Abstract
gamma-Mangostin (gamma-MN) is one of the abundant xanthones separated from Garcinia mangostana (Clusiaceae) pericarps that has been reported to have varied bioactivities such as neuroprotective, cytotoxic, antihyperglycemic, antioxidant, and anti-inflammation. Yet, its effect on cholestatic liver damage (CLI) has not been investigated. This study explored the protective activity of gamma-MN against alpha-naphthyl isothiocyanate (ANIT)-induced CLI in mice. The results showed that gamma-MN protected against ANIT-induced CLI as indicated by reduced serum levels of hepatic injury parameters (e.g., ALT, AST, gamma-GT, ALP, LDH, bilirubin, and total bile acids). ANIT-induced pathological lesions were improved in gamma-MN pre-treated groups. gamma-MN exerted potent antioxidant effects as it lowered the parameters of lipid peroxidation (4-HNE, PC, and MDA) and intensified the content and activity of antioxidants (TAC, GSH, GSH-Px, GST, and SOD) in the hepatic tissue. Furthermore, gamma-MN enhanced the sig-nalling of Nrf2/HO-1 as it augmented the mRNA expression of Nrf2/downstream genes (HO-1/GCLc/NQO1/ SOD). The binding capacity and the immuno-expression of Nrf2 were also increased. gamma-MN showed anti-inflammatory capacity as it suppressed the activation of NF-kappa B signalling, it decreased mRNA expression and levels of NF-kappa B/TNF-alpha/IL-6 and the immuno-expression of NF-kappa B/TNF-alpha. In addition, gamma-MN inhibited the acti-vation of NLRP3 inflammasome as it lowered the mRNA expression of NLRP3/caspase-1/IL-1 beta along with their levels as well as the immuno-expression of caspase-1/IL-1 beta. gamma-MN also reduced the level of the pyroptotic parameter GSDMD. Collectively, this study demonstrated the potent hepatoprotective potential of gamma-MN against CLI which was linked to its ability to potentiate Nrf2/HO-1 and to offset NF-kappa B/NLRP3/Caspase-1/IL-1 beta/ GSDMD. Hence, gamma-MN may be suggested as a new candidate for cholestatic patients.