Abstract
Abstract Objectives This study evaluated the protective efficacy of combination treatment with ginsenoside-Mc1 and silibinin against hepatic ischemia-reperfusion (IR) injury in diabetic-aged rats, and further explored AMPK’s role in this protection. Methods A high-fat diet/streptozotocin was used to induce type-2 diabetes in aged rats (20–24 months). Diabetic-aged rats were pretreated with ginsenoside-Mc1 (10 mg/kg, IP) and silibinin (50 mg/kg, IP), alone or in combination, for 4 weeks before induction of hepatic IR injury. Results Induction of IR injury in diabetic-aged rats significantly elevated plasma levels of hepatic alanine and aspartate aminotransferases and negatively affected liver histology. Levels of 8-isoprostane, ROS production, Bax, and cleaved-caspase-3 expression were higher and manganese-superoxide dismutase (MnSOD), glutathione, and Bcl2 and p-AMPK were lower in IR-receiving group. In comparison to individual treatments, the combination of ginsenoside-Mc1 and silibinin powerfully restored IR-induced changes in liver enzymes and histopathological indices, oxidative markers, AMPK, and apoptotic protein expressions. Inhibition of AMPK using compound-C in H2O2-stimulated HepG2 cells significantly abolished the protective effects of combination treatment. Conclusions Combination of ginsenoside-Mc1 and silibinin was superior to their alone usage in protecting hepatocytes of diabetic-aged rats from oxidative/apoptotic damages following IR injury, through an AMPK-mediated mechanism.
Highlights
It was confirmed that diabetes mellitus and aging have a synergistic effect in disturbing many vital organ functions over time
It is well documented that the interaction of aging and diabetes contributes to the development of a vicious cycle between oxidative stress and inflammation, which leads to the production of excessive reactive oxygen species (ROS) and subsequent activation of pro-apoptotic mediators, resulting in chronic complications associated with liver dysfunction [2, 3]
Based on the above, it is hypothesized that the combined usage of compounds can significantly block the interfering effect of aging and diabetes on liver protection against IR injury. For this purpose, using diabetic aged rats and hepatocyte HepG2 cells, we investigated the effect of ginsenoside Mc1 and silibinin combination therapy on liver protection from IR-induced oxidative stress and apoptosis and further explored the role of AMPK in this protection
Summary
It was confirmed that diabetes mellitus and aging have a synergistic effect in disturbing many vital organ functions over time. It is well documented that the interaction of aging and diabetes contributes to the development of a vicious cycle between oxidative stress and inflammation, which leads to the production of excessive reactive oxygen species (ROS) and subsequent activation of pro-apoptotic mediators, resulting in chronic complications associated with liver dysfunction [2, 3]. The occurrence of liver damage via increased oxidative stress and apoptosis has been associated with the progression of aging and diabetes in various experimental and clinical situations [4,5,6]. Most pathophysiological mechanisms of IR injury are the same as those of diabetes and the occurrence of hepatic IR-related complications increases in the presence of diabetes in aged subjects [7]. Finding out new targets and therapies as well as understanding the underlying mechanisms of hepatocyte protection against IR-mediated injury in the aged liver need further experimental researches
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