Chinese Patent Medicine Liuweiwuling Tablet had Potent Inhibitory Effects on Both Wild-Type and Entecavir-Resistant Hepatitis B Virus (HBV) in vitro and Effectively Suppressed HBV Replication in Mouse Model

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.

Antiviral activities of Polygonum perfoliatum L. extract and related phenolic acid constituents against hepatitis B virus

“…With a long history of wide use in the treatment of viral infections, Chinese herbal formulas, single herbs, and derived natural compounds have been reported to possess antiviral activities 17,21,32 . Among these, single herbs like Phyllanthus urinaria , Salvia Miltiorrhiza , Rheum palmatum , and Sophora flavescens and their derived natural constituents including flavonoids, phenolic acids, oxymatrine, and alkaloids have been reported having anti‐HBV activities 19,33–36 . Our recent study also showed the ethanol extract of Ranunculus japonicus Thunb.…”

“…17,21,32 Among these, single herbs like Phyllanthus urinaria, Salvia Miltiorrhiza, Rheum palmatum, and Sophora flavescens and their derived natural constituents including flavonoids, phenolic acids, oxymatrine, and alkaloids have been reported having anti-HBV activities. 19,[33][34][35][36] Our recent study also showed the ethanol extract of Ranunculus japonicus Thunb. could inhibit HBV replication at multiple steps.…”

Discovery and mechanistic study of Imperatorin that inhibits HBsAg expression and cccDNA transcription

“…Liuweiwuling Tablet has displayed potent inhibitory effects against both wild-type and ETV-resistant HBV in both in vitro and in vivo settings. 35 Maoto, also recognized as Ma Huang Tang, has been reported to suppress HBV production by impeding the incorporation of HBV nucleocapsids into virions. 36 Luteolin-7-O-glucoside, a natural compound isolated from leafy vegetable lettuce, has displayed significant reductions in HBsAg production.…”

Classic mechanisms and experimental models for the anti‐inflammatory effect of traditional Chinese medicine

“…In fact, due to the complexity of Chinese medicine and the inter‐relationship of signaling pathways, TCM, especially Chinese medicine preparations, may affect most of the signaling pathways. Many outstanding studies using omics technology such as transcriptomics, 52 proteomics 53 and metabolomics have revealed the mechanisms of the anti‐inflammatory effects of TCM 54 and show that it is possible that multiple pathways may be involved in these effects.…”