Modulation of hippocampal gene expression of microRNA-146a/microRNA-155-nuclear factor-kappa B inflammatory signaling by troxerutin in healthy and diabetic rats.

OBJECTIVES: Inflammation plays a critical role in the progression of diabetic complications such as neurological disorders. Previous reports have indicated the memory-improving effect of troxerutin, in rat hippocampus, but the underlying mechanisms are unclear. Hence, we have investigated the effect of troxerutin pretreatment on gene expressions of inflammation-related microRNAs (miRs), miR-146a and miR-155, and nuclear factor-kappa B (NF-κB) signaling pathway in the hippocampus of healthy and diabetic rats. MATERIALS AND METHODS: Wistar rats were randomly divided into four groups (control, control + troxerutin, diabetic, and diabetic + troxerutin). Diabetes was induced by a single i.p. injection of streptozotocin (50 mg/kg). Troxerutin (150 mg/kg) was orally administered in animals for 1 month. After 10 weeks of diabetes, animals were anesthetized and decapitated for the isolation of hippocampus. The expression of miR-146a and miR-155 and the messenger RNA (mRNA) expressions of NF-κB, interleukin-1 receptor-associated kinase-1 (IRAK-1), and tumor necrosis factor receptor-associated factor-6 (TRAF-6) were analyzed by real-time polymerase chain reaction. RESULTS: Diabetes significantly increased hippocampal mRNA levels of NF-κB, IRAK-1, and TRAF-6 compared with nondiabetic rats (P < 0.05); however, pretreatment with troxerutin decreased them in both diabetic and nondiabetic animals, independent of its glycemic effect (P < 0.05). The expression levels of miR-146a and miR-155 were decreased in diabetic group as compared to the control (P < 0.01). CONCLUSION: These findings showed that troxerutin could inhibit the inflammatory NF-κB pathway in the hippocampus of diabetic rats, which may be due to the negative feedback loop regulated by miR-146a.

Mitochondrial ATP-sensitive K+ channels mediate the antioxidative influence of diosgenin on myocardial reperfusion injury in rat hearts.

The contribution of reactive oxygen species and oxidative stress in the pathogenesis of ischemia-reperfusion (I/R) injury has been supported by many studies. The effect of diosgenin on oxidative stress induced by I/R injury was evaluated in this study. Rat hearts were subjected to 30 minutes of global ischemia followed by 90 minutes of reperfusion. 5-hydroxydecanoate (5-HD) was used before administration of diosgenin and before ischemia. The activities of myocardial creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured. Administration of diosgenin before ischemia significantly lowered CK and MDA levels as compared with control group (p < 0.05) and increased GPX (p < 0.05) and SOD (p < 0.01) activities in comparison with control group. Pre-administration of 5-HD significantly attenuated the protective effects of diosgenin. In conclusion, opening of mitochondrial ATP-sensitive K(+) channels and attenuating of oxidative stress can be suggested as underlying mechanisms for cardioprotective effect of diosgenin in I/R injury.

Contribution of apoptosis in myocardial reperfusion injury and loss of cardioprotection in diabetes mellitus.

Ischemic heart disease is one of the major causes of death worldwide. Ischemia is a condition in which blood flow of the myocardium declines, leading to cardiomyocyte death. However, reperfusion of ischemic regions decreases the rate of mortality, but it can also cause later complications. In a clinical setting, ischemic heart disease is always coincident with other co-morbidities such as diabetes. The risk of heart disease increases 2-3 times in diabetic patients. Apoptosis is considered to be one of the main pathophysiological mechanisms of myocardial ischemia-reperfusion injury. Diabetes can disrupt the anti-apoptotic intracellular signaling cascades involved in myocardial protection. Therefore, targeting these changes may be an effective cardioprotective approach in the diabetic myocardium against ischemia-reperfusion injury. In this article, we review the interaction of diabetes with the pathophysiology of myocardial ischemia-reperfusion injury, focusing on the contribution of apoptosis in this context, and then discuss the alterations of pro-apoptotic or anti-apoptotic pathways probably responsible for the loss of cardioprotection in diabetes.