No abstract

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.

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.

No abstract

Cadmium (Cd) is an environmental pollutant and has posed a potential threat for the growth and survival of freshwater crabs. Low-molecular-weight chitosan (LMWC) may promote growth in crab culture. The present study was designed to investigate the Cd-induced oxidative damage and the protective role of LMWC against oxidation caused by Cd 21 in freshwater crab (Sinopotamon yangtsekiense Bott 1967). The results showed that Cd 21 signi¢cantly inhibited the activities of total antioxidant capacity, superoxide dismutase, catalase, glutathione peroxidase and peroxidase, while it increased malondialdehyde levels in the hepatopancreas and the gill. Moreover, Cd 21 at the concentration tested obviously increased the protein carbonyl contents and DNA^protein crosslinks coe⁄cients in the hepatopancreas, gill, heart and muscle tissues of S. yangtsekiense in a dose-dependent manner. In addition, Cd 21 induced a signi¢cant increase in the levels of nitric oxide and inducible nitric oxide synthase in the hepatopancreas, gill and muscle. The results also showed that LMWC plus Cd 21 signi¢cantly improved antioxidant markers. The observations suggested that the severe oxidative damage in multiple crab tissues was one of the important causes of the adverse in£uence of Cd 21 on S. yangtsekiense growth and indicated that LMWC could provide a protective e¡ect against such an injury.