Tacrolimus(TAC),also called FK506,is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation.However,it has been proved to be associated with post-transplant hyperlipemia.The...Tacrolimus(TAC),also called FK506,is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation.However,it has been proved to be associated with post-transplant hyperlipemia.The mechanism behind this is unknown,and it is urgent to explore preventive strategies for hyperlipemia after transplantation.Therefore,we established a hyperlipemia mouse model to investigate the mechanism,by injecting TAC intraperitoneally for eight weeks.After TAC treatment,the mice developed hyperlipemia(manifested as elevated triglyceride(TG)and low-density lipoprotein cholesterol(LDL-c),as well as decreased high-density lipoprotein cholesterol(HDL-c)).Accumulation of lipid droplets was observed in the liver.In addition to lipid accumulation,TAC induced inhibition of the autophagy-lysosome pathway(microtubule-associated protein 1light chain 3β(LC3B)II/I and LC3B II/actin ratios,transcription factor EB(TFEB),protein 62(P62),and lysosomal-associated membrane protein 1(LAMP1))and downregulation of fibroblast growth factor 21(FGF21)in vivo.Overexpression of FGF21may reverse TAC-induced TG accumulation.In this mouse model,the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway.We conclude that TAC downregulates FGF21and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway.Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.展开更多
The research fields of dynamic capabilities and strategic entrepreneurship have developed concurrently but separately. This study aims to bridge the gap in research on the underlying linkage between the two independen...The research fields of dynamic capabilities and strategic entrepreneurship have developed concurrently but separately. This study aims to bridge the gap in research on the underlying linkage between the two independent areas, both of which are critical for firms to sustain competitiveness in changing industrial environments. Drawing upon insights from the integrated perspective of hierarchical dynamic capabilities, strategic entrepreneurship, and environmental dynamics, an explicit theoretical framework is put forward to achieve a better understanding of the ways through which hierarchical dynamic capabilities promote strategic entrepreneurship. Moreover, through the proposed theoretical lens, this study further explores the detailed mechanisms of how first-order and second-order dynamic capabilities improve strategic entrepreneurship with regard to uncertainty of market conditions.展开更多
Hepatocellular carcinoma(HCC)is one of the most aggressive human malignancies with a dismal survival rate.Few strategies can effectively prevent the occurrence of HCC.Although immunotherapy has significantly improved ...Hepatocellular carcinoma(HCC)is one of the most aggressive human malignancies with a dismal survival rate.Few strategies can effectively prevent the occurrence of HCC.Although immunotherapy has significantly improved HCC-related survival in recent years,this systemic therapy is very expensive and lays a heavy burden on most HCC patients.Aspirin,which is currently one of the most widely used medications in analgesic and cardiovascular diseases,is reported to have anti-tumor effects on HCC.Most importantly,long-term administration of low-dose aspirin does not significantly increase the risk of gastrointestinal bleeding.Owing to its costeffectiveness and wide use,aspirin can be easily applied as an HCC treatment and is affordable for a wide range of patients.Therefore,deeper understanding and more attention are needed to extend the frontline of aspirin's preventive and therapeutic potential into cancer research and management.In this review,we discuss the preventive effect of aspirin on HCC in the context of different etiological factors,including hepatitis B or hepatitis C virus infection,non-alcoholic fatty liver disease,and alcohol-associated liver disease.The therapeutic role of aspirin in resectable or unresectable HCC management is also discussed.Furthermore,the mechanisms underlying the anti-cancer effects of aspirin on HCC are fully reviewed and discussed in the following two aspects:the effect of aspirin on multi-oncogenic signaling pathways in HCC(e.g.,AMPK,Wnt/β-catenin,NF-κB)and aspirinmediated immunometabolic responses in liver diseases.These findings indicate aspirin is a promising agent for populations at risk and HCC patients to prevent or treat HCC.展开更多
基金supported by the National Key Research and Development Program of China(No.2021YFA1100500)the National Natural Science Foundation of China(Nos.92159202,81930016,and 82102910)+3 种基金the Key Research&Development Plan of Zhejiang Province(No.2019C03050)the Construction Fund of Key Medical Disciplines of Hangzhou(No.0020200093)the Postdoctoral Science Foundation(No.2020M671762)the Medical and Health Technology Program in Zhejiang Province(No.WKJ-ZJ-2120),China.
文摘Tacrolimus(TAC),also called FK506,is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation.However,it has been proved to be associated with post-transplant hyperlipemia.The mechanism behind this is unknown,and it is urgent to explore preventive strategies for hyperlipemia after transplantation.Therefore,we established a hyperlipemia mouse model to investigate the mechanism,by injecting TAC intraperitoneally for eight weeks.After TAC treatment,the mice developed hyperlipemia(manifested as elevated triglyceride(TG)and low-density lipoprotein cholesterol(LDL-c),as well as decreased high-density lipoprotein cholesterol(HDL-c)).Accumulation of lipid droplets was observed in the liver.In addition to lipid accumulation,TAC induced inhibition of the autophagy-lysosome pathway(microtubule-associated protein 1light chain 3β(LC3B)II/I and LC3B II/actin ratios,transcription factor EB(TFEB),protein 62(P62),and lysosomal-associated membrane protein 1(LAMP1))and downregulation of fibroblast growth factor 21(FGF21)in vivo.Overexpression of FGF21may reverse TAC-induced TG accumulation.In this mouse model,the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway.We conclude that TAC downregulates FGF21and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway.Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.
文摘The research fields of dynamic capabilities and strategic entrepreneurship have developed concurrently but separately. This study aims to bridge the gap in research on the underlying linkage between the two independent areas, both of which are critical for firms to sustain competitiveness in changing industrial environments. Drawing upon insights from the integrated perspective of hierarchical dynamic capabilities, strategic entrepreneurship, and environmental dynamics, an explicit theoretical framework is put forward to achieve a better understanding of the ways through which hierarchical dynamic capabilities promote strategic entrepreneurship. Moreover, through the proposed theoretical lens, this study further explores the detailed mechanisms of how first-order and second-order dynamic capabilities improve strategic entrepreneurship with regard to uncertainty of market conditions.
基金This work was supported by the Key Research&Development Plan of Zhejiang Province(No.2019C03050)Youth Program of National Natural Science Foundation of China(82003248).
文摘Hepatocellular carcinoma(HCC)is one of the most aggressive human malignancies with a dismal survival rate.Few strategies can effectively prevent the occurrence of HCC.Although immunotherapy has significantly improved HCC-related survival in recent years,this systemic therapy is very expensive and lays a heavy burden on most HCC patients.Aspirin,which is currently one of the most widely used medications in analgesic and cardiovascular diseases,is reported to have anti-tumor effects on HCC.Most importantly,long-term administration of low-dose aspirin does not significantly increase the risk of gastrointestinal bleeding.Owing to its costeffectiveness and wide use,aspirin can be easily applied as an HCC treatment and is affordable for a wide range of patients.Therefore,deeper understanding and more attention are needed to extend the frontline of aspirin's preventive and therapeutic potential into cancer research and management.In this review,we discuss the preventive effect of aspirin on HCC in the context of different etiological factors,including hepatitis B or hepatitis C virus infection,non-alcoholic fatty liver disease,and alcohol-associated liver disease.The therapeutic role of aspirin in resectable or unresectable HCC management is also discussed.Furthermore,the mechanisms underlying the anti-cancer effects of aspirin on HCC are fully reviewed and discussed in the following two aspects:the effect of aspirin on multi-oncogenic signaling pathways in HCC(e.g.,AMPK,Wnt/β-catenin,NF-κB)and aspirinmediated immunometabolic responses in liver diseases.These findings indicate aspirin is a promising agent for populations at risk and HCC patients to prevent or treat HCC.
