The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular t...The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.展开更多
BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate ...BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS:Fasting glucose,insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients.Insulin content,SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS:Insulinoma patients presented the typical demons-trations of Whipple’s triad.Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L,and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose.Immunohistochemistry and immunofluorescence staining showed that SUR1 increased,but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS:The hypersecretion of insulin in insulinomas might be,at least partially,due to the enrichment of SUR1. In contrast,MRP1,which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.展开更多
目的研究妊娠期糖尿病(GDM)孕妇胎盘组织中性激素结合球蛋白(SHBG)、胰岛素信号转导蛋白及葡萄糖转运蛋白表达,探讨其在GDM发病过程中的作用。方法收集足月妊娠且非肥胖(BMI<25 kg/m2)GDM孕妇(GDM组)和同期糖代谢正常(正常组)孕妇胎...目的研究妊娠期糖尿病(GDM)孕妇胎盘组织中性激素结合球蛋白(SHBG)、胰岛素信号转导蛋白及葡萄糖转运蛋白表达,探讨其在GDM发病过程中的作用。方法收集足月妊娠且非肥胖(BMI<25 kg/m2)GDM孕妇(GDM组)和同期糖代谢正常(正常组)孕妇胎盘组织各10例,应用Western blotting、实时PCR方法检测2组胎盘组织中SHBG和胰岛素信号转导蛋白(IRS-1、ISR-2、PI3K p85α)和葡萄糖转运蛋白(GLUT-1、GLUT-3、GLUT-4)的表达,各指标进行直线回归依存关系分析。结果与正常组比较,GDM组胎盘组织中SHBG m RNA、蛋白表达降低(P<0.05);IRS-1蛋白、IRS-2 m RNA表达降低(P<0.05);PI3K p85α和GLUT-1蛋白及其m RNA表达无统计学差异(P>0.05);GLUT-3蛋白,GLUT-4 m RNA、蛋白表达降低(P<0.05)。直线回归分析结果显示SHBG m RNA与IRS-2 m RNA、PI3K p85αm RNA、GLUT-4 m RNA的表达呈正相关(均P<0.05);IRS-2 m RNA和GLUT-4 m RNA的表达呈正相关(P<0.01);IRS-1 m RNA和PI3K p85αm RNA、GLUT-3 m RNA的表达呈负相关(P<0.05);IRS-2m RNA和GLUT-1 m RNA的表达正相关(P<0.01)。结论 GDM孕妇胎盘中胰岛素信号转导和葡萄糖转运蛋白存在异常,SHBG可能参与胰岛素信号通路的调节,GDM时胎盘滋养细胞合成和分泌SHBG减少,引起胰岛素信号转导通路相关蛋白表达降低,从而导致胰岛素抵抗及GDM的发生。展开更多
胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相...胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相关蛋白(multidrug-associated protein.MRP)等转运体介导的胆红素转运、PXR和CAR等核受体对UGTlAl介导的胆红素代谢调控、药物对胆红素代谢的抑制和诱导,及其与胆红素相关病症关系等方面的最新进展进行归纳和总结,为进一步研究和揭示黄疸、高胆红素血症、新生儿黄疸等胆红素相关病症的发生原因和发生机制提供参考,并为其诊断、预防和治疗提供最新科学依据。展开更多
Seizures may be the first or sometimes the only manifestation of patients with glioma in clinics. The aim of operation is to eliminate epilepsy far beyond mere resection of tumor mass. The underlyling mechanisms of gl...Seizures may be the first or sometimes the only manifestation of patients with glioma in clinics. The aim of operation is to eliminate epilepsy far beyond mere resection of tumor mass. The underlyling mechanisms of glioma-associated epileptogenesis are poorly understood. Recently the theory of amino-acid like neurotransmitters in chemical synapse is gradually accepted. However, the molecular mechanisms remain to be further investigated on how glutamate release is regulated and how synaptic homeostasis in peripheral neurons is kept or disturbed. So detailed studies are needed to clarify specific molecular target and provide proper evidence for optimal antiepileptic drugs in glioma-associated epileptoge-nesis.展开更多
基金Grants from Agencia Nacional de Promoción Científicay Tecnológica (PICT N° 05-26306)Consejo Nacional de Investigaciones Científicasy Técnicas (PIP N° 6442)Universidad Nacional de Rosario,Argentina
文摘The canalicular membrane represents the excretory pole of hepatocytes.Bile is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MDR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,respectively.At transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these transporters.This complex system is also responsible for alterations occurring in specific liver pathologies.We briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance proteins.Several therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these NRs.We provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.
文摘BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS:Fasting glucose,insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients.Insulin content,SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS:Insulinoma patients presented the typical demons-trations of Whipple’s triad.Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L,and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose.Immunohistochemistry and immunofluorescence staining showed that SUR1 increased,but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS:The hypersecretion of insulin in insulinomas might be,at least partially,due to the enrichment of SUR1. In contrast,MRP1,which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.
文摘目的研究妊娠期糖尿病(GDM)孕妇胎盘组织中性激素结合球蛋白(SHBG)、胰岛素信号转导蛋白及葡萄糖转运蛋白表达,探讨其在GDM发病过程中的作用。方法收集足月妊娠且非肥胖(BMI<25 kg/m2)GDM孕妇(GDM组)和同期糖代谢正常(正常组)孕妇胎盘组织各10例,应用Western blotting、实时PCR方法检测2组胎盘组织中SHBG和胰岛素信号转导蛋白(IRS-1、ISR-2、PI3K p85α)和葡萄糖转运蛋白(GLUT-1、GLUT-3、GLUT-4)的表达,各指标进行直线回归依存关系分析。结果与正常组比较,GDM组胎盘组织中SHBG m RNA、蛋白表达降低(P<0.05);IRS-1蛋白、IRS-2 m RNA表达降低(P<0.05);PI3K p85α和GLUT-1蛋白及其m RNA表达无统计学差异(P>0.05);GLUT-3蛋白,GLUT-4 m RNA、蛋白表达降低(P<0.05)。直线回归分析结果显示SHBG m RNA与IRS-2 m RNA、PI3K p85αm RNA、GLUT-4 m RNA的表达呈正相关(均P<0.05);IRS-2 m RNA和GLUT-4 m RNA的表达呈正相关(P<0.01);IRS-1 m RNA和PI3K p85αm RNA、GLUT-3 m RNA的表达呈负相关(P<0.05);IRS-2m RNA和GLUT-1 m RNA的表达正相关(P<0.01)。结论 GDM孕妇胎盘中胰岛素信号转导和葡萄糖转运蛋白存在异常,SHBG可能参与胰岛素信号通路的调节,GDM时胎盘滋养细胞合成和分泌SHBG减少,引起胰岛素信号转导通路相关蛋白表达降低,从而导致胰岛素抵抗及GDM的发生。
文摘胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相关蛋白(multidrug-associated protein.MRP)等转运体介导的胆红素转运、PXR和CAR等核受体对UGTlAl介导的胆红素代谢调控、药物对胆红素代谢的抑制和诱导,及其与胆红素相关病症关系等方面的最新进展进行归纳和总结,为进一步研究和揭示黄疸、高胆红素血症、新生儿黄疸等胆红素相关病症的发生原因和发生机制提供参考,并为其诊断、预防和治疗提供最新科学依据。
文摘Seizures may be the first or sometimes the only manifestation of patients with glioma in clinics. The aim of operation is to eliminate epilepsy far beyond mere resection of tumor mass. The underlyling mechanisms of glioma-associated epileptogenesis are poorly understood. Recently the theory of amino-acid like neurotransmitters in chemical synapse is gradually accepted. However, the molecular mechanisms remain to be further investigated on how glutamate release is regulated and how synaptic homeostasis in peripheral neurons is kept or disturbed. So detailed studies are needed to clarify specific molecular target and provide proper evidence for optimal antiepileptic drugs in glioma-associated epileptoge-nesis.
