Macroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.
Methods 40 male BABL/c mice were divided into two groups, the DCM group and the control. The DCM group mice were peritoneal injected Coxsackievirus B3 (CVB3) monthly. After 180 days, all mice were sacrificed and IL-17 mRNA of splenocytes were measured by RT-PCR. Results In the DCM mice, the heart weight was higher, and the ventricular wall was thinner than the control, and fibrosis in hearts were observed. IL-17 mRNA of splenocytes in DCM mice could be detected and the controls' were zero (0.1560.04 vs 0.0060.00, p<0.01). Conclusion We successfully built murine DCM model by monthly peritoneal injection of CVB3 for 180 days in the DCM group. In the DCM mice, the heart weight was higher, and the ventricular wall was thinner than the control, and fibrosis in heart was observed. The mRNA levels of IL-17 were promoted in Coxsackievirus induced DCM mice. This result suggested that IL 17 which secreted by Th17 subset could be detected in DCM mice, it seems that the Th17 cells might differentiated in DCM mice. Aim Postconditioning is brief cycles of reperfusion and ischaemia during the early phase of reperfusion following a prolonged ischaemic insult. Opioids are well-known endogenous triggers of preconditioning. Because postconditioning shares the protective pathways with preconditioning, G proteinecoupled receptor activation may serve as an essential mechanism that triggers protection of postconditioning. Receptor binding studies showed that k opioid receptor (k-OR) is a predominant opioid receptor in heart. Therefore, we determined whether endogenous agonist of k-OR, dynorphin, triggers postconditioning, especially reduces apoptosis of I/R myocardium and to identify its underlying mechanism. Methods Besides the vehicle, the other SD rats underwent a 30 min left anterior descending occlusion followed by 120 min of reperfusion with or without a postconditioning stimulus (three cycles of 10 s reperfusion and 10 s reocclusion) initiated at the onset of reperfusion. The selective k opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 2 mg/kg, intravenously), administered 5 min before the reperfusion. The blood plasma was analysed spectrophotometrically for determination of CK and LDH levels. Myocardial apoptosis was quantitatively analysed by detection of TUNEL with an apoptosis detection kit. Six fields from the periinfarct zone were analysed and the number of TUNEL positive cardiomyocytes was counted on 400 high power fields. Immunoreactive Dynorphin were measured by an antigen competitive ELISA. Results CK (U/L) and LDH (U/L) were significantly higher in I/R group than those in the control (34016251 vs 689676, 23296216 vs 753697, p<0.01). Postconditioning significantly reduced the release of CK and LDH from I/R myocardium (20266268 vs 34016251, 15436169 vs 23296216, p<0.01). These reduction were abolished by nor-BNI (p<0.01). Regional myocardial I/R resulted in a significant increase in cardiomyocyte apoptosis (18.762.5 vs 160.25, p<0.01). Postconditioning exerted a significant anti-apoptotic effect (10.461.3 vs 18...
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