Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in...Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in the gene coding for hOCT1 are important factors causing Imatinib resistance. We investigated the frequency of hOCT1 SNP C480G among Egyptian CML patients and its relation to early molecular response as an indicator of treatment outcome. Materials and Methods: Two groups of CML patients were included in this study. Group I consisted of 25 patients responding to Imatinib treatment (Imatinib responsive) and group II consisted of 25 patients resistant to Imatinib (Imatinib resistant). Response criteria were assessed according to the NCCN (National Comprehensive Cancer Network) guidelines 2017. Twenty healthy controls of matched age and sex were also included (group III). For all patients, we studied hOCT1 C480G at initial presentation using Taqman drug metabolism genotyping as well as BCR-ABL percent at diagnosis and after 3 months interval. Results: hOCT1 C480G was present in 32% of studied CML patients. CC (wild) was detected in 68% of group I and 64% of group II. CG (mutant heterozygous) was present in 28% of group I and 36% of group II while GG (mutant homozygous) was detected in only one case in group I. CG was also detected in 15% of control subjects There was no significant difference between hOCT1 C480G polymorphism and Early Molecular Response (χ2 = 0.089, p = 0.765). Conclusions: hOCT1 C480G polymorphism has no association with Imatinib resistance in Egyptian population. However, further studies on a larger number of patients are still needed to confirm this finding.展开更多
Employing cathode materials with multiple redox couples and electrolytes with efficient cation transport kinetics are two effective approaches to improving the electrochemical performance of batteries.In this work,for...Employing cathode materials with multiple redox couples and electrolytes with efficient cation transport kinetics are two effective approaches to improving the electrochemical performance of batteries.In this work,for the first time,we present a design strategy of simultaneously realizing reversible cationic and anionic redox chemistries as well as selective anion/cation transport in the viologen-based COFs(BAVCOF:X,coordinated anions of X=Cl^(-),Br^(-),I^(-),and ClO_(4)^(-))for high-performance Na-ion cathodes.Besides the cationic redox of viologen segments,the different redox activities of anions effectively tune the total capacities of the COFs.Meanwhile,electrochemical analysis and ab-initial molecular dynamics(AIMD)calculation illustrate that the anion/cation transport kinetics of electrolytes caged in the COFs'channels can be selectively tuned by the coordinated anions.As a result,combining high-potential Br-/Br_(2)redox couple,cationic redox of viologen segments,and enhanced Na+transport kinetics,the BAV-COF:Brdemonstrates stable performance with energy densities of 358.7 and 145.2 Wh kg^(-1)at power densities of 116.5 and 2124.1 W kg^(-1),respectively.This study offers new insight into the fabrication of organic cathodes with anionic redox and the advantages of COFs electrode materials in anion/cation transport selectivity for energy storage applications.展开更多
Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal...Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal Oct expressions using bile duct ligation(BDL)rats.Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure,associated with decreased intestinal absorption and increased urinary excretion.Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2.In vitro cell experiments show that chenodeoxycholic acid(CDCA),bilirubin and farnesoid X receptor(FXR)agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1,which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR.Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL,which are confirmed using CDCA-treated and bilirubin-treated rats.A disease-based physiologically based pharmacokinetic model characterizing intestinal,hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats.In conclusion,BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats,finally,decreasing plasma exposure and impairing hypoglycemic effects of metformin.BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.展开更多
AIM: To evaluate the inhibitory effects of apigenin and kaempferol on the uptake of several important solute carrier(SLC) transporters.METHODS: Various SLC transporters including the essential human organic anion tran...AIM: To evaluate the inhibitory effects of apigenin and kaempferol on the uptake of several important solute carrier(SLC) transporters.METHODS: Various SLC transporters including the essential human organic anion transporter 1(OAT1), OAT2, OAT3 and OAT4 as well as the important organic cation transporter 1(OCTN1) and OCTN2, were overexpressed in human embryonic kidney(HEK)-293 cells, a well-established cell model of transporter studies. Transport uptake assay was performed 24 h after the transfection. The transport activity was assessed with the uptake of previously determined transporter model substrates and the inhibitory effect of apigenin and kaempferol was evaluated with the substrate uptake in the presence of 10 μmol/L of each compound. Uptakemeasurements with varying concentrations of inhibitors(ranged from 0.0001 to 50 μmol/L) were performed to further characterize the inhibitory potency of apigenin and kaempferol. The IC50 value(the concentration that inhibits 50% of the transporter function) of each compound was then calculated by the nonlinear regression model of Graphpad Prism 6.0 software.RESULTS: Our data indicated that apigenin could potently inhibit the uptake of estrone-3-sulfate(ES) mediated by the HEK-293 cells expressing OAT2, OAT3 and OAT4 as well as the L-ergothioneine uptake via OCTN1-expressing HEK-293 cells. Among these transporters, the most prominent inhibition of apigenin was observed in the case of OAT3. Kaempferol showed significant inhibitory effects on the uptake of ES mediated through OAT2 and OAT3. Impaired L-ergothioneine uptake due to the presence of kaempferol was also observed in OCTN1-expressing HEK-293 cells. Similar to apigenin, kaempferol showed the most potent inhibitory effect on OAT3 as well. To further assess the inhibitory potencies of these two compounds on the uptake of ES mediated by OAT3-expressing HEK-293 cells, their IC50 values were then determined. Both chemicals showed pronounced inhibitory potencies on OAT3 with the IC50 values of 1.7 ± 0.1 and 1.0 ± 0.1 μmol/L(P < 0.01) for apigenin and kaempferol, respectively. CONCLUSION: Both apigenin and kaempferol are potent inhibitors of OAT3; precautions will be necessary when co-administrating them with drugs that are substrates of OAT3.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
MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte...MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].展开更多
文摘Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in the gene coding for hOCT1 are important factors causing Imatinib resistance. We investigated the frequency of hOCT1 SNP C480G among Egyptian CML patients and its relation to early molecular response as an indicator of treatment outcome. Materials and Methods: Two groups of CML patients were included in this study. Group I consisted of 25 patients responding to Imatinib treatment (Imatinib responsive) and group II consisted of 25 patients resistant to Imatinib (Imatinib resistant). Response criteria were assessed according to the NCCN (National Comprehensive Cancer Network) guidelines 2017. Twenty healthy controls of matched age and sex were also included (group III). For all patients, we studied hOCT1 C480G at initial presentation using Taqman drug metabolism genotyping as well as BCR-ABL percent at diagnosis and after 3 months interval. Results: hOCT1 C480G was present in 32% of studied CML patients. CC (wild) was detected in 68% of group I and 64% of group II. CG (mutant heterozygous) was present in 28% of group I and 36% of group II while GG (mutant homozygous) was detected in only one case in group I. CG was also detected in 15% of control subjects There was no significant difference between hOCT1 C480G polymorphism and Early Molecular Response (χ2 = 0.089, p = 0.765). Conclusions: hOCT1 C480G polymorphism has no association with Imatinib resistance in Egyptian population. However, further studies on a larger number of patients are still needed to confirm this finding.
基金supported by the NSFC/RGC Joint Research Scheme 2020/21(Project No:N_City U104/20)。
文摘Employing cathode materials with multiple redox couples and electrolytes with efficient cation transport kinetics are two effective approaches to improving the electrochemical performance of batteries.In this work,for the first time,we present a design strategy of simultaneously realizing reversible cationic and anionic redox chemistries as well as selective anion/cation transport in the viologen-based COFs(BAVCOF:X,coordinated anions of X=Cl^(-),Br^(-),I^(-),and ClO_(4)^(-))for high-performance Na-ion cathodes.Besides the cationic redox of viologen segments,the different redox activities of anions effectively tune the total capacities of the COFs.Meanwhile,electrochemical analysis and ab-initial molecular dynamics(AIMD)calculation illustrate that the anion/cation transport kinetics of electrolytes caged in the COFs'channels can be selectively tuned by the coordinated anions.As a result,combining high-potential Br-/Br_(2)redox couple,cationic redox of viologen segments,and enhanced Na+transport kinetics,the BAV-COF:Brdemonstrates stable performance with energy densities of 358.7 and 145.2 Wh kg^(-1)at power densities of 116.5 and 2124.1 W kg^(-1),respectively.This study offers new insight into the fabrication of organic cathodes with anionic redox and the advantages of COFs electrode materials in anion/cation transport selectivity for energy storage applications.
基金supported by the National Natural Science Foundation of China(Nos.82173884,81872930,82073922 and 81872833)the“Double First-Class”university project(No.CPU2018GY22,China)。
文摘Body is equipped with organic cation transporters(OCTs).These OCTs mediate drug transport and are also involved in some disease process.We aimed to investigate whether liver failure alters intestinal,hepatic and renal Oct expressions using bile duct ligation(BDL)rats.Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure,associated with decreased intestinal absorption and increased urinary excretion.Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2.In vitro cell experiments show that chenodeoxycholic acid(CDCA),bilirubin and farnesoid X receptor(FXR)agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1,which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR.Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL,which are confirmed using CDCA-treated and bilirubin-treated rats.A disease-based physiologically based pharmacokinetic model characterizing intestinal,hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats.In conclusion,BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats,finally,decreasing plasma exposure and impairing hypoglycemic effects of metformin.BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.
基金Supported by Internal funding from Faculty of Pharmacy,the University of Sydney,Australia
文摘AIM: To evaluate the inhibitory effects of apigenin and kaempferol on the uptake of several important solute carrier(SLC) transporters.METHODS: Various SLC transporters including the essential human organic anion transporter 1(OAT1), OAT2, OAT3 and OAT4 as well as the important organic cation transporter 1(OCTN1) and OCTN2, were overexpressed in human embryonic kidney(HEK)-293 cells, a well-established cell model of transporter studies. Transport uptake assay was performed 24 h after the transfection. The transport activity was assessed with the uptake of previously determined transporter model substrates and the inhibitory effect of apigenin and kaempferol was evaluated with the substrate uptake in the presence of 10 μmol/L of each compound. Uptakemeasurements with varying concentrations of inhibitors(ranged from 0.0001 to 50 μmol/L) were performed to further characterize the inhibitory potency of apigenin and kaempferol. The IC50 value(the concentration that inhibits 50% of the transporter function) of each compound was then calculated by the nonlinear regression model of Graphpad Prism 6.0 software.RESULTS: Our data indicated that apigenin could potently inhibit the uptake of estrone-3-sulfate(ES) mediated by the HEK-293 cells expressing OAT2, OAT3 and OAT4 as well as the L-ergothioneine uptake via OCTN1-expressing HEK-293 cells. Among these transporters, the most prominent inhibition of apigenin was observed in the case of OAT3. Kaempferol showed significant inhibitory effects on the uptake of ES mediated through OAT2 and OAT3. Impaired L-ergothioneine uptake due to the presence of kaempferol was also observed in OCTN1-expressing HEK-293 cells. Similar to apigenin, kaempferol showed the most potent inhibitory effect on OAT3 as well. To further assess the inhibitory potencies of these two compounds on the uptake of ES mediated by OAT3-expressing HEK-293 cells, their IC50 values were then determined. Both chemicals showed pronounced inhibitory potencies on OAT3 with the IC50 values of 1.7 ± 0.1 and 1.0 ± 0.1 μmol/L(P < 0.01) for apigenin and kaempferol, respectively. CONCLUSION: Both apigenin and kaempferol are potent inhibitors of OAT3; precautions will be necessary when co-administrating them with drugs that are substrates of OAT3.
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.
基金supported by"H+Die Spitaler der Schweiz" the Swiss Agency for Development and Cooperation(DEZA)by the University Hospital Zurich/Switzerland
文摘MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].
