Abstract
Treatment with direct-acting antivirals (DAAs) cures most patients infected with hepatitis C virus (HCV) in the real world. However, some patients, especially those with the underlying advanced liver disease, have a limited reduction of liver injury after achieving a sustained viral response (SVR). Bicyclol was widely used in clinics for the treatment of a variety of liver injuries but with an unknown mechanism for the treatment of hepatitis C. We investigated the anti-inflammatory effects and mechanisms of bicyclol in HCV-infected hepatocytes and further confirmed the putative results in a mouse hepatitis model induced by the coinjection of polyinosinic-polycytidylic acid [poly (I:C)] and D-galactosamine (D-GalN). The results showed that the activation of nuclear factor kappa B (NF-κB) and the subsequent increase of inflammatory factors were directly induced by HCV infection and were persistent after clearance of the virus in Huh7.5 cells. Bicyclol decreased the activation of NF-κB and the levels of inflammatory factors in HCV-infected hepatocytes by inhibiting the activation of the ROS-MAPK-NF-κB pathway, and the effect was synergistic with DAAs in HCV-infected hepatocytes. Bicyclol attenuated the ROS-MAPK-NF-κB axis via recovering mitochondrial function without a dependence on dihydronicotinamide adenine dinucleotide phosphate oxidase and superoxide dismutases. The anti-inflammatory effects and mechanism of bicyclol were verified in mouse hepatitis induced by the coinjection of poly(I:C)/D-GalN. Bicyclol directly ameliorates the chronic inflammation caused by HCV infection and might be used with DAAs or after DAA therapy for ultimately curing chronic hepatitis C.
Highlights
Hepatitis C, caused by infection of hepatitis C virus (HCV), is a worldwide prevailing disease
To corroborate that the increased inflammatory response was mediated by HCV infection or by the increased inflammatory mediators in the supernatants, we compared the role of infectious HCV (HCV stock or HCV particles obtained by ultracentrifugation), UV-inactivated HCV (HCV-UV), and the virus-free supernatants
The results showed that infectious HCV increased tumor necrosis factor-α (TNF-α), IL-6, and MIP-1β mRNA levels, while the culture supernatants with HCV particle-free or inactivated HCV were unable to show this upregulation (Figure 1C), suggesting that the inflammatory response was exclusively activated by the HCV infection but not the inflammatory mediator in our infectious system
Summary
Hepatitis C, caused by infection of hepatitis C virus (HCV), is a worldwide prevailing disease. Antiviral therapy does not drastically eliminate the liver disease progression, as evidenced by persistent progressive cirrhosis, liver failure, and HCC in a subset of patients who achieved an SVR (Conti et al, 2016; Reig et al, 2016; Jacobson et al, 2017; D’Ambrosio et al, 2018). Beyond merely achieving an SVR, the prevention of subsequent excessive inflammation, concurrently with other therapeutic regimens, is imperative for eliminating hepatitis C (Koike and Miyoshi, 2006; Castello et al, 2010)
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