Salidroside alleviates liver inflammation in furan-induced mice by regulating oxidative stress and endoplasmic reticulum stress

Abstract

Furan is a genotoxic and carcinogenic toxicant formed during the food thermal processing. Our previous studies confirmed that salidroside (SAL) displayed excellent protective effects against furan-induced hepatotoxicity and inflammation, whereas the underlying mechanism was still unclear. In the current study, Balb/c mice were divided to the control group (CON), the furan model group (FUR8, 8 mg/kg BW furan for 30 days) and SAL intervention groups (SAL10/20/40, 8 mg/kg BW furan for 30 days + 10/20/40 mg/kg BW SAL from day 16 to day 30). The alleviative effects and the mechanisms of SAL against furan-induced liver inflammation in mice were investigated through oxidative stress (OS) and endoplasmic reticulum stress (ERS). Liver metabonomics data, molecular docking and Western-blotting results implied that SAL suppressed the activity and the high expression of hepatic CYP2E1, and alleviated liver OS induced by furan. Levels of key markers (GRP78, CHOP and Caspase-12) of ERS and proteins in IRE1α pathway of the UPR branch increased by furan were prominently reduced after SAL treatment. Levels of phosphorylated proteins JNK, ERK, p38, IKKα/β, IκB and p65 in MAPK and NF-κB pathways were also suppressed by SAL. We further confirmed that SAL inhibited furan-induced inflammation by reducing the levels of NLRP3, ASC, Cleaved Caspase-1 and IL-1β and decreasing the production of pro-inflammatory cytokines. Our results shed light into the alleviating mechanisms behind furan-induced liver inflammation, and suggested that SAL inhibited OS, ERS and related MAPK and NF-κB pathways and therefore inhibited the NLRP3 inflammasome activation, which may be its potential mechanism of alleviating liver inflammation.

Keywords: Endoplasmic reticulum stress (ERS); Furan; Inflammation; NLRP3 inflammasome; Oxidative stress (OS); Salidroside (SAL).