Study on the mechanism of quercetin in Sini Decoction Plus Ginseng Soup to inhibit liver cancer and HBV virus replication through CDK1

IF 3.2 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Chemical Biology & Drug Design Pub Date : 2024-06-10 DOI:10.1111/cbdd.14567

Liyuan Hao, Shenghao Li, Guo Chen, Aiyu Nie, Liang Zeng, Zhonghui Xiao, Xiaoyu Hu

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Abstract

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.

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研究四逆汤加人参汤中的槲皮素通过 CDK1 抑制肝癌和 HBV 病毒复制的机制。

背景：探讨四逆汤抗肿瘤和抗病毒的主要活性成分及其作用机制：探讨四逆汤的抗肿瘤和抗病毒主要活性成分及其作用机制：方法：采用网络药理学方法对四逆汤的主要成分进行分析，确定槲皮素为四逆汤的关键活性成分。然后，我们利用 Drugbank、PharmMapper 和 SwissTargetPrediction 数据库获得了槲皮素的靶点。然后，我们利用 Genecards 数据库获得了 HBV 相关肝细胞癌（HBV 相关 HCC）的靶点。此外，利用 GEO 数据库中 HBV 相关 HCC 患者的基因表达谱和 GEPIA 2 数据库中存活率差异最大的基因，确定了槲皮素的潜在靶点。此外，还通过GO、KEGG分析和PPI网络研究了潜在基因的作用机制。利用AUC和生存分析评估细胞周期蛋白依赖性激酶1（CDK1）和CCNB1的诊断和预后价值。最后，在体外验证了槲皮素对 Hep3B 和 HepG2215 细胞增殖以及 CDK1 和 CCNB1 水平的影响。在槲皮素干预 HepG2215 细胞 24 小时和 48 小时后，用 ELISA 检测乙肝表面抗原（HBsAg）和乙肝 e 抗原（HBeAg）的表达水平：结果：确定了SNRS的前10种关键成分，其中槲皮素是最关键的成分。结果：确定了 SNRS 的前 10 种关键成分，其中槲皮素是最关键的成分；确定了 101 个治疗 HBV 相关 HCC 的潜在槲皮素靶点。GO和KEGG显示，101个潜在靶点富集于癌症和细胞周期调控领域。通过Venn分析，CDK1和CCNB1是交叉靶点，可作为槲皮素作用于HBV相关HCC的潜在靶点。此外，CDK1和CCNB1在高危组中表达量高，而OS率低。CDK1和CCNB1的1年、3年和5年曲线下面积（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，槲皮素能抑制 Hep3B 和 HepG2215 细胞的增殖并降低 CDK1 的表达。随着槲皮素和 CDK1 抑制剂干预时间的延长，HepG2215 细胞上清液和细胞中 HBsAg 和 HBeAg 的表达量逐渐下降：结论：槲皮素是抗 HBV 相关 HCC 活性的关键成分，可通过抑制 CDK1 抑制 SNRS 中 HBV 的复制。

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来源期刊

Chemical Biology & Drug Design 医学-生化与分子生物学

CiteScore

5.10

自引率

3.30%

发文量

164

审稿时长

4.4 months

期刊介绍： Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.