Yuan Ningning, Chen Yuchi, Yan Yangtian, Wang Fujing, Xu Xinyao, Wang Mingqing, Diao Jianxin, Xiao Wei
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China.
Heliyon. 2024 Jul 27;10(16):e35234. doi: 10.1016/j.heliyon.2024.e35234. eCollection 2024 Aug 30.
Diabetic nephropathy (DN), a leading cause of end-stage renal disease, remains a formidable challenge in diabetes management due to the complex nature of its pathogenesis, particularly the epithelial-mesenchymal transition (EMT) process. Our innovative study leverages network pharmacology to explore the therapeutic potentials of Myricetin, a natural flavonoid, focusing on its effects against NOX4, a critical mediator in DN progression. This investigation marks a pioneering approach by integrating network pharmacology to predict and elucidate the inhibitory relationship between Myricetin and NOX4. Utilizing a high-fat diet/streptozotocin (HFD/STZ) induced DN mouse model, we delved into the effects of Myricetin on renal EMT processes. Through network pharmacology analyses coupled with molecular docking studies, we identified and confirmed Myricetin's binding efficacy to NOX4. Extensive in vitro and in vivo experiments further established Myricetin's significant impact on mitigating EMT by modulating the NOX4-NF-κB-Snail signaling pathway. Results from our research demonstrated notable improvements in renal function and reductions in tissue fibrosis among treated HFD/STZ mice. By curtailing NOX4 expression, Myricetin effectively reduced reactive oxygen species (ROS) production, thereby inhibiting NF-κB activation and subsequent Snail expression, crucial steps in the EMT pathway. Supported by both theoretical predictions and empirical validations, this study unveils the mechanism underlying Myricetin's modulation of EMT in DN through disrupting the NOX4-NF-κB-Snail axis. These findings not only contribute a new therapeutic avenue for DN treatment but also underscore the utility of network pharmacology in advancing drug discovery processes.
糖尿病肾病（DN）是终末期肾病的主要原因，由于其发病机制复杂，尤其是上皮-间质转化（EMT）过程，在糖尿病管理中仍然是一个巨大的挑战。我们的创新性研究利用网络药理学来探索杨梅素（一种天然黄酮类化合物）的治疗潜力，重点关注其对DN进展中的关键介质NOX4的作用。这项研究通过整合网络药理学来预测和阐明杨梅素与NOX4之间的抑制关系，标志着一种开创性的方法。利用高脂饮食/链脲佐菌素（HFD/STZ）诱导的DN小鼠模型，我们深入研究了杨梅素对肾脏EMT过程的影响。通过网络药理学分析和分子对接研究，我们鉴定并证实了杨梅素与NOX4的结合效力。广泛的体外和体内实验进一步证实了杨梅素通过调节NOX4-NF-κB-Snail信号通路对减轻EMT有显著影响。我们的研究结果表明，治疗后的HFD/STZ小鼠的肾功能有显著改善，组织纤维化减少。通过降低NOX4表达，杨梅素有效减少了活性氧（ROS）的产生，从而抑制了NF-κB的激活和随后的Snail表达，这是EMT途径中的关键步骤。在理论预测和实证验证的支持下，本研究揭示了杨梅素通过破坏NOX4-NF-κB-Snail轴调节DN中EMT的机制。这些发现不仅为DN治疗提供了一条新的治疗途径，也强调了网络药理学在推进药物发现过程中的实用性。
