Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated i...Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.展开更多
BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transp...BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transport protein NTCP in hepatocytes.A variety of clinical manifestations and genetic mutation loci have been reported for this disease.However,specific therapeutic measures are lacking,and the long-term effects are unknown.CASE SUMMARY An infant with elevated bile acids and behavioral neurodevelopmental delay failed to respond to bile acid-lowering therapy.Genetic testing for metabolic liver disease revealed that the child had NTCP deficiency due to the SLC10A1 mutation:c.422dupA(p.Y141X),which is a novel mutation site.The current followup revealed a gradual decrease in bile acid levels after 1 year of age,but the child still had behavioral neurodevelopmental delays.CONCLUSION The clinical manifestations,genetic characteristics,treatment and long-term prognosis due to NTCP deficiency remain poorly defined and need to be further confirmed by more studies and reports.展开更多
Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting th...Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting the need for the development of novel therapeutics.Sodium taurocholate cotransporting polypeptide(NTCP)was identified as a functional receptor for HBV entry,making it a promising therapeutic target for developing novel anti-HBV agents.展开更多
Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key rol...Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key role in the viral life cycle.Hepatocyte nuclear factor 4α(HNF4α)acts as a major transcriptional factor that stimulates Cp.In this work,we reported that BEL7404 cell line displayed a high efficiency of DNA transfection and high levels of HBV antigen expression after transfection of HBV replicons without prominent viral replication.The introduction of exogenous HNF4αand human sodium taurocholate cotransporting polypeptide(h NTCP)expression into BEL7404made it permissive for HBV replication and susceptible to HBV infection.BEL7404-derived cell lines with induced HBV permissiveness and susceptibility were constructed by stable co-transfection of h NTCP and Tet-inducible HNF4αfollowed by limiting dilution cloning.HBV replication in such cells was sensitive to inhibition by nucleotide analog tenofovir,while the infection was inhibited by HBV entry inhibitors.This cell culture system provides a new and additional tool for the study of HBV replication and infection as well as the characterization of antiviral agents.展开更多
钠离子牛磺胆酸共转运多肽(Na+-taurocholate cotransporting polypeptide,NTCP)是乙型肝炎病毒(hepatitis B virus,HBV)感染的受体,此发现为抗HBV新药研发提供了新靶标。本文综合了近3年来对NTCP受体的研究,全面阐述了目前HBV治疗中的...钠离子牛磺胆酸共转运多肽(Na+-taurocholate cotransporting polypeptide,NTCP)是乙型肝炎病毒(hepatitis B virus,HBV)感染的受体,此发现为抗HBV新药研发提供了新靶标。本文综合了近3年来对NTCP受体的研究,全面阐述了目前HBV治疗中的瓶颈、NTCP发现的意义及其表达调节,以及进入抑制剂的种类、作用机制和研究进展。进入抑制剂将成为抗HBV感染的新靶点,并有可能成为抗HBV感染的新的策略之一。展开更多
目的:本研究以牛磺胆酸钠转运蛋白(Na+/taurocholate cotransporting polypeptide,Ntcp)为研究对象,通过分析Ntcp在高脂血症大鼠模型肝脏中的表达状况,寻求新的高脂血症治疗措施.方法:取♂Wistar大鼠(体质量150 g±5 g)60只,随机均...目的:本研究以牛磺胆酸钠转运蛋白(Na+/taurocholate cotransporting polypeptide,Ntcp)为研究对象,通过分析Ntcp在高脂血症大鼠模型肝脏中的表达状况,寻求新的高脂血症治疗措施.方法:取♂Wistar大鼠(体质量150 g±5 g)60只,随机均分为实验组及对照组.喂食90 d,建立高脂血症模型,喂食期间定期取血检测胆固醇及胆汁酸含量,建模成功后,分别取两组大鼠肝脏组织.应用逆转录-聚合酶链反应(RT-polymerase chain reaction,RTP C R)技术检测肝脏组织的N t c p基因表达的状况.应用免疫组织化学SP(streptavidinperosidase)法检测肝脏组织的Ntcp蛋白表达的状况.结果:实验组胆固醇及胆汁酸含量提高明显.电泳结果显示:两组肝脏组织都出现了位于425 bp的内参β-actin基因的扩增带和位于325 bp的Ntcp基因扩增带,实验组Ntcp基因扩增带亮度减弱;免疫组织化学结果显示:实验组Ntcp表达阳性率为23.6%,对照组N t c p表达阳性率为75.2%,差异有统计学意义(χ2=9.858,P<0.05).结论:实验组大鼠的Ntcp基因的表达明显减弱,提示我们Ntcp基因可能会成为高脂血症及其相关疾病新的药物治疗靶点.展开更多
基金supported by National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2018ZX09735005)the National Natural Science Foundation of China(Nos.81922064,81874290,81673290,81803347 and 81903502)+1 种基金the Natural Science Foundation of Guangdong Province(No.2018A030313707)Post-Doctor Research Project,West China Hospital,Sichuan University(No.2019HXBH034)。
文摘Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.
基金Yunnan Science Foundation Project,No.2019-81960102.
文摘BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transport protein NTCP in hepatocytes.A variety of clinical manifestations and genetic mutation loci have been reported for this disease.However,specific therapeutic measures are lacking,and the long-term effects are unknown.CASE SUMMARY An infant with elevated bile acids and behavioral neurodevelopmental delay failed to respond to bile acid-lowering therapy.Genetic testing for metabolic liver disease revealed that the child had NTCP deficiency due to the SLC10A1 mutation:c.422dupA(p.Y141X),which is a novel mutation site.The current followup revealed a gradual decrease in bile acid levels after 1 year of age,but the child still had behavioral neurodevelopmental delays.CONCLUSION The clinical manifestations,genetic characteristics,treatment and long-term prognosis due to NTCP deficiency remain poorly defined and need to be further confirmed by more studies and reports.
基金supported by the National Key R&D Program of China(2022YFA1303600)National Natural Science Foundation of China[No.22137002 to Y.D.,No.92353303,22277010 and 22477013 to Z.G.,No.U23A20472 and 82273423 to J.C.,No.82302507 to H.Y.]+5 种基金Ministry of Human Resources and Social Security Funding Scheme for High-Level Overseas Chinese Students’Return of China[to Z.G.]China Postdoctoral Science Foundation[No.2021T140784 and 2020M683638XB to J.H.]Natural Science Foundation of Chongqing[No.CSTB2022NSCQ-MSX1061 to Z.G.]Chongqing Postdoctoral Science Foundation[No.CSTB2022NSCQ-BHX0616 to J.H.]CQMU Program for Youth Innovation in Future Medicine[No.W0074 to Z.G.]Joint Project of Pinnacle Disciplinary Group of the Second Affiliated Hospital of Chongqing Medical University.
文摘Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting the need for the development of novel therapeutics.Sodium taurocholate cotransporting polypeptide(NTCP)was identified as a functional receptor for HBV entry,making it a promising therapeutic target for developing novel anti-HBV agents.
基金the National Natural Science Foundation of China(81971921,81971931)the National base cultivation project(20DZ2210404)the Major science and technology project for the prevention and treatment of major infectious diseases(2018ZX10301208)。
文摘Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key role in the viral life cycle.Hepatocyte nuclear factor 4α(HNF4α)acts as a major transcriptional factor that stimulates Cp.In this work,we reported that BEL7404 cell line displayed a high efficiency of DNA transfection and high levels of HBV antigen expression after transfection of HBV replicons without prominent viral replication.The introduction of exogenous HNF4αand human sodium taurocholate cotransporting polypeptide(h NTCP)expression into BEL7404made it permissive for HBV replication and susceptible to HBV infection.BEL7404-derived cell lines with induced HBV permissiveness and susceptibility were constructed by stable co-transfection of h NTCP and Tet-inducible HNF4αfollowed by limiting dilution cloning.HBV replication in such cells was sensitive to inhibition by nucleotide analog tenofovir,while the infection was inhibited by HBV entry inhibitors.This cell culture system provides a new and additional tool for the study of HBV replication and infection as well as the characterization of antiviral agents.
文摘钠离子牛磺胆酸共转运多肽(Na+-taurocholate cotransporting polypeptide,NTCP)是乙型肝炎病毒(hepatitis B virus,HBV)感染的受体,此发现为抗HBV新药研发提供了新靶标。本文综合了近3年来对NTCP受体的研究,全面阐述了目前HBV治疗中的瓶颈、NTCP发现的意义及其表达调节,以及进入抑制剂的种类、作用机制和研究进展。进入抑制剂将成为抗HBV感染的新靶点,并有可能成为抗HBV感染的新的策略之一。
文摘目的:本研究以牛磺胆酸钠转运蛋白(Na+/taurocholate cotransporting polypeptide,Ntcp)为研究对象,通过分析Ntcp在高脂血症大鼠模型肝脏中的表达状况,寻求新的高脂血症治疗措施.方法:取♂Wistar大鼠(体质量150 g±5 g)60只,随机均分为实验组及对照组.喂食90 d,建立高脂血症模型,喂食期间定期取血检测胆固醇及胆汁酸含量,建模成功后,分别取两组大鼠肝脏组织.应用逆转录-聚合酶链反应(RT-polymerase chain reaction,RTP C R)技术检测肝脏组织的N t c p基因表达的状况.应用免疫组织化学SP(streptavidinperosidase)法检测肝脏组织的Ntcp蛋白表达的状况.结果:实验组胆固醇及胆汁酸含量提高明显.电泳结果显示:两组肝脏组织都出现了位于425 bp的内参β-actin基因的扩增带和位于325 bp的Ntcp基因扩增带,实验组Ntcp基因扩增带亮度减弱;免疫组织化学结果显示:实验组Ntcp表达阳性率为23.6%,对照组N t c p表达阳性率为75.2%,差异有统计学意义(χ2=9.858,P<0.05).结论:实验组大鼠的Ntcp基因的表达明显减弱,提示我们Ntcp基因可能会成为高脂血症及其相关疾病新的药物治疗靶点.
