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
Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided i...Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided into three groups: blank control group, model group and Cangfudaotan Tang group, 12 cases in each one. After PCOS rat models were made, rats of Cangfudaotan Tang group were treated with Cangfudaotan Tang (1.42 g/kg/d) by intragastric administration for 14 days;blank control and model group were given with isodose saline. The expression of oatp2b1 mRNA/Protein in liver and kidney tissues was measured and the level of testosterone (T), follicle stimulating hormone(FSH), estradiol (E<sub>2</sub>), luteinizing hormone(LH), Serum total cholesterol (TG), Triacylglycerols (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were detected at the same time. Results: Compared with blank control group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL, LH, FSH, T in model group were significantly increased (P < 0. 05), while the level of HDL was significantly decreased (P < 0. 05);compared with model group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL in Cangfudaotan Tang group were significantly lowered (P < 0.05);the level of HDL was significantly higher;the oatp2b1 protein in kidney and liver tissues had different degrees of expression, while there was no statistical significance among the three groups. Conclusions: Oatp2b1 might be one of the material bases participating in transportation and transformation of phlegmy dampness. The mechanism of Cangfudaotan Tang treating phlegm dampness type of PCOS may be achieved by regulating the expression of oatp2b1.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
Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectiv...Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectively.They are expressed in many tissues,such as the liver and kidney,and mediate the absorption and excretion of many endogenous and exogenous substances,including various drugs.Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm.OATs and OATPs are abundantly expressed in the liver,where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs.However,differences in the locations of glycosylation sites,phosphorylation sites,and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver,which ultimately results in their different roles in the liver.To date,few articles have addressed these aspects of OAT and OATP structures,and we study further the similarities and differences in their structures,tissue distribution,substrates,and roles in liver diseases.展开更多
To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam,renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats.A b...To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam,renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats.A bacteremia model was established to investigate the pharmacokinetic properties of piperacillin and tazobactam under different conditions.Renal slices were taken to examine the uptake of piperacillin and tazobactam.Pharmacokinetic studies ofβ-lactamase in rats were performed to study the contribution of rOat1/3 to the inhibition of tazobactam onβ-lactamase.The AUC(from 2.93±0.58 to 6.52±1.44 mg·min/ml)and the plasma clearance(CL P)(from 2.41±1.20 to 0.961±0.212 ml/min/kg)of tazobactam were both altered after the intravenous coadministration of piperacillin and tazobactam in the bacteremia rats.The renal clearance(CL R)of tazobactam decreased from 1.30±0.50 to 0.361±0.043 ml/min/kg.In summary,there was a beneficial interaction between piperacillin and tazobactam mediated by rOat1 and rOat3.Piperacillin enhances the inhibitory effect of tazobactam onβ-lactamase through the inhibition of rOat1 and rOat3 in rats.The contribution rate of rOat1/3 for the synergistic effect was 20%when the two drugs were coadministered.展开更多
In this paper,we demonstrate that modification of anion-transport:active l,3-bis(benzimidazol-2-yl)benzene with strongly electron-withdrawing trifluoromethyl and nitro groups leads to a dramatic increase in the aniono...In this paper,we demonstrate that modification of anion-transport:active l,3-bis(benzimidazol-2-yl)benzene with strongly electron-withdrawing trifluoromethyl and nitro groups leads to a dramatic increase in the anionophoric activity,and the activity may be greatly regulated by the curvatures of the liposomes used.展开更多
Organic anion transporter 3(OAT3)plays a vital role in removing a broad variety of anionic drugs from kidney,thus avoiding their possible toxicity in the body.In the current study,we investigated the role of insulin-l...Organic anion transporter 3(OAT3)plays a vital role in removing a broad variety of anionic drugs from kidney,thus avoiding their possible toxicity in the body.In the current study,we investigated the role of insulin-like growth factor 1(IGF-1)in the regulation of OAT3.We showed that IGF-1 induced a dose-and time-dependent increase in OAT3 transport activity,which correlated well with an increase in OAT3 expression.The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A(PKA)inhibitor H89.Moreover,IGF-1 induced an increase in OAT3 phosphorylation,which was also blocked by H89.These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway.To further confirm the involvement of PKA,we treated OAT3-expressing cells with PKA activator Bt’2-cAMP,followed by examining OAT activity and phosphorylation.We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells.Finally,linsitinib,an anticancer drug that blocks the IGF-1 receptor,abrogated IGF-1-stimulated OAT3 transport activity.In conclusion,our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway,possibly by phosphorylating the transporter.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
BACKGROUND Neoadjuvant chemotherapy can cause hepatic sinusoidal obstruction syndrome(SOS)in patients with colorectal cancer liver metastases and increases posto-perative morbidity and mortality.AIM To evaluate T1 map...BACKGROUND Neoadjuvant chemotherapy can cause hepatic sinusoidal obstruction syndrome(SOS)in patients with colorectal cancer liver metastases and increases posto-perative morbidity and mortality.AIM To evaluate T1 mapping based on gadoxetic acid-enhanced magnetic resonance imaging(MRI)for diagnosis of hepatic SOS induced by monocrotaline.METHODS Twenty-four mice were divided into control(n=10)and experimental(n=14)groups.The experimental groups were injected with monocrotaline 2 or 6 days before MRI.MRI parameters were:T1 relaxation time before enhancement;T1 relaxation time 20 minutes after enhancement(T_(1post));a reduction in T1 relaxation time(△T_(1)%);and first enhancement slope percentage of the liver parenchyma(ESP).Albumin and bilirubin score was determined.Histological results served as a reference.Liver parenchyma samples from the control and experimental groups were analyzed by western blotting,and organic anion transporter polypeptide 1(OATP1)was measured.RESULTS T_(1post),△T_(1)%,and ESP of the liver parenchyma were significantly different between two groups(all P<0.001)and significantly correlated with the total histological score of hepatic SOS(r=-0.70,0.68 and 0.79;P<0.001).△T_(1)%and ESP were positively correlated with OATP1 levels(r=0.82,0.85;P<0.001),whereas T_(1post) had a negative correlation with OATP1 levels(r=-0.83;P<0.001).INTRODUCTION Hepatic sinusoidal obstruction syndrome(SOS)is also known as hepatic veno-occlusive disease of the liver[1].The main pathological feature of hepatic SOS is damage to liver terminal vessels,and the clinical symptoms of it include ascites and abdominal pain[2].It was first proposed in 1979 as an early complication of hematopoietic stem cell transplantation[3].The prevalence ranges from 5%to 60%,and hepatic SOS is a potentially severe complication and can even lead to death in severe cases[4].Recently,systemic neoadjuvant chemotherapy became widely regarded as one of the causes hepatic SOS in the patients with advanced metastatic colorectal cancer[5,6],especially those were treated with oxaliplatin[7,8].Oxaliplatin-based preoperative chemotherapy is used for patients with colorectal liver metastases as the standard regimen[8,9],because it could improve tumor resection outcome by shrinking the metastatic sites and reducing recurrence rate[10].Nevertheless,chemotherapy-induced hepatic SOS has been associated with a higher risk of postresection morbidity[11],such as intraoperative bleeding,intraoperative transfusions,and postoperative liver failure[12].Therefore,it is important to detect and diagnose of hepatic SOS timely.Currently,the gold standard is still based on liver biopsy[13],but it is an invasive procedure and has several limitations and complications,such as hemorrhage[14].A noninvasive diagnostic modality is needed for the assessment of hepatic SOS.Some noninvasive tools have been used for diagnosis of hepatic SOS.Researchers have utilized a preoperative platelet count and aspartate aminotransferase to platelet ratio index[15].In addition,some imaging methods such as shear wave ultrasonography,computed tomography,and gadoxetic acid-enhanced magnetic resonance imaging(MRI)have been promoted as useful methods for evaluation of hepatic SOS[16-18].Recent studies with monocrotaline(MCT)-treated rats were conducted to investigate diagnosis and prediction of severity of SOS.For example,intravoxel incoherent motion diffusion-weighted imaging,non-Gaussian diffusion models,and T1 rho quantification[19,20].The MCT-induced hepatic SOS animal model was reproducible,with a detailed pathological scoring criteria[21].Gadoxetic acid is a hepatocyte-specific contrast substance,which can provide parenchymal contrast in the hepato-biliary phase.It is reported that gadoxetic acid is absorbed into the liver parenchyma via organic anion transporter polypeptide 1(OATP1)on the hepatocyte membranes[22-24].Recently,several authors have described the feasibility of gadoxetic acid-enhanced MRI for the diagnosis of oxaliplatin-induced hepatic SOS[25].They mainly diagnosed hepatic SOS based on the signal intensity of the hepatobiliary specific phase.However,there were several limitations due to the inconsistency between signal intensity of the liver parenchyma and the concentration of contrast agent for evaluation of the degree of hepatic SOS[26].Therefore,we measured T1 relaxation time on parametric mapping because it is linearly related to the concentration of the contrast agent and is not affected by other factors[27].Yang et al[28]demonstrated T1 mapping on gadoxetic acid-enhanced MRI for the assessment of oxaliplatin-induced liver injury in a C57BL/6 mouse model.However,the main pathological changes in their model were hepatocyte degeneration and fibrosis.Therefore,we aimed to explore the effectiveness of T1 mapping based on gadoxetic acid-enhanced MRI for the diagnosis of hepatic SOS in a C57BL/6 mouse model,as well as a possible relation between OATP1 Levels and MRI parameters.展开更多
GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address th...GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address the question, first, 5’ Rapid amplification of cDNA end (RACE) was used to determine GAT1 transcriptional starting sites in neonatal mouse cerebral cortex and intestine, adult mouse brain and adult rat testis. The products of 5’RACE were confirmed by DNA sequencing. We found that the transcript of GAT1 in neonatal mouse cerebral cortex and adult mouse brain starts at the same site (inside of exon 1), while in mouse intestine, GAT1 starts transcription in intron 1, and in rat testis, the transcript of GAT1 has an additional untranslation exon to the 5’ direction.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
AIM: We have previously demonstrated that cholangiocytes, the epithelial cells lining intrahepatic bile ducts,encode two functional bile acid transporters via alternative splicing of a single gene to facilitate bile a...AIM: We have previously demonstrated that cholangiocytes, the epithelial cells lining intrahepatic bile ducts,encode two functional bile acid transporters via alternative splicing of a single gene to facilitate bile acid vectorial transport. Cholangiocytes possess ASBT,an apical sodium-dependent bile acid transporter to take up bile acids,and t-ASBT,a basolateral alternatively spliced and truncated form of ASBT to efflux bile acids.Though hepatocyte and ileal bile acid transporters are in part regulated by the flux of bile acids, the effect of alterations in bile acid flux on the expression of t-ASBT in terminal ileocytes remains undear.Thus,we tested the hypothesis that expression of ASBT and t-ASBT in cholangiocytes and ileocytes was regulated by bile acid flux. METHODS: Expression of ASBT and t-ASBT message and protein in cholangiocytes and ileocytes isolated from pair- fed rats given control (C) and 1% taurocholate (TCA) or 5% cholestyramine (CY) enriched diets,were assessed by both quantitative RNase protection assays and quantitative immunoblotting.The data obtained from each of the control groups were pooled to reflect the changes observed following TCA and CY treatments with respect to the control diets. Cholangiocyte taurocholate uptake was determined using a novel microperfusion technique on intrahepatic bile duct units (IBDUs) derived from C,TCA and CY fed rats. RESULTS: In cholangiocytes,both ASBT and t-ASBT message RNA and protein were significantly decreased in response to TCA feeding compared to C diet.In contrast, message and protein of both bile acid transporters significantly increased following CY feeding compared to C diet.In the ileum,TCA feeding significantly up-regulated both ASBT and t-ASBT message and protein compared to C diet,while CY feeding significantly down-regulated message and protein of both bile acid transporters compared to C diet.As anticipated from alterations in cholangiocyte ASBT expression,the uptake of taurocholate in microperfused IBDUs derived from rats on TCA diet decreased 2.7-fold,whereas it increased 1.7-fold in those on CY diet compared to C diet fed groups. CONCLUSION: These data demonstrate that expression of ASBT and t-ASBT in cholangiocytes is regulated by a negative feedback loop while the expression of these transporters in terminal ileum is modified via positive feedback.Thus, while transcriptional regulatory mechanisms in response to alterations in bile acid pool size are operative in both cholangiocytes and ileocytes,each cell type responds differently to bile acid supplementation and depletion.展开更多
BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane tr...BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.展开更多
AIM: To examine renal expression of organic anion transporter 5(Oat5) and sodium-dicarboxylate cotransporter 1(Na DC1), and excretion of citrate in rats with acute extrahepatic cholestasis.METHODS: Obstructive jaundic...AIM: To examine renal expression of organic anion transporter 5(Oat5) and sodium-dicarboxylate cotransporter 1(Na DC1), and excretion of citrate in rats with acute extrahepatic cholestasis.METHODS: Obstructive jaundice was induced in rats by double ligation and division of the common bile duct(BDL group). Controls underwent sham operation that consisted of exposure, but not ligation, of the common bile duct(Sham group). Studies were performed 21 h after surgery. During this period, animals were maintained in metabolic cages in order to collect urine. The urinary volume was determined by gravimetry. The day of the experiment, blood samples were withdrawn and used to measure total and direct bilirubin as indicative parameters of hepatic function. Serum and urine samples were used for biochemical determinations. Immunoblotting for Oat5 and Na DC1 were performed in renal homogenates and brush border membranes from Sham and BDL rats. Immunohistochemistry studies were performed in kidneys from both experimental groups. Total RNA was extracted from rat renal tissue in order to perform reverse transcription polymerase chain reaction. Another set of experimental animals were used toevaluate medullar renal blood flow(m RBF) using fluorescent microspheres.RESULTS: Total and direct bilirubin levels were significantly higher in BDL animals, attesting to the adequacy of biliary obstruction. An important increase in m RBF was determined in BDL group(Sham: 0.53 ± 0.12 m L/min per 100 g body weight vs BDL: 1.58 ± 0.24 m L/min per 100 g body weight, P < 0.05). An increase in the urinary volume was observed in BDL animals. An important decrease in urinary levels of citrate was seen in BDL group. Besides, a decrease in urinary citrate excretion(Sham: 0.53 ± 0.11 g/g creatinine vs BDL: 0.07 ± 0.02 g/g creatinine, P < 0.05) and an increase in urinary excretion of H+(Sham: 0.082 ± 0.03 μmol/g creatinine vs BDL: 0.21 ± 0.04 μmol/g creatinine, P < 0.05) were observed in BDL animals. We found upregulations of both proteins Oat5 and Na DC1 in brush border membranes where they are functional. Immunohistochemistry technique corroborated these results for both proteins. No modifications were observed in Oat5 m RNA and in Na DC1 m RNA levels in kidney from BDL group as compared with Sham ones.CONCLUSION: Citrate excretion is decreased in BDL rats, at least in part, because of the higher Na DC1 expression. Using the outward gradient of citrate generated by Na DC1, Oat5 can reabsorb/eliminate different organic anions of pathophysiological importance.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.
文摘Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided into three groups: blank control group, model group and Cangfudaotan Tang group, 12 cases in each one. After PCOS rat models were made, rats of Cangfudaotan Tang group were treated with Cangfudaotan Tang (1.42 g/kg/d) by intragastric administration for 14 days;blank control and model group were given with isodose saline. The expression of oatp2b1 mRNA/Protein in liver and kidney tissues was measured and the level of testosterone (T), follicle stimulating hormone(FSH), estradiol (E<sub>2</sub>), luteinizing hormone(LH), Serum total cholesterol (TG), Triacylglycerols (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were detected at the same time. Results: Compared with blank control group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL, LH, FSH, T in model group were significantly increased (P < 0. 05), while the level of HDL was significantly decreased (P < 0. 05);compared with model group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL in Cangfudaotan Tang group were significantly lowered (P < 0.05);the level of HDL was significantly higher;the oatp2b1 protein in kidney and liver tissues had different degrees of expression, while there was no statistical significance among the three groups. Conclusions: Oatp2b1 might be one of the material bases participating in transportation and transformation of phlegmy dampness. The mechanism of Cangfudaotan Tang treating phlegm dampness type of PCOS may be achieved by regulating the expression of oatp2b1.
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Organic anion transporters(OATs)and organic anion transporter polypeptides(OATPs)are classified within two SLC superfamilies,namely,the SLC22A superfamily and the SLCO superfamily(formerly the SLC21A family),respectively.They are expressed in many tissues,such as the liver and kidney,and mediate the absorption and excretion of many endogenous and exogenous substances,including various drugs.Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm.OATs and OATPs are abundantly expressed in the liver,where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs.However,differences in the locations of glycosylation sites,phosphorylation sites,and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver,which ultimately results in their different roles in the liver.To date,few articles have addressed these aspects of OAT and OATP structures,and we study further the similarities and differences in their structures,tissue distribution,substrates,and roles in liver diseases.
基金supported by the National Natural Science Foundation of China(Nos.81874324,81473280,U1608283,81603186)
文摘To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam,renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats.A bacteremia model was established to investigate the pharmacokinetic properties of piperacillin and tazobactam under different conditions.Renal slices were taken to examine the uptake of piperacillin and tazobactam.Pharmacokinetic studies ofβ-lactamase in rats were performed to study the contribution of rOat1/3 to the inhibition of tazobactam onβ-lactamase.The AUC(from 2.93±0.58 to 6.52±1.44 mg·min/ml)and the plasma clearance(CL P)(from 2.41±1.20 to 0.961±0.212 ml/min/kg)of tazobactam were both altered after the intravenous coadministration of piperacillin and tazobactam in the bacteremia rats.The renal clearance(CL R)of tazobactam decreased from 1.30±0.50 to 0.361±0.043 ml/min/kg.In summary,there was a beneficial interaction between piperacillin and tazobactam mediated by rOat1 and rOat3.Piperacillin enhances the inhibitory effect of tazobactam onβ-lactamase through the inhibition of rOat1 and rOat3 in rats.The contribution rate of rOat1/3 for the synergistic effect was 20%when the two drugs were coadministered.
基金Financial support from the National Natural Science Foundation of China(No.21877057)Jiangmen Program for Innovative Research Team,China(No.2018630100180019806)is acknowledged.
文摘In this paper,we demonstrate that modification of anion-transport:active l,3-bis(benzimidazol-2-yl)benzene with strongly electron-withdrawing trifluoromethyl and nitro groups leads to a dramatic increase in the anionophoric activity,and the activity may be greatly regulated by the curvatures of the liposomes used.
基金supported by grants(to Dr.Guofeng You)from National Institute of General Medical Sciences(R01-GM079123 and R01-GM097000,USA).
文摘Organic anion transporter 3(OAT3)plays a vital role in removing a broad variety of anionic drugs from kidney,thus avoiding their possible toxicity in the body.In the current study,we investigated the role of insulin-like growth factor 1(IGF-1)in the regulation of OAT3.We showed that IGF-1 induced a dose-and time-dependent increase in OAT3 transport activity,which correlated well with an increase in OAT3 expression.The IGF-1-induced increase in OAT3 expression was blocked by protein kinase A(PKA)inhibitor H89.Moreover,IGF-1 induced an increase in OAT3 phosphorylation,which was also blocked by H89.These data suggest that the IGF-1 modulation of OAT3 occurred through PKA signaling pathway.To further confirm the involvement of PKA,we treated OAT3-expressing cells with PKA activator Bt’2-cAMP,followed by examining OAT activity and phosphorylation.We showed that OAT3 activity and phosphorylation were much enhanced in Bt2-cAMP-treated cells as compared to that in control cells.Finally,linsitinib,an anticancer drug that blocks the IGF-1 receptor,abrogated IGF-1-stimulated OAT3 transport activity.In conclusion,our study demonstrated that IGF-1 regulates OAT3 expression and transport activity through PKA signaling pathway,possibly by phosphorylating the transporter.
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the National Science Foundation for Young Scientists of China,No.81701682.
文摘BACKGROUND Neoadjuvant chemotherapy can cause hepatic sinusoidal obstruction syndrome(SOS)in patients with colorectal cancer liver metastases and increases posto-perative morbidity and mortality.AIM To evaluate T1 mapping based on gadoxetic acid-enhanced magnetic resonance imaging(MRI)for diagnosis of hepatic SOS induced by monocrotaline.METHODS Twenty-four mice were divided into control(n=10)and experimental(n=14)groups.The experimental groups were injected with monocrotaline 2 or 6 days before MRI.MRI parameters were:T1 relaxation time before enhancement;T1 relaxation time 20 minutes after enhancement(T_(1post));a reduction in T1 relaxation time(△T_(1)%);and first enhancement slope percentage of the liver parenchyma(ESP).Albumin and bilirubin score was determined.Histological results served as a reference.Liver parenchyma samples from the control and experimental groups were analyzed by western blotting,and organic anion transporter polypeptide 1(OATP1)was measured.RESULTS T_(1post),△T_(1)%,and ESP of the liver parenchyma were significantly different between two groups(all P<0.001)and significantly correlated with the total histological score of hepatic SOS(r=-0.70,0.68 and 0.79;P<0.001).△T_(1)%and ESP were positively correlated with OATP1 levels(r=0.82,0.85;P<0.001),whereas T_(1post) had a negative correlation with OATP1 levels(r=-0.83;P<0.001).INTRODUCTION Hepatic sinusoidal obstruction syndrome(SOS)is also known as hepatic veno-occlusive disease of the liver[1].The main pathological feature of hepatic SOS is damage to liver terminal vessels,and the clinical symptoms of it include ascites and abdominal pain[2].It was first proposed in 1979 as an early complication of hematopoietic stem cell transplantation[3].The prevalence ranges from 5%to 60%,and hepatic SOS is a potentially severe complication and can even lead to death in severe cases[4].Recently,systemic neoadjuvant chemotherapy became widely regarded as one of the causes hepatic SOS in the patients with advanced metastatic colorectal cancer[5,6],especially those were treated with oxaliplatin[7,8].Oxaliplatin-based preoperative chemotherapy is used for patients with colorectal liver metastases as the standard regimen[8,9],because it could improve tumor resection outcome by shrinking the metastatic sites and reducing recurrence rate[10].Nevertheless,chemotherapy-induced hepatic SOS has been associated with a higher risk of postresection morbidity[11],such as intraoperative bleeding,intraoperative transfusions,and postoperative liver failure[12].Therefore,it is important to detect and diagnose of hepatic SOS timely.Currently,the gold standard is still based on liver biopsy[13],but it is an invasive procedure and has several limitations and complications,such as hemorrhage[14].A noninvasive diagnostic modality is needed for the assessment of hepatic SOS.Some noninvasive tools have been used for diagnosis of hepatic SOS.Researchers have utilized a preoperative platelet count and aspartate aminotransferase to platelet ratio index[15].In addition,some imaging methods such as shear wave ultrasonography,computed tomography,and gadoxetic acid-enhanced magnetic resonance imaging(MRI)have been promoted as useful methods for evaluation of hepatic SOS[16-18].Recent studies with monocrotaline(MCT)-treated rats were conducted to investigate diagnosis and prediction of severity of SOS.For example,intravoxel incoherent motion diffusion-weighted imaging,non-Gaussian diffusion models,and T1 rho quantification[19,20].The MCT-induced hepatic SOS animal model was reproducible,with a detailed pathological scoring criteria[21].Gadoxetic acid is a hepatocyte-specific contrast substance,which can provide parenchymal contrast in the hepato-biliary phase.It is reported that gadoxetic acid is absorbed into the liver parenchyma via organic anion transporter polypeptide 1(OATP1)on the hepatocyte membranes[22-24].Recently,several authors have described the feasibility of gadoxetic acid-enhanced MRI for the diagnosis of oxaliplatin-induced hepatic SOS[25].They mainly diagnosed hepatic SOS based on the signal intensity of the hepatobiliary specific phase.However,there were several limitations due to the inconsistency between signal intensity of the liver parenchyma and the concentration of contrast agent for evaluation of the degree of hepatic SOS[26].Therefore,we measured T1 relaxation time on parametric mapping because it is linearly related to the concentration of the contrast agent and is not affected by other factors[27].Yang et al[28]demonstrated T1 mapping on gadoxetic acid-enhanced MRI for the assessment of oxaliplatin-induced liver injury in a C57BL/6 mouse model.However,the main pathological changes in their model were hepatocyte degeneration and fibrosis.Therefore,we aimed to explore the effectiveness of T1 mapping based on gadoxetic acid-enhanced MRI for the diagnosis of hepatic SOS in a C57BL/6 mouse model,as well as a possible relation between OATP1 Levels and MRI parameters.
基金foundations from Chinese Academy of Sciences and Special Funds for Major State Basic reseaxch of China (G1999053903).
文摘GABA transporter 1(GAT1) takes important roles in multiple physiological processes through the uptake and release of GABA, but the regulation of GAT1 gene expression in different tissues is rarely known. To address the question, first, 5’ Rapid amplification of cDNA end (RACE) was used to determine GAT1 transcriptional starting sites in neonatal mouse cerebral cortex and intestine, adult mouse brain and adult rat testis. The products of 5’RACE were confirmed by DNA sequencing. We found that the transcript of GAT1 in neonatal mouse cerebral cortex and adult mouse brain starts at the same site (inside of exon 1), while in mouse intestine, GAT1 starts transcription in intron 1, and in rat testis, the transcript of GAT1 has an additional untranslation exon to the 5’ direction.
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].
文摘AIM: We have previously demonstrated that cholangiocytes, the epithelial cells lining intrahepatic bile ducts,encode two functional bile acid transporters via alternative splicing of a single gene to facilitate bile acid vectorial transport. Cholangiocytes possess ASBT,an apical sodium-dependent bile acid transporter to take up bile acids,and t-ASBT,a basolateral alternatively spliced and truncated form of ASBT to efflux bile acids.Though hepatocyte and ileal bile acid transporters are in part regulated by the flux of bile acids, the effect of alterations in bile acid flux on the expression of t-ASBT in terminal ileocytes remains undear.Thus,we tested the hypothesis that expression of ASBT and t-ASBT in cholangiocytes and ileocytes was regulated by bile acid flux. METHODS: Expression of ASBT and t-ASBT message and protein in cholangiocytes and ileocytes isolated from pair- fed rats given control (C) and 1% taurocholate (TCA) or 5% cholestyramine (CY) enriched diets,were assessed by both quantitative RNase protection assays and quantitative immunoblotting.The data obtained from each of the control groups were pooled to reflect the changes observed following TCA and CY treatments with respect to the control diets. Cholangiocyte taurocholate uptake was determined using a novel microperfusion technique on intrahepatic bile duct units (IBDUs) derived from C,TCA and CY fed rats. RESULTS: In cholangiocytes,both ASBT and t-ASBT message RNA and protein were significantly decreased in response to TCA feeding compared to C diet.In contrast, message and protein of both bile acid transporters significantly increased following CY feeding compared to C diet.In the ileum,TCA feeding significantly up-regulated both ASBT and t-ASBT message and protein compared to C diet,while CY feeding significantly down-regulated message and protein of both bile acid transporters compared to C diet.As anticipated from alterations in cholangiocyte ASBT expression,the uptake of taurocholate in microperfused IBDUs derived from rats on TCA diet decreased 2.7-fold,whereas it increased 1.7-fold in those on CY diet compared to C diet fed groups. CONCLUSION: These data demonstrate that expression of ASBT and t-ASBT in cholangiocytes is regulated by a negative feedback loop while the expression of these transporters in terminal ileum is modified via positive feedback.Thus, while transcriptional regulatory mechanisms in response to alterations in bile acid pool size are operative in both cholangiocytes and ileocytes,each cell type responds differently to bile acid supplementation and depletion.
文摘BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.
基金Supported by Grants from Fondo para la Investigación Científica y Tecnológica(FONCy T),Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET),Universidad Nacional de Rosario(UNR)
文摘AIM: To examine renal expression of organic anion transporter 5(Oat5) and sodium-dicarboxylate cotransporter 1(Na DC1), and excretion of citrate in rats with acute extrahepatic cholestasis.METHODS: Obstructive jaundice was induced in rats by double ligation and division of the common bile duct(BDL group). Controls underwent sham operation that consisted of exposure, but not ligation, of the common bile duct(Sham group). Studies were performed 21 h after surgery. During this period, animals were maintained in metabolic cages in order to collect urine. The urinary volume was determined by gravimetry. The day of the experiment, blood samples were withdrawn and used to measure total and direct bilirubin as indicative parameters of hepatic function. Serum and urine samples were used for biochemical determinations. Immunoblotting for Oat5 and Na DC1 were performed in renal homogenates and brush border membranes from Sham and BDL rats. Immunohistochemistry studies were performed in kidneys from both experimental groups. Total RNA was extracted from rat renal tissue in order to perform reverse transcription polymerase chain reaction. Another set of experimental animals were used toevaluate medullar renal blood flow(m RBF) using fluorescent microspheres.RESULTS: Total and direct bilirubin levels were significantly higher in BDL animals, attesting to the adequacy of biliary obstruction. An important increase in m RBF was determined in BDL group(Sham: 0.53 ± 0.12 m L/min per 100 g body weight vs BDL: 1.58 ± 0.24 m L/min per 100 g body weight, P < 0.05). An increase in the urinary volume was observed in BDL animals. An important decrease in urinary levels of citrate was seen in BDL group. Besides, a decrease in urinary citrate excretion(Sham: 0.53 ± 0.11 g/g creatinine vs BDL: 0.07 ± 0.02 g/g creatinine, P < 0.05) and an increase in urinary excretion of H+(Sham: 0.082 ± 0.03 μmol/g creatinine vs BDL: 0.21 ± 0.04 μmol/g creatinine, P < 0.05) were observed in BDL animals. We found upregulations of both proteins Oat5 and Na DC1 in brush border membranes where they are functional. Immunohistochemistry technique corroborated these results for both proteins. No modifications were observed in Oat5 m RNA and in Na DC1 m RNA levels in kidney from BDL group as compared with Sham ones.CONCLUSION: Citrate excretion is decreased in BDL rats, at least in part, because of the higher Na DC1 expression. Using the outward gradient of citrate generated by Na DC1, Oat5 can reabsorb/eliminate different organic anions of pathophysiological importance.