基于“多维谱效关系—目标成分敲出/敲入”策略的萆薢治疗糖尿病肾病有效成分（群）的发现研究

Diabetic nephropathy (DN) is a refractory disease that poses a serious hazard to human health. Currently, safe and effective drugs for treating DN are unavailable. Our preliminary experiment and clinical practice found that Dioscoreae Hypoglaucae Rhizoma (DHR) exhibited strong anti-diabetic nephropathy activity. However, the active ingredient(s) rendering DHR effective against diabetic nephropathy are undefined, indicating an urgent need for further research. Given this need, our group designed a “multi-dimensional spectrum-effect relationship and target composition knockout/knockin” strategy to identify the active compound(s) in DHR. The in vivo fingerprint spectrum of DHR will be established using UPLC-Q/TOF-MS technology. The effects of DHR on indexes related to the core link of diabetic nephropathy will be determined. The multi-dimensional spectrum-effect relationship will be analyzed to calculate the regression coefficient and rate of contribution and identify the compounds in DHR that render it effective against diabetic nephropathy. Changes in efficacy due to knockout or knockin of each specific ingredient will be determined to identify active ingredient(s) in DHR. This project recognizes and explores the holistic nature of traditional Chinese medicine (TCM), and integrates multi-disciplinary technology to mine information on chemical constituents and pharmacological activities of TCMs based on in vivo processes. This project will explain the efficacy of DHR in treating diabetic nephropathy, and provide a scientific foundation for clinical applications, quality control, and innovative drug development based on studies of DHR.

糖尿病肾病（DN）是严重威胁人类健康的难治性疾病，目前缺乏有效的治疗药物。临床实践和预实验表明，治疗“尿浊症”之首药萆薢具有显著的抗DN作用，但其有效成分尚不清楚，亟待进一步研究。鉴于此，本课题拟以萆薢口服后体内过程为切入点，采用UPLC-Q/TOF-MS等技术全面表征萆薢体内化学成分，建立其指纹图谱；针对DN发病核心环节设计多靶细胞的活性评价体系，综合评价萆薢体内成分抗DN的药理活性，并进行多维谱效关系分析，筛选萆薢抗DN的目标成分；以目标成分为核心，分析目标成分敲出、敲入前后萆薢药理活性的变化，发现并确定萆薢抗DN的有效成分（群）。本课题从中医学整体观出发，以中药口服后体内过程为切入点，综合运用多学科技术处理萆薢化学成分信息和药理活性信息，力求阐明萆薢治疗DN的真正药效物质基础，为萆薢的临床应用、质量控制和创新药物开发提供科学依据。

糖尿病肾病（DN）是严重威胁人类健康的难治性疾病，目前缺乏有效的治疗药物。本课题选择治疗“尿浊症”之首药萆薢，探讨其治疗DN有效成分。本课题首先收集不同产地的萆薢药材，表征了萆薢体内外化学成分，建立了指纹图谱数据；针对DN发病核心环节设计了细胞药理模型，获取萆薢治疗DN的药理活性数据；进而对指纹图谱数据和药理活性数据进行多维谱效关系分析，确定其治疗DN的目标成分，发现其治疗DN的有效成分群，并进行了在体验证。力求阐明萆薢治疗DN的真正药效物质基础，为萆薢的临床应用、质量控制和创新药物开发提供科学依据。课题研究过程中发现，粉萆薢中部分皂苷类化合物入血成分较少；而体内药效实验显示，这些皂苷类成分对萆薢治疗糖尿病药效不可或缺，因此推测萆薢治疗糖尿病肾病的成分并非都需要入血后才能发挥药效，鉴于此，本课题在原有计划的基础上增加了萆薢通过影响肠道菌群改善血脂，进而治疗糖尿病肾病的研究，更全面、客观的发现萆薢治疗糖尿病肾病的物质基础。