Hepatoprotective Effect of Cynarin on Alpha-Naphthyl Isothiocyanate-Induced Cholestatic Liver Injury: Associated Modulation of TXNIP/NLRP3 and HMGB1/NF-κB Signaling Cascades

TL;DR

Cynarin, a plant compound, protects the liver from injury caused by a toxic chemical by reducing inflammation and oxidative stress.

Contribution

This study reveals the novel protective mechanism of cynarin against cholestatic liver injury via modulating specific inflammatory pathways.

Findings

Cynarin reduced liver damage and restored redox balance in mice with cholestatic injury.

Cynarin suppressed key inflammatory markers like TXNIP, NLRP3, and HMGB1/NF-κB pathways.

Cynarin decreased pro-inflammatory cytokines such as IL-1β and IL-18 in hepatic tissue.

Abstract

Background: Cholestatic liver injury (CLI) is characterized by complex pathogenesis; however, oxidative stress-mediated inflammatory response due to bile acid accumulation in the liver is considered a primary cause. Cynarin (CN), an artichoke phytochemical, has demonstrated different biological activities, including antioxidant and anti-inflammatory ones. The current study aimed to explore the potential hepatoprotective effect of CN on CLI induced by alpha-naphthyl isothiocyanate (ANIT) in mice and investigate the possible involved mechanisms. Methods: Mice received CN (25 and 50 mg/kg) for four consecutive days and were challenged with ANIT (75 mg/kg) once on the second day. Liver injury was examined through biochemical determination of liver injury biomarkers and confirmed by histopathological evaluation. Oxidative stress biomarkers and pro-inflammatory cytokines were detected in the hepatic tissue. RT-PCR, Western blotting, and ELISA were applied to address gene and protein expression of potential underlying molecular targets, including thioredoxin-interacting protein (TXNIP), NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and high-mobility group box 1 (HMGB1). Moreover, nuclear factor kappa-B (NF-κB) activation was determined by immunohistochemical analysis. Results: Our findings revealed that CN remarkably ameliorated ANIT-induced hepatic necro-inflammatory changes and biliary duct injury and restored redox balance in the liver. Mechanistically, CN markedly decreased the expression of TXNIP, NLRP3, active caspase-1, gasdermin D N-terminal (GSDMD-N), interleukin (IL)-1β, and IL-18, which were elevated upon ANIT administration. Moreover, CN suppressed ANIT-induced expression of HMGB1 and NF-κB. Conclusions: Our findings suggest that CN has a protective effect against ANIT-induced CLI in mice that is associated with modulation of the TXNIP/NLRP3 and HMGB1/NF-κB signaling cascades.

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