wen Su

Sesamin ameliorates doxorubicin-induced cardiotoxicity: Involvement of Sirt1 and Mn-SOD pathway

Oxidative stress caused by doxorubicin (DOX) is believed to be a major underlying molecular mechanism of DOX-induced cardiotoxicity. Sesamin (Ses), an active component extracted from sesame seeds, exhibits antioxidative and anti-inflammatory effects. In the present study, possible protective mechanisms of Ses on DOX-induced cardiotoxicity were investigated in rats and cultured H9C2 cells. We demonstrated that Ses exhibits a significant protective effect on cardiac tissue in animal and cell models of DOX-induced cardiac injury. Moreover, Ses can ameliorate DOX-induced oxidative stress and mitochondrial damage. Further studies suggested that Ses is able to up-regulate the protein expression of Mn-SOD in normal rats and to restore the decreased expression of Mn-SOD in DOX-induced cardiac injury rats. Exposure to Ses or DOX alone slightly increased the protein expression of Sirt1; however, a more remarkable increase in Sirt1 protein level was detected in the Ses+DOX group. Treatment with a pan-sirtuin inhibitor (nicotinamide) or a Sirt1-specific inhibitor (EX-527) partially antagonised the effect of Ses on DOX-induced mitochondrial damage and completely abolished the effect of Ses on Mn-SOD expression. These findings indicate that the protective mechanisms of Ses on DOX-induced cardiotoxicity are involved in the alleviation of oxidative stress injury and Mn-SOD dysfunction, partially via the activation of Sirt1.

Na+/K+‐ATPase inhibition upregulates NMDA‐evoked currents in rat hippocampal CA1 pyramidal neurons

Na+/K+‐ATPase and N‐methyl‐d‐aspartate (NMDA) receptor in hippocampus play very important roles in the regulation of learning and memory. Here, we showed that dihydroouabain (DHO, 10−5–10−3 m), a Na+/K+‐ATPase inhibitor, significantly potentiated NMDA current in rat hippocampal CA1 pyramidal neurons, which was blocked by PP2 (the selective Src tyrosine kinase inhibitor) and PD‐98059 [the selective inhibitor of the mitogen‐activated protein kinases (MAPK) cascade]. These findings reported here uncover that Src mediates the cross‐talk between Na+/K+‐ATPase and NMDA receptor to transduce the signals from Na+/K+‐ATPase to the MAPK cascade and provide new insights into therapeutic target for deeper understanding of the nature of cognitive disorder.

Alleviation of doxorubicin–induced hepatorenal toxicities with sesamin via the suppression of oxidative stress

Hepatorenal toxicities are an important side effect of anthracycline antibiotics. The objective of this study was to determine whether sesamin (Ses) protects against acute doxorubicin (DOX)-induced hepatorenal toxicities. Rats received daily treatment with either 0.5% carboxymethylcellulose (10 mL/kg) or Ses (10, 20 and 40 mg/kg) orally for 10 days, followed by an intravenous injection at day 8 of either saline (10 mL/kg) or DOX (20 mg/kg). Hepatorenal toxicity was assessed by measuring the levels of serum creatinine (Cre), blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). The protein expression of 4-hydroxynonenal (4-HNE) in hepatorenal tissues was evaluated using immunohistochemistry. The malondialdehyde (MDA) content and antioxidant activity in the kidney and liver tissues were also measured. The results suggest that pretreatment with Ses ameliorated DOX-induced liver and kidney injury by lowering the serum ALT, AST, ALP, Cre and BUN levels (p < 0.05 or p < 0.01), and the histological damage to the liver and kidney tissues induced by DOX compared to control were also significantly attenuated by Ses. Furthermore, Ses significantly decreased the DOX-induced increase of MDA and 4-HNE and increased the activity of CAT, SOD and GPX compared to the DOX-treated rats (p < 0.05 or p < 0.01), whereas the change of DOX + Ses (10 mg/kg) group is not significant compared to the DOX-treated group (p > 0.05). These findings indicate that Ses elicits a typical protective effect against DOX-induced acute hepatorenal toxicity via the suppression of oxidative stress.

Protective effect of berberine on aconite‑induced myocardial injury and the associated mechanisms

Aconitum plants, which have analgesic, diuretic and anti-inflammatory effects, have been widely used to treat various types of disease. However, the apparent toxicity of Aconitum-derived agents, particularly in the cardiovascular system, has largely limited their clinical use. Thus, the present study investigated whether berberine (Ber), an isoquinoline alkaloid, may reduce myocardial injury induced by aconitine (AC) in rats and the underlying mechanisms. Rats (n=40) were randomly divided into four groups: Control, Chuan-wu and Chuan-wu + Ber (8 and 16 mg/kg doses). Electrocardiograms (ECG) of the rats were recorded and serum biomarkers of cardiac function [lactate dehydrogenase (LDH), creatine kinase (CK) and CK-MB] were assayed. Histopathological changes were assessed using myocardial tissue sectioning and hematoxylin and eosin staining. Additionally, the effects of Ber on AC-induced arrhythmias in rats were observed. The changes in ECG following AC perfusion were observed, and the types and onset time of arrhythmias were analyzed. Furthermore, the effects of Ber and AC on papillary muscle action potentials were observed. The results suggested that Ber ameliorated myocardial injury induced by Chuan-wu, which was indicated by reduced arrhythmias and decreased LDH, CK and CK-MB levels in serum. Furthermore, histological damage, including dilation of small veins and congestion, was also markedly attenuated by Ber. In addition, the occurrence of arrhythmias was significantly delayed, and the dosage of AC required to induce arrhythmias was also increased by Ber pretreatment. Additionally, AC-induced changes in action potential amplitude, duration of 30% repolarization and duration of 90% repolarization in the papillary muscle were attenuated by Ber. All of these results indicate that Ber had a preventive effect on acute myocardial injury induced by Chuan-wu and arrhythmias caused by AC, which may be associated with the inhibition of delayed depolarization and triggered activity caused by AC. Thus, combination treatment of Ber with Aconitum plants may be a novel strategy to prevent AC-induced myocardial injury in clinical practice.

Different Na + /K + -ATPase signal pathways was involved in the increase of (Ca 2+ ) i induced by strophanthidin in normal and failing isolated guinea pig ventricular myocytes

AbstractAim:To determine whether different Na+/K+ -ATPase signal transduction pathways have positive inotropic effects on normal ventricular myocytes (NC) and failing ventricular myocytes (FC), and are involved in an increase of [Ca2+]i induced by strophanthidin (Str).Methods:A guinea pig model of congestive heart failure was made by constricting descending aorta. The left ventricular myocytes were enzymatically isolated. The effects of 25 μmol/L Str with different signal-transducing inhibitors on contractility and the calcium transient of NC or FC from guinea pigs were simultaneously assessed and compared with those in the 25 μmol/L Stronly group by a video-based, motion-edge detection system.Results:Str at 1, 10, and 25 μmol/L in NC and Str at 0.1, 1, 10, and 25 μmol/L) in FC elevated the calcium transient amplitude and increased the positive inotropic effects in a concentration-dependent manner, respectively. At the same concentration, the effects of Str were more potent in FC than in NC. In FC, both the mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS) signal transduction pathway of Na+/K+-ATPase were involved in the increase of the calcium transient induced by Str, but only activation of the MAPK pathway increased the calcium transient in NC. However, only the ROS pathway was involved in positive inotropic effects both in NC and FC.Conclusion:The present study suggests that Na+/K+-ATPase signaling pathways involved in the inotropic effects of Str in NC and FC are consistent, and Na+/K+-ATPase signaling pathways involved in the increase of [Ca2+]i by Str in NC and FC are different.