Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available.Wuzhi Tablet(WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepatoprotective herb, exert...Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available.Wuzhi Tablet(WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepatoprotective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ andthe target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.展开更多
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 oxi...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 APAPinduced 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 signifi-cantly prevented APAP-induced NRF2 activation,reduced the transcriptional activities of GSTm andNQO1 and the m RNA levels of Nrf2,Ho-1,Gsta and Gstm.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 m RNA was significantly down-regulated in P53à/àmice.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.展开更多
基金supported by the National Natural Science Foundation of China (Grant Nos. 81373470, 81573489, 81522047 and 81402998)the Natural Science Foundation of Guangdong Province (No. 2015A030313124)
文摘Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available.Wuzhi Tablet(WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepatoprotective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ andthe target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.
基金supported by the National Natural Science Foundation of China(Grants 81603185,81973392,and 82025034)the Natural Science Foundation of Guangdong Province(Grant 2020A1515011452,China)+1 种基金the National Key Research and Development Project(Grant 2017YFE0109900,China)the Sanming Project of Medicine in Shenzhen(SZSM201406007 and SZSM201606088,China)
文摘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 APAPinduced 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 signifi-cantly prevented APAP-induced NRF2 activation,reduced the transcriptional activities of GSTm andNQO1 and the m RNA levels of Nrf2,Ho-1,Gsta and Gstm.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 m RNA was significantly down-regulated in P53à/àmice.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.
