与神经毒性”、“治疗妊娠疾病与胚胎毒性”的内在机制，揭示附子毒效整合作用的科学内涵，为临床安全合理应用提供科学依据。

本项目选择毒性大、效果好、毒效关系密切的常用中药附子作为研究对象，首次提出了中药“毒-效“多维评价与整合分析的研究思路，围绕附子毒效共同的靶部位，建立了病证结合模型、离体靶器官模型、细胞模型、斑马鱼模型；应用化学生物学技术，研究了附子的多种“毒-效”物质基础，研究了附子不同组分、不同成分、不同配伍组合对机体不同病证状态、不同层面（整体、器官、细胞、分子）的毒效作用和增效减毒原理。取得的显著突破主要包括：（1）全面阐释了附子毒-效物质基础，获得化合物84个，含新化合物19个；并基于组分控制策略建立附子生物碱的HSQC核磁定量新方法，为附子质量控制提供新模式；（2）创建多种病证结合动物模型，为毒效多维评价和整合分析提供可靠工具；（3）从整体-靶器官组织-细胞分子水平，对附子提取物-组分-成分不同层次，进行了心脏、神经和胚胎毒-效评价，阐释了附子毒效物质基础、剂量和机制；（4）获得附子脂溶性生物碱心脏毒作用和水溶性生物碱强心作用的生物标志物，从代谢组学角度揭示附子不同生物碱的毒-效作用及机制；（5）揭示附子—人参和附子—白芍配伍增效减毒的原理，为安全用药提供依据。本项目基本阐明了附子“治疗心衰与心脏毒性”、“治疗风湿痹痛与神经毒性”、“治疗妊娠疾病与胚胎毒性”的科学内涵，共发表学术论文63篇，含SCI 19篇，获四川省科技进步一等奖；培养博士后3名、硕博士研究生20名；项目组获国家自然科学基金优秀青年基金1人、中央组织部青年拔尖人才1人、岐黄学者1人、青年岐黄学者1人。此外，项目组还承担了2020版《中国药典》附子饮片的标准修订；承担国家标准化项目参附注射液标准化建设；受SFDA药品审评中心委托，负责起草了“中药药源性心脏毒性临床评价指导原则”；形成了中药毒理学研究方法和毒效整合分析思路，创立了国家中医药管理局重点培育学科中药毒理学，为有毒中药的多维评价与整合分析提供示范。