Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively. Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress, inhibited cell viability and proliferation, and downregulated CCNA1, CCND1 and CKD4 protein levels. Sirt6 knockdown significantly prevented APAP-induced NRF2 activation, reduced the transcriptional activities of GSTμ and NQO1 and the mRNA levels of Nrf2 , Ho-1 , Gstα and Gstμ . Furthermore, SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation (Co-IP) assay. Additionally, the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6 -dependent. The Sirt6 mRNA was significantly down-regulated in P53 −/− mice. P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6. Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation, and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.

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Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.

Background Embryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear. Methods In this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro. Results We found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9+ cells. Conclusions ESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.