Abstract
Liuweiwuling Tablet (LWWL) is a licensed Chinese patent medicine (approval number: Z20060238) included in the national health insurance for anti-inflammation of chronic HBV infection, whereas its anti-HBV effect remains clarification. The study aimed to clarify its antiviral effect and related mechanisms. HepG2.2.15 cells (wild-type HBV-replicating cells) and HepG2. A64 cells (entecavir-resistant HBV-replicating cells) were used for in vitro test. Hydrodynamic injection-mediated HBV-replicating mouse model was used for in vivo test. Active compounds and related mechanisms for antiviral effect of LWWL were analyzed using network pharmacology and transcriptomics. The inhibition rates of LWWL (0.8 mg/ml) on HBV DNA, HBsAg, and pgRNA were 57.06, 38.55, and 62.49% in HepG2.2.15 cells, and 51.57, 17.57, and 53.88% in HepG2. A64 cells, respectively. LWWL (2 g kg−1 d−1 for 4 weeks)-treated mice had 1.16 log10 IU/mL decrease of serum HBV DNA, and more than 50% decrease of serum HBsAg/HBeAg and hepatic HBsAg/HBcAg. Compared to tenofovir control, LWWL was less effective in suppressing HBV DNA but more effective in suppressing HBV antigens. Thirteen differentially-expressed genes were found in relation to HBV-host interaction and some of them were enriched in interferon (IFN)-β pathway in LWWL-treated HepG2.2.15 cells. CD3+CD4+ T-cell frequency and serum IFN-γ were significantly increased in LWWL-treated mice compared to LWWL-untreated mice. Among 26 compounds with potential anti-HBV effects that were predicted by network pharmacology, four compounds (quercetin, luteolin, wogonin, and kaempferol) were experimentally confirmed to have antiviral potency. In conclusion, LWWL had potent inhibitory effect on both wild-type and entecavir-resistant HBV, which might be associated with increasing IFN-β and IFN-γ production.
Highlights
Hepatitis B virus (HBV) infection can cause chronic hepatitis B (CHB), increase occurrence risk of liver cirrhosis and hepatocellular carcinoma (HCC)
The antiviral effect of LWWL was evaluated on the first, third and fifth days respectively, and it was found that antiviral effect of LWWL was the best on day 5 of the treatment in both cell models (Figures 1B,D)
Because Chinese patent medicine contains multiple active components against multiple targets related to HBV proliferation, they may have a potential superior in playing multitarget synergistic antiviral effects (Liu et al, 2018; Hepatobiliary Specialized Committee of China Association of Chinese Medicine and Liver Diseases Specialized Committee of China Medical Association of Minorities., 2018)
Summary
Hepatitis B virus (HBV) infection can cause chronic hepatitis B (CHB), increase occurrence risk of liver cirrhosis and hepatocellular carcinoma (HCC). Six NAs are licensed in China for the treatment of HBV-related diseases, including lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (LdT), entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF). These antiviral agents have brought great benefit for patients, while a major challenge is that HBV is hardly to be eliminated from patients with chronic HBV infection using current anti-HBV agents. HBV drugresistance and adverse drug reactions (ADRs) are factors influencing therapeutic efficacy. It is still urgent to develop novel efficacious drugs and therapies to improve clinical cure of chronic hepatitis B (Wang et al, 2019; Seo et al, 2020; Helen et al, 2013; Kim et al, 2017)
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