Autophagy impairment as a key feature for acetaminophen-induced ototoxicity.

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.

MicroRNA-423-5p as a biomarker for early diagnosis and outcome prediction of acute kidney injury in patients with acute decompensated heart failure.

OBJECTIVE: To evaluate the clinical significance of serum and urinary microRNA-423-5p in the prediction of acute kidney injury onset and survival in patients with acute decompensated heart failure. METHODS: A total of 180 acute decompensated heart failure patients, including 57 acute kidney injury cases and 123 non-acute kidney injury cases, were included in this study. Serum and urinary neutrophil gelatinase-associated lipocalin, a biomarker of renal injury of acute kidney injury, was detected using an enzyme-linked immunosorbent assay. Expression of microRNA-423-5p in serum and urine samples was examined using quantitative real-time polymerase chain reaction. The clinical significance of microRNA-423-5p was evaluated using receiver operating characteristic curve and Kaplan-Meier survival analysis. RESULTS: The levels of neutrophil gelatinase-associated lipocalin and microRNA-423-5p in serum and urine samples were elevated in patients with acute kidney injury compared with the non-acute kidney injury cases (all P < 0.05). Serum and urinary microRNA-423-5p had relatively high predictive performance for acute kidney injury onset in acute decompensated heart failure patients, and this predictive value was more significant when combined with urinary neutrophil gelatinase-associated lipocalin. In addition, serum and urinary elevated levels of microRNA-423-5p predicted a poor 180-day survival in the acute kidney injury group. CONCLUSION: Increased serum and urinary microRNA-423-5p can predict the occurrence of acute kidney injury in acute decompensated heart failure patients, and is associated with poor survival of acute kidney injury patients. In addition, the diagnostic value of urine neutrophil gelatinase-associated lipocalin for the early screening of acute kidney injury from acute decompensated heart failure patients might be improved by considering the changes in urinary microRNA-423-5p.

Diagnostic and prognostic significance of aberrant miR-652-3p levels in patients with acute decompensated heart failure and acute kidney injury.

OBJECTIVE: This study aimed to examine a novel microRNA (miR-652-3p) biomarker to improve early diagnosis of acute kidney injury (AKI) in patients with acute decompensated heart failure (ADHF) and to evaluate the survival predictive value of miR-652-3p. METHODS: We retrospectively analyzed the data of 196 patients with ADHF, including 65 who developed AKI during hospitalization. Neutrophil gelatinase-associated lipocalin (NGAL) levels were measured in serum and urine samples. Real-time quantitative PCR was applied to evaluate miR-652-3p mRNA expression. The diagnostic performance of miR-652-3p was examined using receiver operating characteristic curve analysis. The prognostic value of miR-652-3p was also analyzed. RESULTS: Serum and urinary NGAL and miR-652-3p levels were elevated in patients with ADHF and AKI. Serum and urinary miR-652-3p expression had diagnostic value in predicting AKI onset in patients with ADHF, and it had improved diagnostic performance when used with NGAL. Patients with AKI and high miR-652-3p levels had a high failure rate of renal recovery and poor 180-day survival. CONCLUSION: Serum and urinary miR-652-3p may be a candidate biomarker for early diagnosis of AKI in patients with ADHF and for predicting the prognosis of AKI. The combination of NGAL and miR-652-3p may accurately predict AKI onset in ADHF.

Domestic chickens activate a piRNA defense against avian leukosis virus.

PIWI-interacting RNAs (piRNAs) protect the germ line by targeting transposable elements (TEs) through the base-pair complementarity. We do not know how piRNAs co-evolve with TEs in chickens. Here we reported that all active TEs in the chicken germ line are targeted by piRNAs, and as TEs lose their activity, the corresponding piRNAs erode away. We observed de novo piRNA birth as host responds to a recent retroviral invasion. Avian leukosis virus (ALV) has endogenized prior to chicken domestication, remains infectious, and threatens poultry industry. Domestic fowl produce piRNAs targeting ALV from one ALV provirus that was known to render its host ALV resistant. This proviral locus does not produce piRNAs in undomesticated wild chickens. Our findings uncover rapid piRNA evolution reflecting contemporary TE activity, identify a new piRNA acquisition modality by activating a pre-existing genomic locus, and extend piRNA defense roles to include the period when endogenous retroviruses are still infectious.