Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China.
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P.R. China.
Chem Biol Drug Des. 2024 Jun;103(6):e14567. doi: 10.1111/cbdd.14567.
BACKGROUND: To explore the anti-tumor and anti-virus key active ingredients of Sini Decoction Plus Ginseng Soup (SNRS) and their mechanisms. METHODS: The main ingredients of SNRS were analyzed by network pharmacology, and quercetin was identified as the key active ingredient. Then, we obtained the targets of quercetin by using Drugbank, PharmMapper, and SwissTargetPrediction databases. Then, the targets of HBV-related hepatocellular carcinoma (HBV-related HCC) were obtained by using Genecards database. In addition, using the gene expression profiles of HBV-related HCC patients in GEO database and the genes with the greatest survival difference in GEPIA 2 database identified the potential targets of quercetin. In addition, the mechanism of potential genes was studied through GO, KEGG analysis, and PPI network. Using AUC and survival analysis to evaluate the diagnostic and prognostic value of cyclin-dependent kinase 1 (CDK1) and CCNB1. Finally, the effects of quercetin on proliferation of Hep3B and HepG2215 cells and the level of CDK1 and CCNB1 were verified in vitro. ELISA was used to measure the expression levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) after the intervention by quercetin for 24 h and 48 h in HepG2215 cell. RESULTS: The first 10 key ingredients of SNRS were identified, and quercetin was the most key ingredient. The 101 potential quercetin targets were identified for the treatment of HBV-related HCC. GO and KEGG showed that 101 potential target enrichment in cancer and cell cycle regulation. By Venn analysis, CDK1 and CCNB1 were intersection targets, which could be used as potential targets for the action of quercetin on HBV-related HCC. Moreover, the expression of CDK1 and CCNB1 was highly expressed in the high-risk group, while the OS rate was low. The 1-year, 3-year and 5-year area under the curve (AUC) curves of CDK1 and CCNB1 were 0.724, 0.676, 0.622 and 0.745, 0.678, 0.634, respectively. Moreover, experimental results also showed that quercetin inhibited cell proliferation and reduced CDK1 expression in Hep3B and HepG2215 cells. The expressions of HBsAg and HBeAg in HepG2215 cell supernatant and cell gradually decreased with the increase of intervention time of quercetin and CDK1 inhibitor. CONCLUSIONS: Quercetin is a key ingredient of anti-HBV-related HCC activity and inhibits HBV replication in SNRS by inhibiting CDK1.
背景：探讨四逆散加人参汤（SNRS）的抗肿瘤和抗病毒关键活性成分及其作用机制。
方法：采用网络药理学分析 SNRS 的主要成分，鉴定槲皮素为关键活性成分。然后，我们使用 Drugbank、PharmMapper 和 SwissTargetPrediction 数据库获得槲皮素的靶点。然后，使用 Genecards 数据库获得与乙型肝炎相关的肝细胞癌（HBV-related HCC）相关的靶点。此外，使用 GEO 数据库中 HBV 相关 HCC 患者的基因表达谱和 GEPIA2 数据库中生存差异最大的基因，鉴定出槲皮素的潜在靶点。此外，通过 GO、KEGG 分析和 PPI 网络研究潜在基因的机制。使用 AUC 和生存分析评估细胞周期蛋白依赖性激酶 1（CDK1）和细胞周期蛋白 B1（CCNB1）的诊断和预后价值。最后，在体外验证槲皮素对 Hep3B 和 HepG2215 细胞增殖以及 CDK1 和 CCNB1 水平的影响。使用 ELISA 测量在 HepG2215 细胞中干预 24 小时和 48 小时后槲皮素对乙型肝炎表面抗原（HBsAg）和乙型肝炎 e 抗原（HBeAg）表达的影响。
结果：确定了 SNRS 的前 10 种关键成分，槲皮素是最关键的成分。鉴定出 101 种用于治疗 HBV 相关 HCC 的潜在槲皮素靶点。GO 和 KEGG 显示，101 个潜在靶点在癌症和细胞周期调控中富集。通过 Venn 分析，CDK1 和 CCNB1 是交集靶点，可作为槲皮素作用于 HBV 相关 HCC 的潜在靶点。此外，CDK1 和 CCNB1 的表达在高危组中高表达，而 OS 率较低。CDK1 和 CCNB1 的 1 年、3 年和 5 年 AUC 曲线分别为 0.724、0.676、0.622 和 0.745、0.678、0.634。此外，实验结果还表明，槲皮素抑制 Hep3B 和 HepG2215 细胞的增殖，并降低 CDK1 的表达。随着槲皮素和 CDK1 抑制剂干预时间的增加，HepG2215 细胞上清液和细胞中的 HBsAg 和 HBeAg 表达逐渐降低。
结论：槲皮素是 SNRS 抗 HBV 相关 HCC 活性的关键成分，通过抑制 CDK1 抑制 HBV 复制。
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