| Objective:Calorie restriction (CR), which means reducing daily calorie intake without malnutrition, can prolong lifespan and improve health, but the promotion of CR among general population is difficult to achieve because of the sustained strong hunger. In recent years, some scholars have used chemical reagents to mimic the protective benefits of CR via modulating the key regulatory targets of CR, which have promising effects and were termed CR mimetic (CRM). The glycolysis inhibitor 2-deoxyglucose (2-DG) was a representative CRM. The purpose of this study was to investigate the potential effects of 2-DG on deadly acute liver injury induced by the lipopolysaccharide/D-galactosamine (LPS/D-Gal) in mice and the underlying mechanisms.Methods:Acute liver injury was induced in BALB/c mice with intraperitoneal injection of LPS/D-Gal (10μg/kg/700μg/kg). To evaluate the potential pharmacological various dose of 2-DG or vehicle were administered 0.5 h prior to LPS/D-Gal challenge. The present study was divided into three parts. Part 1, the mice were sacrificed at 1.5 h after LPS/D-Gal challenge. The blood samples were harvested for measuringTNF-a levels. Part 2, the mice were sacrificed at 6 h after LPS/D-Gal challenge. The blood samples and liver tissue were harvested for determining the level of plasma aminotransferases (ALT and AST), the contents of hepatic malondialdehyde (MDA) and myeloperoxidase (MPO), the activities of caspase-3,-8,-9 and the protein level of cleaved caspase-3 and phosphorylated JNK. In addition, the liver tissues were stained with hematoxylin-eosin (HE) routinely for morphological evaluation and hepatic apoptosis was determining by TUNEL analysis. Part 3, the mice were observed every 6 h and the survival rate of each group was recorded.Result:The experimental data suggested that effectively alleviated LPS/D-Gal-induced fatal liver injury and suppressed the pro-apoptotic signals. These effects were evidenced by the following data:(1) 2-DG suppressed LPS/D-Gal-induced elevation of ALT and AST in plasma, reduced the content of MDA and MPO in liver tissue, attenuated histopathological abnormalities of the liver. (2) The production of pro-apoptotic cytokine TNF-a in LPS/D-Gal-exposed mice was significantly suppressed by 2-DG. (3) 2-DG suppressed the phosphorylation of pro-apoptotic JNK. (4) 2-DG inhibited the activities of caspase-3,-8,-9, downregulated the protein level of cleaved caspase-3 and reduced the number of TUNEL-positive cell in liver sections from LPS/D-Gal-exposed mice. (5) 2-DG suppressed LPS/D-Gal-induced mortality.Conclusion:These data indicate that 2-DG obvious protective effects on acute fatal liver injury induced by LPS/D-Gal, its protective effect might be associated with the decreased production of pro-apoptotic factor TNF-α and the suppressed activation of pro-apoptotic signal JNK. Our data suggests that CRM such as 2-DG might have broad application potentiality, but the molecular mechanism of 2-DG underlying the anti-inflammatory and anti-apoptotic effects remains to be further identified. |
