Sinomenine pretreatment alleviates hepatic ischemia/reperfusion injury through activating Nrf-2/HO-1 pathway

Introduction: Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated. Methods: This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury. Results: Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the down-regulated activities of serum alanine amino-transferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-alpha, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects. Conclusions: Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.

Automated summary

In this study, the impact of sinomenine (SIN) on hepatic ischemia-reperfusion (IR) injury and the related signaling pathway was investigated. The results showed that SIN pretreatment significantly prevented IR-induced liver injury, including decreased levels of liver enzymes, reduced oxidative stress, suppressed inflammatory responses, and attenuated apoptosis. The histopathological changes in the livers of IR rats were also alleviated by SIN pretreatment, and Nrf-2/HO-1 activation was induced. The use of a selective inhibitor for Nrf-2 effectively reversed the effects induced by SIN. These findings suggest that SIN may be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.