AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and con...AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.展开更多
目的利福平(Rifampicin,RIF)具有肝毒性,但其机制尚不清楚。本研究在RIF诱导的肝内胆汁淤积小鼠中,探讨RIF对肝细胞胆汁酸转运体胆汁酸输出泵(bile salt exportpump,Bsep)和多药抵抗相关蛋白-2(multidrug resistance-associated protein...目的利福平(Rifampicin,RIF)具有肝毒性,但其机制尚不清楚。本研究在RIF诱导的肝内胆汁淤积小鼠中,探讨RIF对肝细胞胆汁酸转运体胆汁酸输出泵(bile salt exportpump,Bsep)和多药抵抗相关蛋白-2(multidrug resistance-associated protein-2,Mrp2)表达和定位影响。方法 48只♀ICR小鼠随机分为4组,RIF1wk组:经灌胃给予RIF(200mg.kg-1.d-1),连续1周,于末次给药后6h取材;RIF6h组:单次灌胃给予RIF(200mg.kg-1)后6h取材;RIF1周对照组(CON1wk)与RIF6h对照组(CON6h):经灌胃给予等容积生理盐水。所有小鼠均收集血液和肝组织,常规生化检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)、总胆红素(TB)和结合胆红素(DB),并检测小鼠血清和肝组织总胆汁酸(TBA)水平。HE染色分析肝组织病理改变。RT-PCR测定肝脏肝细胞胆汁酸转运体Bsep和Mrp2mRNA表达。免疫荧光法分析Bsep和Mrp2在肝细胞的位置。结果给予RIF1周后,小鼠血清TB由(1.25±0.69)μmol.L-1上升至(65.73±12.08)μmol.L-1,上升近70倍,DB由(0.77±0.40)μmol.L-1上升至(53.33±12.43)μmol.L-1,上升约80倍,ALP由(110.2±13.8)U.L-1上升至(279.5±80.4)U.L-1,上升约1.5倍,TBA由(3.15±0.89)μmol.L-1上升至(13.54±6.51)μmol.L-1,上升约5倍并伴有血清ALT和AST轻度升高;肝脏组织TBA由(0.15±0.04)μmol.g-1liver上升至(0.30±0.19)μmol.g-1liver,上升约2倍;肝脏组织HE染色显示肝细胞出现脂肪变性、轻度坏死和炎症。单次给予RIF6h后血清TB、DB、ALP、ALT、AST和TBA明显上升,但未观察到小鼠肝脏组织病理发生改变。免疫荧光分析显示,给予小鼠RIF1wk与单次给予RIF6h后肝细胞中Bsep和Mrp2的定位发生了改变。而无论单次给予RIF还是连续给药1周,肝细胞Bsep和Mrp2mRNA表达水平均未发生变化。结论肝细胞胆汁酸转运体Bsep和Mrp2定位改变可能是RIF诱发肝内胆汁淤积的重要机制。展开更多
急性髓系白血病(AML)是以骨髓和血液中的骨髓原始细胞克隆性增殖为特征的血液系统恶性肿瘤。尽管研究者们不断提出新的治疗方案,但患者的总体预后并没有产生显著改善。核输出蛋白1(nuclear export protein 1,XPO1)抑制剂通过抑制导致肿...急性髓系白血病(AML)是以骨髓和血液中的骨髓原始细胞克隆性增殖为特征的血液系统恶性肿瘤。尽管研究者们不断提出新的治疗方案,但患者的总体预后并没有产生显著改善。核输出蛋白1(nuclear export protein 1,XPO1)抑制剂通过抑制导致肿瘤发生的关键物质穿过癌细胞核膜而在癌症中发挥重要作用,其能促进AML细胞的细胞周期停滞和凋亡,与其他靶向药物或化疗方案组合能发挥广泛的抗癌作用并有较好的安全性。该文主要对XPO1抑制剂塞利尼索治疗AML的研究进展进行综述。展开更多
BACKGROUND: Cholecyst cholesterol lithiasis is a common disease of the digestive system; however, the cause of lithogenesis is still unclear. Although bile salt export pump (BSEP), multidrug resistance protein 2 (MRP2...BACKGROUND: Cholecyst cholesterol lithiasis is a common disease of the digestive system; however, the cause of lithogenesis is still unclear. Although bile salt export pump (BSEP), multidrug resistance protein 2 (MRP2), and multiple drug resistance 3 (MDR3 ) are 3 well-known transporting proteins, their effect on lithogenesis has not been elucidated. This study was undertaken to examine the relationship between BSEP, MRP2, MDR3, and cholesterol calculus formation. METHODS: Liver tissue specimens were taken from 20 patients with cholesterol calculus and from 10 patients with normal liver. mRNA and protein expressions of BSEP, MRP2, and MDR3 were determined by reverse tran-scriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. This study was approved by the ethics committee of China Medical University and informed consent was obtained from all patients. RESULTS: mRNA and protein expressions of BSEP, MRP2, and MDR3 were significantly down-regulated in the liver tissue of the patients with cholesterol calculus compared with normal liver tissue of the controls. CONCLUSION: The down-regulation of BSEP, MRP2, and MDR3 may be correlated with the formation of cholesterol calculus.展开更多
核输出蛋白是细胞核质运输中的重要蛋白。核输出蛋白1(export protein 1,XPO1)可介导包括p53在内的多种肿瘤抑制蛋白以及细胞周期调节蛋白的转运。抑制XPO1的转运功能可影响细胞增殖、分化、凋亡等过程,达到抗肿瘤目的。本文就核输出蛋...核输出蛋白是细胞核质运输中的重要蛋白。核输出蛋白1(export protein 1,XPO1)可介导包括p53在内的多种肿瘤抑制蛋白以及细胞周期调节蛋白的转运。抑制XPO1的转运功能可影响细胞增殖、分化、凋亡等过程,达到抗肿瘤目的。本文就核输出蛋白抑制剂在血液肿瘤常见基因突变和部分常用抗肿瘤药物耐药性方面的研究展开综述,探讨核输出蛋白抑制剂在血液肿瘤以及更多领域的应用。展开更多
核输出蛋白(NEP)是一个由甲型流感病毒第8段基因编码的约为14 k D的蛋白。NEP最初被认为参与病毒核糖核蛋白复合体的出核。相对于流感病毒的其他几个蛋白,关于NEP的研究很少被报道。近年来,随着蛋白立体结构的确定、研究的不断深入,NEP...核输出蛋白(NEP)是一个由甲型流感病毒第8段基因编码的约为14 k D的蛋白。NEP最初被认为参与病毒核糖核蛋白复合体的出核。相对于流感病毒的其他几个蛋白,关于NEP的研究很少被报道。近年来,随着蛋白立体结构的确定、研究的不断深入,NEP在流感病毒活动中很多意想不到的作用不断被发现。这些研究显示NEP参与病毒的转录和复制,促进H5N1禽流感病毒在哺乳动物体内的适应以及参与病毒的出芽。本文系统总结了NEP的功能,包括参与病毒核糖核蛋白复合体的出核的过程、调节病毒聚合酶的活性以及帮助H5N1禽流感病毒实现跨种间传播等,为进一步研究NEP奠定基础。展开更多
目的探讨胆汁酸盐输出泵(bile salt export pump,BSEP)、多药耐药相关蛋白2(multidrug resistant protein 2,MRP2)和多药耐药糖蛋白3(multidrug resistance associated protein 3,MDR3)在原发性胆汁性胆管炎(primary biliary cholangiti...目的探讨胆汁酸盐输出泵(bile salt export pump,BSEP)、多药耐药相关蛋白2(multidrug resistant protein 2,MRP2)和多药耐药糖蛋白3(multidrug resistance associated protein 3,MDR3)在原发性胆汁性胆管炎(primary biliary cholangitis,PBC)患者肝组织中的表达特点。方法收集2009年1月至2019年12月于南昌市第九医院住院且经肝组织病理诊断为PBC的46例患者临床资料,根据PBC严重程度分为PBC早期组(Ⅰ~Ⅱ期,31例)和PBC晚期组(Ⅲ~Ⅳ期,15例),比较两组患者血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate transaminase,AST)、总胆汁酸(total bile acid,TBA)、总胆红素(total bilirubin,TBil)、直接胆红素(direct bilirubin,DBil)、碱性磷酸酶(alkaline phosphatase,ALP)、γ-谷氨酰转移酶(gamma-glutamyltransferase,GGT)、高密度脂蛋白(high-density lipoprotein,HDL)、总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白(low-density lipoprotein,LDL)等的差异。选取10例慢性乙型肝炎病毒(hepatitis B virus,HBV)携带者作为对照组。对所有入选病例肝组织进行BSEP、MDR3、MRP2免疫组织化学标记,观察各组肝组织病理形态及3种转运蛋白表达差异。结果PBC晚期组患者血清ALP(中位数:404 U/L vs 281 U/L)、GGT(中位数:437 U/L vs 245 U/L)、TC(中位数:6.58 mg/L vs 4.50 mg/L)、TG(中位数:1.72 mg/L vs 1.24 mg/L)、LDL(中位数:3.61 mg/L vs 2.27 mg/L)水平均显著低于PBC早期组,差异有统计学意义(P均<0.05)。两组患者年龄、性别、血清ALT、AST、TBA、TBil、DBil、HDL水平及AMA阳性率差异均无统计学意义(P均>0.05)。与PBC早期组相比,PBC晚期组患者炎症活动度和纤维化程度均较重,差异有统计学意义(χ^(2)=14.71,P=0.0006;χ^(2)=20.57,P<0.001)。PBC早期组与PBC晚期组患者肝细胞CK7和CK19染色阳性率无统计学差异[54.84%(17/31)vs 46.67%(7/15),χ^(2)=0.271、P=0.755;74.19%(23/31)vs 86.67%(13/15),连续校正χ^(2)=0展开更多
基金Supported by Grants from the Gebert Rüf Foundation, the Forschungskredit of the University Zurichthe Swiss National Science Foundation, Grants PP00B-108511/1 and 31-64140.00
文摘AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.
文摘急性髓系白血病(AML)是以骨髓和血液中的骨髓原始细胞克隆性增殖为特征的血液系统恶性肿瘤。尽管研究者们不断提出新的治疗方案,但患者的总体预后并没有产生显著改善。核输出蛋白1(nuclear export protein 1,XPO1)抑制剂通过抑制导致肿瘤发生的关键物质穿过癌细胞核膜而在癌症中发挥重要作用,其能促进AML细胞的细胞周期停滞和凋亡,与其他靶向药物或化疗方案组合能发挥广泛的抗癌作用并有较好的安全性。该文主要对XPO1抑制剂塞利尼索治疗AML的研究进展进行综述。
文摘BACKGROUND: Cholecyst cholesterol lithiasis is a common disease of the digestive system; however, the cause of lithogenesis is still unclear. Although bile salt export pump (BSEP), multidrug resistance protein 2 (MRP2), and multiple drug resistance 3 (MDR3 ) are 3 well-known transporting proteins, their effect on lithogenesis has not been elucidated. This study was undertaken to examine the relationship between BSEP, MRP2, MDR3, and cholesterol calculus formation. METHODS: Liver tissue specimens were taken from 20 patients with cholesterol calculus and from 10 patients with normal liver. mRNA and protein expressions of BSEP, MRP2, and MDR3 were determined by reverse tran-scriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. This study was approved by the ethics committee of China Medical University and informed consent was obtained from all patients. RESULTS: mRNA and protein expressions of BSEP, MRP2, and MDR3 were significantly down-regulated in the liver tissue of the patients with cholesterol calculus compared with normal liver tissue of the controls. CONCLUSION: The down-regulation of BSEP, MRP2, and MDR3 may be correlated with the formation of cholesterol calculus.
文摘核输出蛋白是细胞核质运输中的重要蛋白。核输出蛋白1(export protein 1,XPO1)可介导包括p53在内的多种肿瘤抑制蛋白以及细胞周期调节蛋白的转运。抑制XPO1的转运功能可影响细胞增殖、分化、凋亡等过程,达到抗肿瘤目的。本文就核输出蛋白抑制剂在血液肿瘤常见基因突变和部分常用抗肿瘤药物耐药性方面的研究展开综述,探讨核输出蛋白抑制剂在血液肿瘤以及更多领域的应用。
文摘核输出蛋白(NEP)是一个由甲型流感病毒第8段基因编码的约为14 k D的蛋白。NEP最初被认为参与病毒核糖核蛋白复合体的出核。相对于流感病毒的其他几个蛋白,关于NEP的研究很少被报道。近年来,随着蛋白立体结构的确定、研究的不断深入,NEP在流感病毒活动中很多意想不到的作用不断被发现。这些研究显示NEP参与病毒的转录和复制,促进H5N1禽流感病毒在哺乳动物体内的适应以及参与病毒的出芽。本文系统总结了NEP的功能,包括参与病毒核糖核蛋白复合体的出核的过程、调节病毒聚合酶的活性以及帮助H5N1禽流感病毒实现跨种间传播等,为进一步研究NEP奠定基础。
文摘目的探讨胆汁酸盐输出泵(bile salt export pump,BSEP)、多药耐药相关蛋白2(multidrug resistant protein 2,MRP2)和多药耐药糖蛋白3(multidrug resistance associated protein 3,MDR3)在原发性胆汁性胆管炎(primary biliary cholangitis,PBC)患者肝组织中的表达特点。方法收集2009年1月至2019年12月于南昌市第九医院住院且经肝组织病理诊断为PBC的46例患者临床资料,根据PBC严重程度分为PBC早期组(Ⅰ~Ⅱ期,31例)和PBC晚期组(Ⅲ~Ⅳ期,15例),比较两组患者血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate transaminase,AST)、总胆汁酸(total bile acid,TBA)、总胆红素(total bilirubin,TBil)、直接胆红素(direct bilirubin,DBil)、碱性磷酸酶(alkaline phosphatase,ALP)、γ-谷氨酰转移酶(gamma-glutamyltransferase,GGT)、高密度脂蛋白(high-density lipoprotein,HDL)、总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白(low-density lipoprotein,LDL)等的差异。选取10例慢性乙型肝炎病毒(hepatitis B virus,HBV)携带者作为对照组。对所有入选病例肝组织进行BSEP、MDR3、MRP2免疫组织化学标记,观察各组肝组织病理形态及3种转运蛋白表达差异。结果PBC晚期组患者血清ALP(中位数:404 U/L vs 281 U/L)、GGT(中位数:437 U/L vs 245 U/L)、TC(中位数:6.58 mg/L vs 4.50 mg/L)、TG(中位数:1.72 mg/L vs 1.24 mg/L)、LDL(中位数:3.61 mg/L vs 2.27 mg/L)水平均显著低于PBC早期组,差异有统计学意义(P均<0.05)。两组患者年龄、性别、血清ALT、AST、TBA、TBil、DBil、HDL水平及AMA阳性率差异均无统计学意义(P均>0.05)。与PBC早期组相比,PBC晚期组患者炎症活动度和纤维化程度均较重,差异有统计学意义(χ^(2)=14.71,P=0.0006;χ^(2)=20.57,P<0.001)。PBC早期组与PBC晚期组患者肝细胞CK7和CK19染色阳性率无统计学差异[54.84%(17/31)vs 46.67%(7/15),χ^(2)=0.271、P=0.755;74.19%(23/31)vs 86.67%(13/15),连续校正χ^(2)=0
