Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substan...Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.展开更多
目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB...目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。展开更多
BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-t...BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-threatening situations.Here,we report a patient with mutations in the uridine 5’-diphospho-glucuronosyltrans-ferase 1A1(UGT1A1)and bile salt export pump(adenosine triphosphate-binding cassette subfamily B member 11,ABCB11)genes who presented multiple intrahe-patic bile duct stones and cholestasis,and the jaundice of the patient increased after partial hepatectomy.CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23,2021,with a progressive exacerbation of jaundice,was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis.Subsequently,the patient underwent left hepatectomy with biliary exploration,stone extraction,T-tube drainage,and cholecystectomy without developing any intraoperative complications.The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments.Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason,including,if not at all,viral infection,cholangitis,autoimmune liver disease,and other causes,the patient underwent whole-exon screening for any genetic diseases,which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes,respectively.Thus,we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient,who eventually declined it and died from liver failure six months later.CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations.A liver transplant may be the best option if active medical treatment fails.展开更多
Mounting evidence indicates that long non-coding RNAs(lncRNAs)have critical roles in colorectal cancer(CRC)progression,providing many potential diagnostic biomarkers,prognostic biomarkers,and treatment targets.Here,we...Mounting evidence indicates that long non-coding RNAs(lncRNAs)have critical roles in colorectal cancer(CRC)progression,providing many potential diagnostic biomarkers,prognostic biomarkers,and treatment targets.Here,we sought to investigate the role and underlying regulatory mechanism of lncRNA small nucleolar RNA host gene 16(SNHG16)in CRC.The expressions of SNHG16 in CRC were identified by RNA-sequencing and quantitative reverse transcription PCR.The functions of SNHG16 were explored by a series of in vitro and in vivo assays(colony formation assay,flow cytometry assay,and xenograft model).Bioinformatics analysis,RNA fluorescence in situ hybridization and luciferase reporter assay were used to investigate the regulatory mechanism of effects of SNHG16.SNHG16 was found to be significantly elevated in human CRC tissues and cell lines.Functional studies suggested that SNHG16 promoted CRC cell growth both in vitro and in vivo.Mechanistically,we identified that SNHG16 is expressed predominantly in the cytoplasm.SNHG16 could interact with miR-214-3p and up-regulated its target ABCB1.This study indicated that SNHG16 plays an oncogenic role in CRC,suggesting it could be a novel biomarker and therapeutic target in CRC.展开更多
近年来,难治性癫痫的病因与多药耐药基因以及多药耐药基因与抗癫痫治疗的因果关系越来越受到关注。P糖蛋白(P-glycopretein,P-gp)是由ATP结合盒B亚家族成员1转运蛋白基因(ATP-binding cassette subfamily B member 1 transporter gene,A...近年来,难治性癫痫的病因与多药耐药基因以及多药耐药基因与抗癫痫治疗的因果关系越来越受到关注。P糖蛋白(P-glycopretein,P-gp)是由ATP结合盒B亚家族成员1转运蛋白基因(ATP-binding cassette subfamily B member 1 transporter gene,ABCB1)编码的产物。它不仅可以限制抗癫痫药物(antiepileptic drug,AED)的消化道吸收,而且可以在细胞和亚细胞水平调控药物在中枢神经系统的运输过程。除了生理和环境因素的影响,P-gp的功能和表达的变化可能主要取决于ABCB1基因的多态性,这是目前研究得最广泛、最深入的多药耐药机制。本文就目前ABCB1基因多态性与难治性癫痫的相关性研究进展作一综述。展开更多
目的探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)患者纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)基因4G/5G及多药耐药性蛋白(ATP-binding cassette subfamily B member 1,ABCB1)基因C3435T多态性分...目的探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)患者纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)基因4G/5G及多药耐药性蛋白(ATP-binding cassette subfamily B member 1,ABCB1)基因C3435T多态性分布特征。方法 79例SLE患者依据脏器损伤情况分为SLE继发股骨头坏死(osteonecrosis of the femeral head,ONFH)组20例,狼疮肾炎(lupus nephritis,LN)组37例,其他组22例。采用数字荧光分子杂交技术检测3组外周血PAI-1基因4G/5G和ABCB1基因C3435T多态性,比较3组PAI-1基因高危4G4G型、ABCB1基因C3435T位点高危CC型分布频率。结果79例患者PAI-1基因4G4G、4G5G、5G5G基因型频率分别为29.1%、51.9%、19.0%,ABCB1基因C3435T位点CC、CT、TT基因型频率分别为41.7%、39.2%、19.1%;SLE-ONFH组、LN组PAI-1基因高危4G4G型分布频率(35.0%、35.1%)与其他组(13.6%)比较差异无统计学意义(P>0.05);SLE-ONFH组、LN组ABCB1基因C3435T位点高危CC型分布频率(50.0%、51.4%)高于其他组(18.2%)(P<0.05);SLE-ONFH组PAI-1基因高危4G4G型、ABCB1基因C3435T位点高危CC型分布频率与LN组比较差异无统计学意义(P>0.05)。结论 ABCB1基因C3435T位点高危CC型可能与SLE患者继发ONFH、LN有关。展开更多
基金supported by funds from the National Institutes of Health (1R15CA143701)St.John's University Research Seed Grant(579-1110-7002) to Dr.Zhe-Sheng Chen.Drs.Suneet ShuklaSuresh V.Ambudkar were supported by the Intramural Research Program,Center for Cancer Research, National Cancer Institute,National Institutes of Health
文摘Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.
文摘目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。
基金Supported by The Science and Technology Planning Projects of Guizhou Province and Zunyi City,No.QKHJCZK[2022]YB642,No.ZSKH·HZ(2022)344,No.gzwjkj2021-071,ZMC·YZ[2018]38,No.ZSKH·HZ[2021]58,and No.ZSKH·HZ[2021]60The General Project of Hubei Province and Jingmen City,No.2021YFYB074.
文摘BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-threatening situations.Here,we report a patient with mutations in the uridine 5’-diphospho-glucuronosyltrans-ferase 1A1(UGT1A1)and bile salt export pump(adenosine triphosphate-binding cassette subfamily B member 11,ABCB11)genes who presented multiple intrahe-patic bile duct stones and cholestasis,and the jaundice of the patient increased after partial hepatectomy.CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23,2021,with a progressive exacerbation of jaundice,was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis.Subsequently,the patient underwent left hepatectomy with biliary exploration,stone extraction,T-tube drainage,and cholecystectomy without developing any intraoperative complications.The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments.Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason,including,if not at all,viral infection,cholangitis,autoimmune liver disease,and other causes,the patient underwent whole-exon screening for any genetic diseases,which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes,respectively.Thus,we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient,who eventually declined it and died from liver failure six months later.CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations.A liver transplant may be the best option if active medical treatment fails.
基金supported by grants from the National Natural Science Foundation of China(Grant No.81972806)Jiangsu Provincial Key Research and Development Plan(Grant No.BE2019614),Key Project of Science and Technology Development of Nanjing Medicine(ZKX21042)+1 种基金Elderly Health Research Project of Jiangsu Province(Grant No.LR2021017)Specialized Cohort Research Project of Nanjing Medical University(Grants No.NMUC2020035 and NMUC2021013A).
文摘Mounting evidence indicates that long non-coding RNAs(lncRNAs)have critical roles in colorectal cancer(CRC)progression,providing many potential diagnostic biomarkers,prognostic biomarkers,and treatment targets.Here,we sought to investigate the role and underlying regulatory mechanism of lncRNA small nucleolar RNA host gene 16(SNHG16)in CRC.The expressions of SNHG16 in CRC were identified by RNA-sequencing and quantitative reverse transcription PCR.The functions of SNHG16 were explored by a series of in vitro and in vivo assays(colony formation assay,flow cytometry assay,and xenograft model).Bioinformatics analysis,RNA fluorescence in situ hybridization and luciferase reporter assay were used to investigate the regulatory mechanism of effects of SNHG16.SNHG16 was found to be significantly elevated in human CRC tissues and cell lines.Functional studies suggested that SNHG16 promoted CRC cell growth both in vitro and in vivo.Mechanistically,we identified that SNHG16 is expressed predominantly in the cytoplasm.SNHG16 could interact with miR-214-3p and up-regulated its target ABCB1.This study indicated that SNHG16 plays an oncogenic role in CRC,suggesting it could be a novel biomarker and therapeutic target in CRC.
文摘近年来,难治性癫痫的病因与多药耐药基因以及多药耐药基因与抗癫痫治疗的因果关系越来越受到关注。P糖蛋白(P-glycopretein,P-gp)是由ATP结合盒B亚家族成员1转运蛋白基因(ATP-binding cassette subfamily B member 1 transporter gene,ABCB1)编码的产物。它不仅可以限制抗癫痫药物(antiepileptic drug,AED)的消化道吸收,而且可以在细胞和亚细胞水平调控药物在中枢神经系统的运输过程。除了生理和环境因素的影响,P-gp的功能和表达的变化可能主要取决于ABCB1基因的多态性,这是目前研究得最广泛、最深入的多药耐药机制。本文就目前ABCB1基因多态性与难治性癫痫的相关性研究进展作一综述。
文摘目的探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)患者纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,PAI-1)基因4G/5G及多药耐药性蛋白(ATP-binding cassette subfamily B member 1,ABCB1)基因C3435T多态性分布特征。方法 79例SLE患者依据脏器损伤情况分为SLE继发股骨头坏死(osteonecrosis of the femeral head,ONFH)组20例,狼疮肾炎(lupus nephritis,LN)组37例,其他组22例。采用数字荧光分子杂交技术检测3组外周血PAI-1基因4G/5G和ABCB1基因C3435T多态性,比较3组PAI-1基因高危4G4G型、ABCB1基因C3435T位点高危CC型分布频率。结果79例患者PAI-1基因4G4G、4G5G、5G5G基因型频率分别为29.1%、51.9%、19.0%,ABCB1基因C3435T位点CC、CT、TT基因型频率分别为41.7%、39.2%、19.1%;SLE-ONFH组、LN组PAI-1基因高危4G4G型分布频率(35.0%、35.1%)与其他组(13.6%)比较差异无统计学意义(P>0.05);SLE-ONFH组、LN组ABCB1基因C3435T位点高危CC型分布频率(50.0%、51.4%)高于其他组(18.2%)(P<0.05);SLE-ONFH组PAI-1基因高危4G4G型、ABCB1基因C3435T位点高危CC型分布频率与LN组比较差异无统计学意义(P>0.05)。结论 ABCB1基因C3435T位点高危CC型可能与SLE患者继发ONFH、LN有关。
