Wang Xue, Zhong Zhu-Jun, Chen Peng-Fei, Deng Chao-Fan, Chen Xiao-Mei, Xin Gui-Zhong, Tang Dan
Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering & Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 2100011, China.
J Ethnopharmacol. 2025 Jan 31;340:119158. doi: 10.1016/j.jep.2024.119158. Epub 2024 Nov 27.
The current treatment for diabetic nephropathy (DN) is inadequate, and there is an urgent need for an effective and minimally adverse alternative therapy. Da-Chai-Hu Decoction (DCHD) is a time-honored herbal remedy from Chinese medicine, boasting a legacy spanning more than 1800 years. Clinical observations suggest that it may provide therapeutic benefits for individuals with type 2 diabetes mellitus (T2DM). Nonetheless, the specific advantages of DCHD in relation to DN and the mechanisms through which it operates are still not well understood.
This research aims to investigate whether DCHD can avert renal damage in mice with T2DM and to elucidate the mechanisms by which DCHD combats DN through the integration of metabolomics and network pharmacology.
The beneficial effects of DCHD on DN was initially evaluated using a renal injury model in T2DM mice. Subsequently, untargeted metabolomics analysis was utilized to investigate the potential mechanisms of DCHD against DN. Additionally, UPLC-HR MS/MS was employed to identify the chemical components in DCHD and the absorption components in DCHD-treated plasma. Network pharmacology and our newly proposed function-guided and network-based complementary methodology (FNICM) was utilized to predict the potential pathway of DCHD intervention in DN. Finally, the core pathway was validated through Western blotting analysis and ELISA.
A total of 260 chemical components were detected in DCHD, and 41 absorption components were found in DCHD-treated plasma by UPLC-HR MS/MS for the first time. Additionally, In vivo experiments revealed that DCHD exerts the ability to regulate the disorder in glucose/lipid metabolism and improves kidney dysfunction. Furthermore, a comprehensive analysis utilizing non-targeted urine metabolomics and the FNICM method identified a total of 33 differential metabolites, which were categorized as core metabolites. Lastly, combined FNICM, network pharmacology and experimental pharmacology studies suggest that DCHD may regulate the AGEs/RAGE/AKT pathways in combating DN.
The results indicate that DCHD treats DN through the inhibition of the AGEs/RAGE/AKT pathway and by regulating metabolic profiles.
目前糖尿病肾病（DN）的治疗方法并不充分，迫切需要一种有效且副作用最小的替代疗法。大柴胡汤（DCHD）是一种源自中医的历史悠久的草药方剂，其历史可追溯到1800多年前。临床观察表明，它可能对2型糖尿病（T2DM）患者具有治疗益处。然而，DCHD在DN方面的具体优势及其作用机制仍未得到充分了解。
本研究旨在探讨DCHD是否能预防T2DM小鼠的肾损伤，并通过代谢组学和网络药理学相结合的方法阐明DCHD对抗DN的机制。
首先使用T2DM小鼠的肾损伤模型评估DCHD对DN的有益作用。随后，利用非靶向代谢组学分析研究DCHD抗DN的潜在机制。此外，采用超高效液相色谱-高分辨质谱/质谱（UPLC-HR MS/MS）鉴定DCHD中的化学成分以及DCHD处理血浆中的吸收成分。利用网络药理学和我们新提出的功能导向和基于网络的互补方法（FNICM）预测DCHD干预DN的潜在途径。最后，通过蛋白质印迹分析和酶联免疫吸附测定（ELISA）验证核心途径。
通过UPLC-HR MS/MS首次在DCHD中检测到总共260种化学成分，并在DCHD处理的血浆中发现41种吸收成分。此外，体内实验表明DCHD具有调节糖/脂代谢紊乱的能力，并改善肾功能障碍。此外，利用非靶向尿液代谢组学和FNICM方法进行的综合分析共鉴定出33种差异代谢物，这些代谢物被归类为核心代谢物。最后，结合FNICM、网络药理学和实验药理学研究表明，DCHD在对抗DN时可能调节晚期糖基化终末产物（AGEs）/晚期糖基化终末产物受体（RAGE）/蛋白激酶B（AKT）途径。
结果表明，DCHD通过抑制AGEs/RAGE/AKT途径和调节代谢谱来治疗DN。
