Albumin-bound kynurenic acid is an appropriate endogenous biomarker for assessment of the renal tubular OATs-MRP4 channel

Renal tubular secretion mediated by organic anion transporters(OATs)and the multidrug resistanceassociated protein 4(MRP4)is an important means of drug and toxin excretion.Unfortunately,there are no biomarkers to evaluate their function.The aim of this study was to identify and characterize an endogenous biomarker of the renal tubular OATs-MRP4 channel.Twenty-six uremic toxins were selected as candidate compounds,of which kynurenic acid was identified as a potential biomarker by assessing the protein-binding ratio and the uptake in OAT1-,OAT3-,and MRP4-overexpressing cell lines.OAT1/3 and MRP4 mediated the transcellular vectorial transport of kynurenic acid in vitro.Serum kynurenic acid concentration was dramatically increased in rats treated with a rat OAT1/3(rOAT1/3)inhibitor and in rOAT1/3 double knockout(rOAT1/3^(-/-))rats,and the renal concentrations were markedly elevated by the rat MRP4(rMRP4)inhibitor.Kynurenic acid was not filtered at the glomerulus(99%of albumin binding),and was specifically secreted in renal tubules through the OAT1/3-MRP4 channel with an appropriate affinity(Km)(496.7 mM and 382.2 mM for OAT1 and OAT3,respectively)and renal clearance half-life(t1/2)in vivo(3.7±0.7 h).There is a strong correlation in area under the plasma drug concentration-time curve(AUC0et)between cefmetazole and kynurenic acid,but not with creatinine,after inhibition of rOATs.In addition,the phase of increased kynurenic acid level is earlier than that of creatinine in acute kidney injury process.These results suggest that albumin-bound kynurenic acid is an appropriate endogenous biomarker for adjusting the dosage of drugs secreted by this channel or predicting kidney injury.

A general strategy to the synthesis of carbon-supported PdM(M=Co,Fe and Ni)nanodendrites as high-performance electrocatalysts for formic acid oxidation

Rational synthesis of a new class of electrocatalysts with high-performance and low-cost is of great significance for future fuel cell devices. Herein, we demonstrate a general one-step simultaneous reduction method to prepare carbon-supported Pd M（M = Co, Fe, Ni） alloyed nanodendrites with the assistance of oleylamine and octadecylene. The morphology, structure and composition of the obtained Pd M nanodendrites/C catalysts have been fully characterized. The combination of the dendritic structural feature and alloyed synergy offer higher atomic utilization efficiency, excellent catalytic activity and enhanced stability for the formic acid oxidation reaction（FAOR）. Strikingly, the as-synthesized Pd Co nanodendrites/C catalyst could afford a mass current density of 2467.7 A g, which is almost 3.53 and 10.4 times higher than those of lab-made Pd/C sample(698.3 A g) and commercial Pd/C catalyst(237.6 A g), respectively. Furthermore, the PdC o nanodendrites/C catalyst also exhibit superior stability relative to the Pd/C catalysts, make it a promising anodic electrocatalyst in practical fuel cells in the future. Additionally, the present feasible synthetic approach is anticipated to provide a versatile strategy toward the preparation of other metal alloy nanodendrites/carbon nanohybrids.

Application of Real-time Fluorescent Quantitative PCR in Studies on Plants

Real-Lime fluorescent quantitative PCR is a method for quantitative analysis of gene expression developed in recent years, which has been widely used in various fields such as basic scientific research, clinical diagnosis, disease study, drug research and development since its appearance. It starts relatively late in study on plants, but has already been used for analysis of gene expression in plants and gene identification of exogenous genes. The principles or advantages and dis- advantages of real-time fluorescent quantitative PCR, or its potential problems and condition optimizations in tests were introduced in this study, and then the appli- cation and prospect of real-time fluorescent quantitative PCR in study on plants were also been discussed.

The utility of endogenous glycochenodeoxycholate-3-sulfate and 4β-hydroxycholesterol to evaluate the hepatic disposition of atorvastatin in rats

The liver is an important organ for drugs disposition,and thus how to accurately evaluate hepatic clearance is essential for proper drug dosing.However,there are many limitations in drug dosage adjustment based on liver function and pharmacogenomic testing.In this study,we evaluated the ability of endogenous glycochenodeoxycholate-3-sulfate(GCDCA-S)and 4β-hydroxycholesterol(4β-HC)plasma levels to evaluate organic anion-transporting polypeptide(Oatps)-mediated hepatic uptake and Cyp3 a-meidated metabolism of atorvastatin(ATV)in rats.The concentration of ATV and its metabolites,2-OH ATV and 4-OH ATV,was markedly increased after a single injection of rifampicin(RIF),an inhibitor of Oatps.Concurrently,plasma GCDCA-S levels were also elevated.After a single injection of the Cyp3 a inhibitor ketoconazole(KTZ),plasma ATV concentrations were significantly increased and 2-OH ATV concentrations were decreased,consistent with the metabolism of ATV by Cyp3 a.However,plasma 4β-HC was not affected by KTZ treatment despite it being a Cyp3 a metabolite of cholesterol.After repeated oral administration of RIF,plasma concentrations of ATV,2-OH ATV and 4-OH ATV were markedly increased and the hepatic uptake ratio of ATV and GCDCA-S was decreased.KTZ did not affect plasma concentrations of ATV,2-OH ATV and 4-OH ATV,but significantly decreased the metabolic ratio of total and 4-OH ATV.However,the plasma level and hepatic metabolism of 4β-HC were not changed by KTZ.The inhibition of hepatic uptake of GCDCA-S by RIF was fully reversed after a 7-d washout of RIF.Plasma concentration and hepatic uptake ratio of GCDCA-S were correlated with the plasma level and hepatic uptake of ATV in rats with ANIT-induced liver injury,respectively.These results demonstrate that plasma GCDCA-S is a sensitive probe for the assessment of Oatps-mediated hepatic uptake of ATV.However,Cyp3 a-mediated metabolism of ATV was not predicted by plasma 4β-HC levels in rats.

腺嘌呤诱导的慢性肾损伤大鼠体内肾脏排泄通道变化

慢性肾功能衰竭(CRF)是一种进行性慢性肾脏疾病,并伴随着物质排泄的改变。然而,在CRF后肾脏排泄通道的变化尚不明确。本研究的目的是评价CRF后大鼠体内内源性和外源性物质肾脏排泄的变化。结果显示,在腺嘌呤(50和100mg/kg)诱导的CRF大鼠中血清胱抑素C、肌酐和尿素氮水平显著增加,肾脏转运体rOCT2表达剂量依赖性增加,rMRP2和rMATE1水平剂量依赖性降低,rMPR4水平在腺嘌呤(50 mg/kg)诱导的CRF大鼠中显著增加。与正常大鼠相比,在腺嘌呤(100 mg/kg)诱导的CRF大鼠中血浆二甲双胍、对氨基马尿酸和呋塞米的浓度显著增加。然而,在腺嘌呤(50 mg/kg)诱导的CRF大鼠血中二甲双胍和对氨基马尿酸浓度没有明显的改变。与此一致,在腺嘌呤(50 mg/kg)诱导的CRF大鼠中二甲双胍和对氨基马尿酸的尿排泄也未发生明显的改变。此外,腺嘌呤(50和100 mg/kg)诱导的CRF大鼠肾脏N1-甲基烟酰胺摄取增加,腺嘌呤(50mg/kg)诱导CRF大鼠肾脏苯基-β-D-葡萄糖醛酸和马尿酸摄取增加。这些结果表明腺嘌呤(100mg/kg)诱导的CRF大鼠中肾脏GFR-r OCTs-RMAT1和GFR-r OAT1/rOAT3-r MRP通路功能降低,而腺嘌呤(50 mg/kg)诱导的CRF大鼠中肾小管rOCTs-RMAT1和rOAT1-MRPs通路转运功能增加。