Wen Xinnian, Lv Chenghao, Zhou Runze, Wang Yixue, Zhou Xixin, Qin Si
Laboratory of Food Function and Nutrigenomics, College of Food Science and Technology, Hunan Agricultural University, Changsha 410128, China.
College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.
Foods. 2024 Jan 22;13(2):344. doi: 10.3390/foods13020344.
Type 2 diabetes mellitus (T2DM) is a chronic and complex disease, and traditional drugs have many side effects. The active compound dihydromyricetin (DHM), derived from natural plants, has been shown in our previous study to possess the potential for reducing blood glucose levels; however, its precise molecular mechanism remains unclear. In the present study, network pharmacology and transcriptomics were performed to screen the molecular targets and signaling pathways of DHM disturbed associated with T2DM, and the results were partially verified by molecular docking, RT-PCR, and Western blotting at in vivo levels. Firstly, the effect of DHM on blood glucose, lipid profile, and liver oxidative stress in db/db mice was explored and the results showed that DHM could reduce blood glucose and improve oxidative stress in the liver. Secondly, GO analysis based on network pharmacology and transcriptomics results showed that DHM mainly played a significant role in anti-inflammatory, antioxidant, and fatty acid metabolism in biological processes, on lipoprotein and respiratory chain on cell components, and on redox-related enzyme activity, iron ion binding, and glutathione transferase on molecular functional processes. KEGG system analysis results showed that the PI3K-Akt signaling pathway, IL17 signaling pathway, HIF signaling pathway, MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and TNF signaling pathway were typical signaling pathways disturbed by DHM in T2DM. Thirdly, molecular docking results showed that VEGFA, SRC, HIF1A, ESR1, KDR, MMP9, PPARG, and MAPK14 are key target genes, five genes of which were verified by RT-PCR in a dose-dependent manner. Finally, Western blotting results revealed that DHM effectively upregulated the expression of AKT protein and downregulated the expression of MEK protein in the liver of db/db mice. Therefore, our study found that DHM played a therapeutic effect partially by activation of the PI3K/AKT/MAPK signaling pathway. This study establishes the foundation for DHM as a novel therapeutic agent for T2DM. Additionally, it presents a fresh approach to utilizing natural plant extracts for chemoprevention and treatment of T2DM.
2型糖尿病（T2DM）是一种慢性复杂疾病，传统药物有许多副作用。天然植物来源的活性化合物二氢杨梅素（DHM）在我们之前的研究中已显示出具有降低血糖水平的潜力；然而，其确切的分子机制仍不清楚。在本研究中，采用网络药理学和转录组学方法筛选与T2DM相关的DHM干扰的分子靶点和信号通路，并在体内水平通过分子对接、RT-PCR和蛋白质印迹对结果进行了部分验证。首先，探究了DHM对db/db小鼠血糖、血脂谱和肝脏氧化应激的影响，结果表明DHM可降低血糖并改善肝脏氧化应激。其次，基于网络药理学和转录组学结果的基因本体（GO）分析表明，DHM在生物过程中的抗炎、抗氧化和脂肪酸代谢、细胞成分中的脂蛋白和呼吸链以及分子功能过程中的氧化还原相关酶活性、铁离子结合和谷胱甘肽转移酶方面主要发挥显著作用。京都基因与基因组百科全书（KEGG）系统分析结果表明，PI3K-Akt信号通路、IL17信号通路、低氧诱导因子（HIF）信号通路、丝裂原活化蛋白激酶（MAPK）信号通路、糖尿病并发症中的晚期糖基化终末产物-晚期糖基化终末产物受体（AGE-RAGE）信号通路和肿瘤坏死因子（TNF）信号通路是T2DM中受DHM干扰的典型信号通路。第三,分子对接结果表明，血管内皮生长因子A（VEGFA）、肉瘤激酶（SRC）、低氧诱导因子1α（HIF1A）、雌激素受体1（ESR1）、激酶插入结构域受体（KDR）、基质金属蛋白酶9（MMP9）、过氧化物酶体增殖物激活受体γ（PPARG）和丝裂原活化蛋白激酶14（MAPK14）是关键靶基因，其中五个基因通过RT-PCR得到剂量依赖性验证。最后，蛋白质印迹结果显示，DHM可有效上调db/db小鼠肝脏中AKT蛋白的表达并下调MEK蛋白的表达。因此，我们的研究发现DHM部分通过激活PI3K/AKT/MAPK信号通路发挥治疗作用。本研究为DHM作为T2DM的新型治疗药物奠定了基础。此外，它为利用天然植物提取物进行T2DM的化学预防和治疗提供了一种新方法。
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