Shi Pengyan, Chen Xiaoying, Cao Jiangtao, Feng Zhe, Xue Boyu
The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
Tai'an Hospital of Traditional Chinese Medicine, Tai'an 271000, Shandong, China.
Comb Chem High Throughput Screen. 2024 Sep 6. doi: 10.2174/0113862073344422240906051007.
INTRODUCTION/OBJECTIVE: The incidence of metabolic-associated fatty liver disease (MAFLD) increases annually. Modified Zexie Decoction (MZXD) can treat this disease; however, their mechanisms of action are uncertain. This study evaluated the mechanisms of MZXD against MAFLD based on network pharmacology, molecular docking, and in vivo experiments.
The main active compounds, targets and signaling pathways of MZXD against MAFLD were obtained using network pharmacological analysis. Underlying mechanisms were validated by molecular docking and in vivo assays.
Forty-one active ingredients and 197 intersection targets were identified. The main active ingredients include quercetin, luteolin, isorhamnetin, 3-methylhexane, and 3β- acetoxyatractylone. The main targets were TP53, JUN, HSP90AA1, MAPK1, MAPK3, AKT1, NF-κB p65, TNF, ESR1, FOS, and IL-6. The pathway enrichment analysis indicated that MZXD was related to the IL-17, TNF, and PI3K-AKT signaling pathways. Molecular docking suggested that these active ingredients bound strongly to TNF, IL-6, and NF-κB p65, which are integral components of the TNF pathway. In the rat MAFLD model, MZXD attenuated high-fat diet( HFD)-induced liver injury and lipid accumulation, decreased the serum levels of the inflammatory mediators TNF-α, IL6, and IL-1β, and inhibited the protein expression of TNF-α, IL6, p- IKB-α and p-NF-κB p65. Furthermore, immunohistochemistry results showed that MZXD attenuated the F4/80 staining intensity of the liver compared with the model group.
Collectively, our results suggested that MZXD could improve MAFLD by downregulating TNF/NF-κB signaling mediated macrophage activation.
引言/目的：代谢相关脂肪性肝病（MAFLD）的发病率逐年上升。加味泽泻汤（MZXD）可治疗该病，但其作用机制尚不明确。本研究基于网络药理学、分子对接和体内实验评估MZXD治疗MAFLD的机制。
采用网络药理学分析方法获取MZXD治疗MAFLD的主要活性成分、靶点和信号通路。通过分子对接和体内实验验证潜在机制。
鉴定出41种活性成分和197个交集靶点。主要活性成分包括槲皮素、木犀草素、异鼠李素、3-甲基己烷和3β-乙酰氧基苍术酮。主要靶点有TP53、JUN、HSP90AA1、MAPK1、MAPK3、AKT1、NF-κB p65、TNF、ESR1、FOS和IL-6。通路富集分析表明，MZXD与IL-17、TNF和PI3K-AKT信号通路相关。分子对接表明，这些活性成分与TNF、IL-6和NF-κB p65紧密结合，它们是TNF通路的重要组成部分。在大鼠MAFLD模型中，MZXD减轻了高脂饮食（HFD）诱导的肝损伤和脂质蓄积，降低了炎症介质TNF-α、IL-6和IL-1β的血清水平，并抑制了TNF-α、IL-6、p-IκB-α和p-NF-κB p65的蛋白表达。此外，免疫组化结果显示，与模型组相比，MZXD减轻了肝脏的F4/80染色强度。
总体而言，我们的结果表明，MZXD可通过下调TNF/NF-κB信号介导的巨噬细胞活化来改善MAFLD。
