Inhibition of hepatitis B virus <i>via</i> selective apoptosis modulation by Chinese patent medicine Liuweiwuling Tablet

作者全名：Ge, Fei-Lin; Yang, Yan; Si, Lan-Lan; Li, Yuan-Hua; Cao, Meng-Zhen; Wang, Jun; Bai, Zhao-Fang; Ren, Zhi-Gang; Xiao, Xiao-He; Liu, Yan

作者地址：[Ge, Fei-Lin] Zhengzhou Univ, Affiliated Hosp 1, Dept Chinese Med, State Key Lab Antiviral Drugs, Zhengzhou 450052, Henan, Peoples R China; [Ge, Fei-Lin; Si, Lan-Lan; Li, Yuan-Hua; Cao, Meng-Zhen; Bai, Zhao-Fang; Xiao, Xiao-He; Liu, Yan] Chinese Peoples Liberat Army Gen Hosp, Med Ctr 5, 100 Xisihuan Middle Rd, Beijing 100039, Peoples R China; [Yang, Yan] Chongqing Med Univ, Coll Tradit Chinese Med, Chongqing 400010, Peoples R China; [Wang, Jun] Peking Univ Ditan Teaching Hosp, Beijing Key Lab Emerging Infect Dis, Beijing 100015, Peoples R China; [Ren, Zhi-Gang] Zhengzhou Univ, Affiliated Hosp 1, Dept Infect Dis, State Key Lab Antiviral Drugs, Zhengzhou 450052, Henan, Peoples R China

通信作者：Liu, Y (通讯作者)，Chinese Peoples Liberat Army Gen Hosp, Med Ctr 5, 100 Xisihuan Middle Rd, Beijing 100039, Peoples R China.

来源：WORLD JOURNAL OF GASTROENTEROLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001208044900010

JCR分区：Q1

影响因子：4.3

年份：2024

卷号：30

期号：13

开始页：　

结束页：　

文献类型：Article

关键词：Hepatitis B virus; Chinese patent medicine; Antiviral activity; Antiviral mechanism; Selective apoptosis

摘要：BACKGROUND Liuweiwuling Tablet (LWWL) is a Chinese patent medicine approved for the treatment of chronic inflammation caused by hepatitis B virus (HBV) infection. Previous studies have indicated an anti-HBV effect of LWWL, specifically in terms of antigen inhibition, but the underlying mechanism remains unclear. AIM To investigate the potential mechanism of action of LWWL against HBV. METHODS In vitro experiments utilized three HBV-replicating and three non-HBV-replicating cell lines. The in vivo experiment involved a hydrodynamic injection-mediated mouse model with HBV replication. Transcriptomics and metabolomics were used to investigate the underlying mechanisms of action of LWWL. RESULTS In HepG2.1403F cells, LWWL (0.8 mg/mL) exhibited inhibitory effects on HBV DNA, hepatitis B surface antigen and pregenomic RNA (pgRNA) at rates of 51.36%, 24.74% and 50.74%, respectively. The inhibition rates of LWWL (0.8 mg/mL) on pgRNA/covalently closed circular DNA in HepG2.1403F, HepG2.2.15 and HepG2.A64 cells were 47.78%, 39.51% and 46.74%, respectively. Integration of transcriptomics and metabolomics showed that the anti-HBV effect of LWWL was primarily linked to pathways related to apoptosis (PI3K-AKT, CASP8-CASP3 and P53 pathways). Apoptosis flow analysis revealed that the apoptosis rate in the LWWL-treated group was significantly higher than in the control group (CG) among HBV-replicating cell lines, including HepG2.2.15 (2.92% +/- 1.01% vs 6.68% +/- 2.04%, P < 0.05), HepG2.A64 (4.89% +/- 1.28% vs 8.52% +/- 0.50%, P < 0.05) and HepG2.1403F (3.76% +/- 1.40% vs 7.57% +/- 1.35%, P < 0.05) (CG vs LWWL-treated group). However, there were no significant differences in apoptosis rates between the non-HBV-replicating HepG2 cells (5.04% +/- 0.74% vs 5.51% +/- 1.57%, P > 0.05), L02 cells (5.49% +/- 0.80% vs 5.48% +/- 1.01%, P > 0.05) and LX2 cells (6.29% +/- 1.54% vs 6.29% +/- 0.88%, P > 0.05). TUNEL staining revealed a significantly higher apoptosis rate in the LWWL-treated group than in the CG in the HBV-replicating mouse model, while no noticeable difference in apoptosis rates between the two groups was observed in the non-HBV-replicating mouse model. CONCLUSION Preliminary results suggest that LWWL exerts a potent inhibitory effect on wild-type and drug-resistant HBV, potentially involving selective regulation of apoptosis. These findings offer novel insights into the anti-HBV activities of LWWL and present a novel mechanism for the development of anti-HBV medications.

基金机构：National Natural Science Foundation of China [81930110]; National Funded Postdoctoral Researcher Program of China [GZC20232406]; Henan Province Traditional Chinese Medicine Science Research Project [2023ZY3040]; Henan Province Medical Science and Technology Research Plan Joint Construction Project [LHGJ20230233]; National Key Research and Development Program of China [2022YFC2303103]

基金资助正文：Supported by National Natural Science Foundation of China, No. 81930110; The National Funded Postdoctoral Researcher Program of China, No. GZC20232406; Henan Province Traditional Chinese Medicine Science Research Project, No. 2023ZY3040; Henan Province Medical Science and Technology Research Plan Joint Construction Project, No. LHGJ20230233; and National Key Research and Development Program of China, No. 2022YFC2303103.