Li Lingling, Zhan Lianghui, Wu Xiaojun, Jiang Xuechun, Pu Jinbao
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Tongde Hospital of Zhejiang Province, Hangzhou 310014, China.
Mediators Inflamm. 2025 Jan 7;2025:4302130. doi: 10.1155/mi/4302130. eCollection 2025.
This study aims to investigate the mechanism of Diels et Gilg flavonoids (THF) on acute hepatic injury (AHI). First, high-performance liquid chromatography (HPLC) fingerprints were established to obtain the main chemical components of THF. According to the network pharmacology databases, collect active targets of AHI and potential targets. Using interaction targets to construct a protein-protein interaction (PPI) network, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, the affinity between the core targets and the main active ingredients was verified by molecular docking. Next, verified network pharmacology predictions with animal experiments. Mice were treated with THF (20, 40, and 80 mg/kg) for 7 days, and then built an acute liver injury model (lipopolysaccharide [LPS], 10 mg/kg). Detecting the liver biochemical indices, observe the liver pathological changes, and verify the key signaling pathway targets. HPLC showed that the main components of THF were quercetin and kaempferol. Seven active ingredients and 193 potential targets were screened, and 259 disease targets related to acute liver injury, quercetin, and kaempferol may be the main active ingredients in THF. PPI network analysis showed that tumor necrosis factor (TNF), interleukin-6 (IL-6), and tumor protein 53 (TP53) were potential targets of THF for the treatment of AHI. KEGG analysis showed that the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway might be one of the main pathways in the treatment of AHI. The molecular docking results showed that active compounds both have strong binding activity with potential targets in PPI. In vivo experiments showed that THF could reduce the fibrosis and inflammation of liver tissue etc. Meanwhile, it could downregulate the alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP) levels, and the protein expressions of phosphorylated phosphoinositide 3-kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), and the ratio of BCL2-associated X (BAX)/B-cell lymphoma-2 (BCL-2) in the liver tissue of the mice with acute liver injury and upregulate the level of interleukin-10 (IL-10). The treatment of acute liver injury with THF is characterized by multicomponents and multitargets, and its mechanism may be related to the alleviation of the inflammatory response, reduction of apoptosis, and regulation of the PI3K/AKT signaling pathway.
本研究旨在探讨地尔斯和吉尔格黄酮类化合物（THF）对急性肝损伤（AHI）的作用机制。首先，建立高效液相色谱（HPLC）指纹图谱以获取THF的主要化学成分。根据网络药理学数据库，收集AHI的活性靶点和潜在靶点。利用相互作用靶点构建蛋白质-蛋白质相互作用（PPI）网络，随后进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。最后，通过分子对接验证核心靶点与主要活性成分之间的亲和力。接下来，用动物实验验证网络药理学预测结果。将小鼠用THF（20、40和80mg/kg）处理7天，然后建立急性肝损伤模型（脂多糖[LPS]，10mg/kg）。检测肝脏生化指标，观察肝脏病理变化，并验证关键信号通路靶点。HPLC显示THF的主要成分是槲皮素和山奈酚。筛选出7种活性成分和193个潜在靶点，以及259个与急性肝损伤相关的疾病靶点，槲皮素和山奈酚可能是THF中的主要活性成分。PPI网络分析显示，肿瘤坏死因子（TNF）、白细胞介素-6（IL-6）和肿瘤蛋白53（TP53）是THF治疗AHI的潜在靶点。KEGG分析表明，磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）信号通路可能是治疗AHI的主要途径之一。分子对接结果表明，活性化合物与PPI中的潜在靶点均具有较强的结合活性。体内实验表明，THF可减轻肝组织纤维化和炎症等。同时，它可下调急性肝损伤小鼠肝组织中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、IL-6、肿瘤坏死因子α（TNF-α）、C反应蛋白（CRP）水平，以及磷酸化磷脂酰肌醇3-激酶（p-PI3K）、磷酸化蛋白激酶B（p-AKT）的蛋白表达和BCL2相关X蛋白（BAX）/B细胞淋巴瘤-2（BCL-2）的比值，并上调白细胞介素-10（IL-10）水平。THF治疗急性肝损伤具有多成分、多靶点的特点，其机制可能与减轻炎症反应、减少细胞凋亡及调节PI3K/AKT信号通路有关。
