Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pa...Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.展开更多
We improve the performance of organic light-emitting diodes （OLEDs） with both a MoO3 hole injection layer （HIL） and a MoO3 doped hole transport layer （HTL）, and present a systematical and comparative investigati...We improve the performance of organic light-emitting diodes （OLEDs） with both a MoO3 hole injection layer （HIL） and a MoO3 doped hole transport layer （HTL）, and present a systematical and comparative investigation on these devices. Compared with OLEDs with only MoO3 HIL or MoO3 doped HTL, OLEDs with both MoO3 HIL and MoO3 doped HTL show superior performance in driving voltage, power efficiency, and stability. Based on the typical NPB/Alq3 heterojunction structure, OLEDs with both MoO3 HIL and MoO3 doped HTL show a driving voltage of 5.4 V and a power efficiency of 1.41 lm/W for 1000 cd/m2, and a lifetime of around 0. 88 h with an initial luminance of 5268 cd/m2 under a constant current of 190 mA/cm2 operation in air without encapsulation. While OLEDs with only MoO3 HIL or MoO3 doped HTL show higher driving voltages of 6.4 V or 5.8 V and lower power efficiencies of 1.201m/W or 1.341m/W for 1000cd/m2, and a shorter lifetime of 0.33 or 0.60h with an initial luminance of around 5122 or 5300cd/m2 under a constant current of 200 or 216mA/cm2 operation. Our results demonstrate clearly that using both MoO3 HIL and MoO3 doped HTL is a simple and effective approach to simultaneoasly improve both the hole injection and transport efficiency, resulting from the lowered energy barrier at the anode interface and the increased hole carrier density in MoO3 doped HTL.展开更多
Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipient...Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipients. Methods Gene mutations ( SLCO1B3 T334G,SLCO1B1 A338G) were detected in 68 recipi-展开更多
目的 ：探讨Oatp3在PFOS诱导的支持细胞毒性中的作用。方法 ：体外分离纯化原代大鼠支持细胞,通过细胞毒性实验,观察PFOS对原代支持细胞生长的影响;利用Oatp3 si RNA构建Oatp3基因敲减模型,观察Oatp3在PFOS诱导的支持细胞毒性中的作用,...目的 ：探讨Oatp3在PFOS诱导的支持细胞毒性中的作用。方法 ：体外分离纯化原代大鼠支持细胞,通过细胞毒性实验,观察PFOS对原代支持细胞生长的影响;利用Oatp3 si RNA构建Oatp3基因敲减模型,观察Oatp3在PFOS诱导的支持细胞毒性中的作用,并采用Western blot法检测PFOS对Oatp3蛋白表达的影响。结果：0-30μmol/L剂量的PFOS对大鼠支持细胞生长无明显影响（P〉0.05）;当PFOS剂量增至40μmol/L时,对支持细胞毒性作用明显（P〈0.01）,PFOS毒作用的IC50值约为45.6μmol/L。40μmol/L的PFOS可明显诱导Oatp3蛋白的表达（P〈0.01）,联合Oatp3 si RNA处理后,其诱导作用明显抑制（P〈0.01）。与转染试剂对照组（Mock）相比,加入40μmol/L的PFOS后,支持细胞存活率明显降低（P〈0.01）,联合Oatp3 si RNA处理后,PFOS诱导的支持细胞毒性明显被抑制（P〈0.05或P〈0.01）。结论：Oatp3很可能参与PFOS诱导支持细胞损伤。展开更多
Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the p...Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates,mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes.Several inherited disorders characterised by impaired bilirubin conjugation(Crigler-Najjar syndrome typeⅠand typeⅡ,Gilbert syndrome)or transport(Dubin-Johnson and Rotor syndrome)result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type.Moreover,disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders.In this review,we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome.The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood,from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3.OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs,such as the intestine and kidney,and for a number of endogenous compounds,xenobiotics and drugs.Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins,sartans,methotrexate or rifampicin.The liverblood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.展开更多
Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells....Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells. Both anisodine and monocrotaline inhibited the OCTs and MATE transporters. The lowest IC50 was 12.9 μmol·L-1 of anisodine on OCT1 and the highest was 1.8 mmol·L-1 of monocrotaline on OCT2. Anisodine was a substrate of OCT2(Km = 13.3 ± 2.6 μmol·L-1 and Vmax = 286.8 ± 53.6 pmol/mg protein/min). Monocrotaline was determined to be a substrate of both OCT1(Km = 109.1 ± 17.8 μmol·L^-1, Vmax = 576.5 ± 87.5 pmol/mg protein/min) and OCT2(Km = 64.7 ± 14.8 μmol·L^-1, Vmax = 180.7 ± 22.0 pmol/mg protein/min), other than OCT3 and MATE transporters. The results indicated that OCT2 may be important for renal elimination of anisodine and OCT1 was responsible for monocrotaline uptake into liver. However neither MATE1 nor MATE2-K could facilitate transcellular transport of anisodine and monocrotaline. Accumulation of these drugs in the organs with high OCT1 expression(liver) and OCT2 expression(kidney) may be expected.展开更多
基金Supported by Grants from FONCYT(PICT 2007,No.00966, PICT 2010,No.2127)CONICET(PIP 2009-2011,No.1665, PIP2012-2015,No.00014)UNR PID(2008-2011/2012-2015)
文摘Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.
基金Supported by the National Natural Science Foundation of China under Grant No 11274402the National Basic Research Program of China under Grant No 2012CB933704+1 种基金the Natural Science Foundation of Guangdong Province under Grant No S2012020011003the Program for Changjiang Scholars and Innovative Research Team in University under Grant No IRT13042
文摘We improve the performance of organic light-emitting diodes （OLEDs） with both a MoO3 hole injection layer （HIL） and a MoO3 doped hole transport layer （HTL）, and present a systematical and comparative investigation on these devices. Compared with OLEDs with only MoO3 HIL or MoO3 doped HTL, OLEDs with both MoO3 HIL and MoO3 doped HTL show superior performance in driving voltage, power efficiency, and stability. Based on the typical NPB/Alq3 heterojunction structure, OLEDs with both MoO3 HIL and MoO3 doped HTL show a driving voltage of 5.4 V and a power efficiency of 1.41 lm/W for 1000 cd/m2, and a lifetime of around 0. 88 h with an initial luminance of 5268 cd/m2 under a constant current of 190 mA/cm2 operation in air without encapsulation. While OLEDs with only MoO3 HIL or MoO3 doped HTL show higher driving voltages of 6.4 V or 5.8 V and lower power efficiencies of 1.201m/W or 1.341m/W for 1000cd/m2, and a shorter lifetime of 0.33 or 0.60h with an initial luminance of around 5122 or 5300cd/m2 under a constant current of 200 or 216mA/cm2 operation. Our results demonstrate clearly that using both MoO3 HIL and MoO3 doped HTL is a simple and effective approach to simultaneoasly improve both the hole injection and transport efficiency, resulting from the lowered energy barrier at the anode interface and the increased hole carrier density in MoO3 doped HTL.
文摘Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipients. Methods Gene mutations ( SLCO1B3 T334G,SLCO1B1 A338G) were detected in 68 recipi-
文摘目的 ：探讨Oatp3在PFOS诱导的支持细胞毒性中的作用。方法 ：体外分离纯化原代大鼠支持细胞,通过细胞毒性实验,观察PFOS对原代支持细胞生长的影响;利用Oatp3 si RNA构建Oatp3基因敲减模型,观察Oatp3在PFOS诱导的支持细胞毒性中的作用,并采用Western blot法检测PFOS对Oatp3蛋白表达的影响。结果：0-30μmol/L剂量的PFOS对大鼠支持细胞生长无明显影响（P〉0.05）;当PFOS剂量增至40μmol/L时,对支持细胞毒性作用明显（P〈0.01）,PFOS毒作用的IC50值约为45.6μmol/L。40μmol/L的PFOS可明显诱导Oatp3蛋白的表达（P〈0.01）,联合Oatp3 si RNA处理后,其诱导作用明显抑制（P〈0.01）。与转染试剂对照组（Mock）相比,加入40μmol/L的PFOS后,支持细胞存活率明显降低（P〈0.01）,联合Oatp3 si RNA处理后,PFOS诱导的支持细胞毒性明显被抑制（P〈0.05或P〈0.01）。结论：Oatp3很可能参与PFOS诱导支持细胞损伤。
基金Supported by The Project(Ministry of Health,Czech Republic)for Development of Research Organization 00023001(IKEM,Prague,Czech Republic),Institutional support
文摘Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates,mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes.Several inherited disorders characterised by impaired bilirubin conjugation(Crigler-Najjar syndrome typeⅠand typeⅡ,Gilbert syndrome)or transport(Dubin-Johnson and Rotor syndrome)result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type.Moreover,disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders.In this review,we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome.The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood,from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3.OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs,such as the intestine and kidney,and for a number of endogenous compounds,xenobiotics and drugs.Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins,sartans,methotrexate or rifampicin.The liverblood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
基金supported by the Natural Science Foundation of Guangdong Province(No.2018A0303100026)German Research Foundation(DFG) Grant Clinical Research Group “Genotype-phenotype relationships and neurobiology of the longitudinal course of psychosis” in work package 3(No. BR2471/1-1) and DFG Grant(No. TZ74/1-1)
文摘Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells. Both anisodine and monocrotaline inhibited the OCTs and MATE transporters. The lowest IC50 was 12.9 μmol·L-1 of anisodine on OCT1 and the highest was 1.8 mmol·L-1 of monocrotaline on OCT2. Anisodine was a substrate of OCT2(Km = 13.3 ± 2.6 μmol·L-1 and Vmax = 286.8 ± 53.6 pmol/mg protein/min). Monocrotaline was determined to be a substrate of both OCT1(Km = 109.1 ± 17.8 μmol·L^-1, Vmax = 576.5 ± 87.5 pmol/mg protein/min) and OCT2(Km = 64.7 ± 14.8 μmol·L^-1, Vmax = 180.7 ± 22.0 pmol/mg protein/min), other than OCT3 and MATE transporters. The results indicated that OCT2 may be important for renal elimination of anisodine and OCT1 was responsible for monocrotaline uptake into liver. However neither MATE1 nor MATE2-K could facilitate transcellular transport of anisodine and monocrotaline. Accumulation of these drugs in the organs with high OCT1 expression(liver) and OCT2 expression(kidney) may be expected.
