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

Abstract

Bicyclol, a novel synthetic antihepatitis drug, has been shown to protect against liver injury via various pharmacological activities. The purpose of the current study was to further investigate the protective effect of bicyclol against carbon tetrachloride (CCl 4)-induced acute liver injury (ALI) and its underlying molecular mechanism, particularly autophagic machinery, antioxidative, and anti-inflammatory potentials. Our results found that treatment with bicyclol significantly reduced CCl 4-induced hepatotoxicity by alleviating histopathological liver changes, decreasing the alanine transaminase levels, promoting autophagic flux, attenuating the expression of inflammatory cytokines, and modulating oxidative markers. Furthermore, bicyclol efficiently induced the conversion of LC3 and enhanced the liver expressions of ATG7 and Beclin-1. Meanwhile, bicyclol induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and p62. These protective effects may be mediated by activation of AMP-activated protein kinase and inhibition of mTOR or MAPK signaling pathways. Taken together, our study firstly suggests that bicyclol has protective potential against CCl 4-induced hepatotoxicity, which might be closely associated with induction of autophagy, concomitant anti-oxidative stress, and anti-inflammatory response.

Bicyclol Alleviates Signs of BDL-Induced Cholestasis by Regulating Bile Acids and Autophagy-Mediated HMGB1/p62/Nrf2 Pathway

“…Bicyclol further increased the LC3-II/I ratio, but caused the accumulation of p62, which in turn activated autophagy to provide protection. Although our experiment did not find that bicyclol could change the expression of pro-autophagy protein Beclin-1, previous study has reported that Beclin-1 and Atg7 were up-regulated by bicyclol ( Zhao et al, 2020 ). All these demonstrate that bicyclol can resist the progression of cholestasis liver injury through autophagy.…”

“…In vitro cell experiments, TCA only up-regulated the level of Nrf2 mRNA without significant difference, while bicyclol up-regulated the mRNA and protein levels of Nrf2 and Nqo1 . So, bicyclol also improved liver damage caused by BDL by activating Nrf2 and its downstream targets Nqo1 and Hmox1 , which is consistent with previous studies ( Zhang et al, 2014 ; Zhao et al, 2020 ).…”

“…Bicyclol has been proven to induce autophagy and inhibit cell proliferation through PI3K/AKT and MEK/ERK pathways ( Wang et al, 2016b ). Previous studies in our laboratory have shown that bicyclol can activate Nrf2 to act against CCl 4 induced hepatotoxicity ( Zhao et al, 2020 ). What’s more, Zhen, Yong-Zhan et al have found that BDL-induced liver fibrosis can be significantly attenuated by bicyclol through reversing fibrogenic gene expression ( Zhen et al, 2015 ).…”

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties

“…It was found that an increase in irisin activity is helpful for diminishing oxidative stress against hepatic toxicity and compensating for the increased energy demand, evident from reduced immunoreactivity of irisin in liver responding to benfotiamine (a thiamine pyrophosphate metabolite with antioxidant effect). CCl 4 has been widely used to elicit hepatotoxicity experimentally and characterised by multiple biological facets including lipid peroxidation, oxidative stress, autophagy and ferroptotic cell death (Refs 87, 88). Rabey et al .…”

Efficacy and safety of bicyclol for treating patients with idiosyncratic acute drug‐induced liver injury: A multicenter, randomized, phase II trial

“…Bicyclol, a hepatoprotective and anti-inflammatory drug that has been approved in China since 2001, can inhibit the expression and activity of several inflammatory factors induced by liver injury, relieve oxidative stress, inhibit hepatocyte apoptosis, stabilize hepatocyte plasma membrane, improve mitochondrial function and protect the structure and function of liver nuclear DNA. 22 It has been used in treating the elevation of aminotransferase levels in patients with chronic viral hepatitis. 23 Previous studies indicated that bicyclol might prevent or reduce the occurrence of DILI in patients with tuberculosis (TB).…”