Andrographolide exerts anti‐hepatitis C virus activity by up‐regulating haeme oxygenase‐1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells

Abstract

BACKGROUND AND PURPOSEThis study aimed to evaluate the anti-hepatitis C virus (HCV) activity of andrographolide, a diterpenoid lactone extracted from Andrographis paniculata, and to identify the signalling pathway involved in its antiviral action. EXPERIMENTAL APPROACHUsing HCV replicon and HCVcc infectious systems, we identified anti-HCV activity of andrographolide by measuring protein and RNA levels. A reporter activity assay was used to determine transcriptional regulation of anti-HCV agents. A specific inhibitor and short hairpin RNAs were used to investigate the mechanism responsible for the effect of andrographolide on HCV replication. KEY RESULTSIn HCV replicon and HCVcc infectious systems, andrographolide time-and dose-dependently suppressed HCV replication. When combined with IFN-α, an inhibitor targeting HCV NS3/4A protease (telaprevir), or NS5B polymerase (PSI-7977), andrographolide exhibited a significant synergistic effect. Andrographolide up-regulated the expression of haeme oxygenase-1 (HO-1), leading to increased amounts of its metabolite biliverdin, which was found to suppress HCV replication by promoting the antiviral IFN responses and inhibiting NS3/4A protease activity. Significantly, these antiviral effects were attenuated by an HO-1-specific inhibitor or HO-1 gene knockdown, indicating that HO-1 contributed to the anti-HCV activity of andrographolide. Andrographolide activated p38 MAPK phosphorylation, which stimulated nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated HO-1 expression, and this was found to be associated with its anti-HCV activity. CONCLUSIONS AND IMPLICATIONSOur results demonstrate that andrographolide has the potential to control HCV replication and suggest that targeting the Nrf2-HO-1 signalling pathway might be a promising strategy for drug development.

Inhibition of andrographolide in RAW 264.7 murine macrophage osteoclastogenesis by downregulating the nuclear factor-kappaB signaling pathway

“…AGP, the major active ingredient of the herbal medicine A. paniculata, has been shown to exert various biological activities, including antitumor (Yang et al, 2014), anti-inflammatory (Ku and Lin, 2013), antiviral (Wen et al, 2014), and hepatoprotective effects (Lee et al, 2014). In this study, we showed that AGP significantly inhibited RANKL-induced osteoclast differentiation from RAW 264.7 murine macrophage cells and decreased the number of osteoclasts and the mRNA expression of TRAP.…”

“…Several studies have demonstrated that AGP exhibits various biological activities, including antitumor (Yang et al, 2014), anti-inflammatory (Ku and Lin, 2013), antiviral (Wen et al, 2014), and hepatoprotective effects (Lee et al, 2014). It has been demonstrated that AGP can attenuate inflammation by inhibiting NF-kappaB activation through covalent modification of the reduced cys62 residue of p50 (Xia et al, 2004).…”

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

“…A. paniculata has long been used as herbal medicine for the prevention and treatment of upper respiratory tract infection in Asian countries and in Scandinavia (14). Andrographolide has been shown to possess various biological activities, including antiviral (15), anticancer (13,16), anti-inflammatory (17,18) and antioxidative (15,19,20) activities.…”

The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection

“…Indeed, this pathway regulates the expression of key antioxidant enzymes that are involved in the neutralization of oxidants generated during viral infections. In addition, the Nrf2 pathway has also been demonstrated to exert antiviral effect against viruses such as hepatitis C virus, respiratory syncytial virus (RSV), and influenza viruses (31)(32)(33)(34)(35). Interestingly, some studies showed that Nrf2 activators, such as sulforaphane and epigallocatechin gallate, significantly decrease influenza virus entry and replication in nasal and alveolar epithelial cells (32,36).…”