从内皮细胞Nrf2-ARE调控网络鉴定真武汤对CRCS的作用靶点及组方优化

Chronic reno-cardiac syndrome (CRCS) showed irreversible progression, limited treatment and poor prognosis. Vascular endothelial cells (EC) injury may play an important role in process of initiation and promotion. Previous studies shown that Zhenwu Decoction can delay the progress of CRCS, and our pre-experiment found that the mechanism involves Nrf2-ARE signaling, However, due to complex mechanism, it is difficult to screen active ingredients and targets. In this study, we have established a strategy for target-component prediction, the potential targets were predicted and verified by RNA-Seq technology and knockout / knockin database. The active components were identified by UPLC-MS / MS. Mechine learning Model and molecular docking were used for predicting drug-target relationships, which were further validated in vivo. Now we aimed to construct the component-target network and further optimize Zhenwu Decoction. Through high-throughput screening, computer modeling and bioinformatics integration, we can identify the mechanism of CRCS progress and the effective substance of Zhenwu based on the Nrf2-ARE network, and provide a new research strategy for optimization of traditional Chinese medicine prescription.

尿毒症相关心衰（CRCS）呈不可逆进行性发展，治疗方法有限，预后不良，EC损伤可能是其重要的启动和促进因素。研究显示真武汤具有保护心肾功能、延缓CRCS进展的作用，预实验发现作用机制涉及EC中Nrf2-ARE作用原件，但由于组方成分和信号调节网络复杂，难以找到确切的物质基础，无法进一步对组方进行标准化和优化。本研究基于我们前期建立的组方靶点-成分预测策略，应用RNA-Seq技术和敲除/过表达数据库预测可能靶点并验证；采用UPLC-MS/MS技术结合数据库明确活性成分；通过机器学习联合分子对接预测药靶关系并验证。本研究通过建活性成分-靶点网络，筛选活性成分群，完成组方优化；最后在转基因动物模型上验证，以期借助高通量筛选、计算机模拟及生物信息技术整合，基于EC中Nrf2-ARE调控网络揭示CRCS进展的内在机制与真武汤的有效物质，为中药复方作用机制的阐明和优化提供新的研究策略。

尿毒症相关心衰（CRCS）呈不可逆进行性发展，治疗方法有限，预后不良，EC损伤可能是其重要的启动和促进因素。研究显示真武汤具有保护心肾功能、延缓CRCS进展的作用，但由于组方成分和信号调节网络复杂，难以找到确切的物质基础，无法进一步对组方进行标准化和优化。本研究基于我们前期建立的组方靶点-成分预测策略，应用RNA-Seq技术和敲除/过表达数据库预测可能靶点并验证；采用UPLC-MS/MS技术结合数据库明确活性成分；通过机器学习联合分子对接预测药靶关系并验证。真武汤减轻5/6肾切除小鼠心功能不全和内皮损伤，其机制可能与炎症过程和氧化应激有关。Nrf2信号通路的激活被预测为真武汤保护内皮细胞的潜在靶点。通过我们的机器学习策略，我们发现真武汤中含有芍药新苷，通过阻断Keap1和激活Nrf2减轻IS诱导的内皮细胞损伤。本研究借助高通量筛选、计算机模拟及生物信息技术整合，基于EC中Nrf2调控网络揭示CRCS进展的内在机制与真武汤的有效物质，为中药复方作用机制的阐明和优化提供新的研究策略。