摘要
基于网络药理学与体内实验探究野菊花(Chrysanthemi Indici Flos,CIF)治疗对乙酰氨基酚(acetaminophen,APAP)所致药物性肝损伤(drug-induced liver injury,DILI)的作用机制。通过网络药理学预测CIF治疗DILI的活性成分、靶点与信号通路,并使用AutoDock Vina 1.1.2分子对接等软件,验证CIF关键活性成分与核心靶点之间的结合能力。最后通过动物实验进行CIF对APAP所致小鼠肝损伤的保护作用及机制研究。网络药理学分析显示CIF主要成分有木犀草素、芹菜素及槲皮素等,其治疗DILI的核心靶点包括丝氨酸/苏氨酸蛋白激酶1(serine/threonine kinase 1,AKT1)及胱天蛋白酶-3(cysteinyl aspartate-specific proteinase-3,Caspase-3)等,且与白细胞介素-17(interleukin-17,IL-17)和肿瘤坏死因子(tumor necrosis factor,TNF)等信号通路密切相关。分子对接结果显示CIF中的主要成分能与Caspase-3、AKT1等核心靶点稳定结合。体内实验结果表明,CIF能够显著降低小鼠血清中丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、乳酸脱氢酶(lactate dehydrogenase,LDH)、总胆红素(total bilirubin,TBIL)、直接胆红素(direct bilirubin,DBIL)及肝组织丙二醛(malondialdehyde,MDA)水平,提高肝组织超氧化物歧化酶(total superoxide dismutase,T-SOD)、谷胱甘肽(glutathione,GSH)水平,显著改善肝组织病理损伤程度、减少炎性细胞浸润,并且明显减少肝细胞凋亡。RT-qPCR结果显示,CIF明显下调DILI小鼠肝组织中Caspase-3、IL-6和IL-1β等基因表达水平。Western blot结果显示,CIF明显上调B细胞淋巴瘤2(B-cell lymphoma 2,BCL-2)蛋白表达水平,同时下调DILI小鼠肝组织中Caspase-3、BCL-2相关X蛋白(BCL-2-associated X protein,BAX)蛋白表达水平,以上结果表明CIF通过抗凋亡作用来减轻APAP诱导的肝损伤,作用机制可能与调节BCL-2/BAX/Caspase-3信号通路有关。
This study investigated the mechanism of Chrysanthemi Indici Flos(CIF)against acetaminophen(APAP)-induced drug-induced liver injury(DILI)through integrated network pharmacology and in vivo experiments.Network pharmacology approaches were employed to predict bioactive components,therapeutic targets,and signaling pathways of CIF against DILI.Molecular docking validation(AutoDock Vina 1.1.2)confirmed binding affinity between key CIF components and core targets.Subsequent animal experiments elucidated the hepatoprotective effects and underlying mechanisms of CIF in APAP-induced liver injury models.Network pharmacology analysis identified luteolin,apigenin,and quercetin as the primary active constituents of CIF.The core therapeutic targets were found to be serine/threonine kinase 1(AKT1)and cysteinyl aspartate-specific proteinase-3(Caspase-3),which are closely associated with interleukin-17(IL-17)and tumor necrosis factor(TNF)signaling pathways.Molecular docking confirmed stable binding interactions between these key CIF components and the core targets(Caspase-3 and AKT1).Animal experiments demonstrated that CIF administration significantly attenuated APAP-induced liver injury,as evidenced by reduced serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH),total bilirubin(TBIL),and direct bilirubin(DBIL),along with decreased hepatic malondialdehyde(MDA)levels.Conversely,CIF enhanced hepatic antioxidant capacity by elevating total superoxide dismutase(T-SOD)and glutathione(GSH)levels.Histopathological analysis revealed that CIF markedly ameliorated liver tissue damage,suppressed inflammatory cell infiltration,and inhibited hepatocyte apoptosis.RT-qPCR analysis revealed that CIF significantly downregulated the expression of Caspase-3,IL-6 and IL-1βgenes in liver tissues of DILI mice.Western blot analysis demonstrated that CIF markedly upregulated B-cell lymphoma 2(BCL-2)protein expression while downregulating Caspase-3 and BCL-2-associated X protein(BAX)levels in the liver tissues of DILI mice.These findings suggest that CIF mitigates APAP-induced liver injury by suppressing apoptosis,potentially through modulation of the BCL-2/BAX/Caspase-3 signaling pathway.
作者
黄训海
丁子瑞
夏子婕
郑思思
姚欣璐
冯天艳
向槿
邓改改
HUANG Xun-hai;DING Zi-rui;XIA Zi-jie;ZHENG Si-si;YAO Xin-lu;FENG Tian-yan;XIANG Jin;DENG Gai-gai(College of Medicine and Health Sciences,China Three Gorges University,Third-grade Pharmacological Laboratory on Traditional Chinese Medicine,Yichang 443002,China;Hospital of Traditional Chinese Medicine,China Three Gorges University,Yichang Hospital of Traditional Chinese Medicine,Yichang 443003,China;Hubei Hengan Fulin Pharm.Inc.,Yichang 443103,China)
出处
《天然产物研究与开发》
北大核心
2026年第1期187-197,共11页
Natural Product Research and Development
基金
宜昌市公立医院改革与高质量发展示范项目中医药科技研发专项(YWGZ24-08)。
