Bicyclol Attenuates Liver Inflammation Induced by Infection of Hepatitis C Virus via Repressing ROS-Mediated Activation of MAPK/NF-κB Signaling Pathway

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.

Bicyclol Attenuates Acute Liver Injury by Activating Autophagy, Anti-Oxidative and Anti-Inflammatory Capabilities in Mice

“…Bicyclol has been widely used in the clinic to treat patients with chronic HBV infection via interruption of virus replication and improvement of liver function (Zhao and Liu, 2001;Wang and Li, 2006;Liu, 2009). More recently, it was reported that bicyclol effectively suppressed inflammatory response by reversing HCVdisturbed mitochondrial transmembrane potential (Li et al, 2018). Intriguingly, Wang et al also demonstrated that bicyclol exhibited potent anti-proliferative activity in hepatoma cells (Wang et al, 2016).…”

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

“…Inhibition of HCV was likely through upregulation of the glycolipid transfer protein, leading to arrest of viral replication ( 313 ). Furthermore, bicyclol reduced liver inflammation in mice infected by HCV via the suppression of MAPK/NF-κB signaling ( 314 ).…”

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease

“…Natural products were widely reported for the therapy of liver diseases ( Li et al, 2019 ). Bicyclol, a synthetic compound that originated from the Chinese traditional herb Schisandra chinensis , is an approved drug for alleviating liver injuries accompanied by elevated transaminases caused by various etiologies, such as viruses, drugs, alcohol, chemicals, and immunogens ( Liu, 2009 ; Li et al, 2018a ; Li et al, 2018b ). A few studies reported the therapeutic efficacy of bicyclol for NAFLD in clinic ( Li et al, 2020 ) and in animal models ( Zhao et al, 2021 ), though more data are needed to show its clinical benefits and the detailed mechanisms.…”