Study of FABP's interactome and detecting new molecular targets in clear cell renal cell carcinoma

Fatty acids (FAs) play a crucial role in the development of clear cell renal cell carcinoma (ccRCC), FAs function requires the participation of fatty-acid-binding protein (FABP). Current studies have shown that different members of the FABP's family play different roles in the tumorigenesis of ccRCC. Therefore, the systematic analysis of FABPs will be of great significance. However, the diverse expression patterns and prognostic values of nine FABPs have yet to be elucidated. In this study, through multiple analysis and verification of multiple databases, such as ONCOMINE, The Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, and cBioPortal, we found that the expression of FABP1 was significantly downregulated and the expression of FABP5/6/7 was significantly upregulated in ccRCC compared with renal tissues, and the patients with high messenger RNA (mRNA) levels of the FABP5/6/7 or low mRNA levels of FABP1 were predicted to have a lower overall survival or disease-free survival. Further analysis by the protein–protein interaction (PPI), Gene Ontology pathway, and Kyoto Encyclopedia of Genes and Genomes pathway showed that FABPs were mainly involved in the peroxisome proliferator-activated receptor (PPAR) pathway. In coexpression analysis, we found that FABP1/5/6/7 was coexpressed with transforming growth factor-β1 (TGF-β1), PPARA, and LPL. This study implied that FABP1/5/6/7 could act as an important tumor biomarker of ccRCC; the role of FABPs may be related to PPAR or TGF-β pathway.     

Identification of methylation-driven genes related to prognosis in clear-cell renal cell carcinoma

With the participation of the existing treatment methods, the prognosis of advanced clear-cell renal cell carcinoma (ccRCC) is poor. More evidence indicates the presence of methylation in ccRCC cancer cells, but there is a lack of studies on methylation-driven genes in ccRCC. We analyzed the open data of ccRCC in The Cancer Genome Atlas database to obtain ccRCC-related methylation-driven genes, and then carried out pathway enrichment, survival, and joint survival analyses. More important, we deeply explored the correlation between differential methylation sites and the expression of these driving genes. Finally, we screened 29 methylation-driven genes via MethylMix, of which six were significantly associated with the survival of ccRCC patients. This study demonstrated that the effect of hypermethylation or hypomethylation on prognosis is different, and the level of methylation of key methylation sites is associated with gene expression. We identified methylation-driven genes independently predicting prognosis in ccRCC, which offers theoretical support in bioinformatics for the study of methylation in ccRCC and a new perspective for the epigenetic study of ccRCC.     

Glycated albumin and diabetes mellitus

Background

Diabetes is a growing worldwide problem that is strongly associated with atherosclerosis. Screening and intervention for diabetes in the earliest stages are advocated for the prevention of diabetic complications and cardiovascular disease.

Scope of review

This review gives a background of and discusses the potential clinical utility of glycated albumin (GA) in diabetes.

Major conclusions

GA is a ketoamine formed via a non-enzymatic glycation reaction of serum albumin and it reflects mean glycemia over two to three weeks. GA can be used for patients with anemia or hemoglobinopathies for whom the clinically measured hemoglobin A1c level may be inaccurate. Because both serum and plasma samples can be used, GA can be analyzed from the same samples as common biological markers. GA is a useful marker for the screening of diabetes in a medical evaluation. It can be also used to determine the effectiveness of treatment before initiating or changing medications for diabetic patients. GA is potentially an atherogenic protein in the development of diabetic atherosclerosis.

General significance

GA measurement is useful as part of a routine examination to screen for both diabetes and atherosclerosis. This article is part of a Special Issue entitled Serum Albumin.     

Mutation c.359_363delGTATTinsATAC in the COL4A5 Causes alport syndrome in a Chinese family

The X-linked form of Alport syndrome is associated with mutations in the COL4A5 gene, which is located at Xq22.3 and encodes the α5 chain of type IV collagen. Here we clinically characterized a Chinese family with Alport Syndrome, but no ocular or hearing abnormalities have been observed in any patient in the family. Through Linkage analysis and direct DNA sequencing, a novel complex deletion/insertion mutation c.359_363delGTATTinsATAC in the COL4A5 gene was identified in the family. The mutation was found in all affected family members, but was not present in the unaffected family individuals or the 200 controls. The predicted mutant protein in the family is a truncated protein consisting of only 153 residues. Our report for the first time revealed that the frameshift mutation in the type IV collagen chain α5 causes only renal disease, without extrarenal lesion. Our study broadens genotypic and phenotypic spectrum of COL4A5 mutations associated with Alport syndrome.     

Constant Pharmacologic Effect and Chronopharmacology: Theoretical Aspects

The theoretical drug infusion rates requisite to obtain a constant pharmacologic effect are determined taking into account chronopharmacologic phenomena. The introduction of chronopharmacology into pharmacokinetic theory leads to a clocktime-dependent infusion rate. The infusion modulation depends both on type of chronophenomenon, chronopharmacokinetics or chronestesy, and plasma clearance rate of the drug. In the presence of chronestesy of a biosystem the pharmacologic effect can be maintained constant only when plasma drug clearance is fast enough to allow an adequate modulation of the plasma drug concentration. Although the established equations proceed from theoretical concept they could be useful for programming drug delivery systems.     

Significant increase in plasma 4β-hydroxycholesterol concentration in patients after kidney transplantation

Several previous studies have shown that renal failure decreases not only renal elimination but also metabolic clearance of drugs, particularly those metabolized by CYP3A. However, whether recovery of renal function results in recovery of hepatic CYP3A activity remains unknown. In this study, we evaluated the effect of renal function on CYP3A activity after kidney transplantation in patients with end-stage renal disease (ESRD) by measuring the change in CYP3A activity using plasma concentration of 4β-hydroxycholesterol as a biomarker. The study enrolled 13 patients with ESRD who underwent the first kidney allograft transplantation. Morning blood samples were collected before and 3, 7, 10, 14, 21, 30, 60, 90, 120, 150 and 180 days after kidney transplantation. Plasma concentration of 4β-hydroxycholesterol was measured using GC-MS. Compared with before kidney transplantation, creatinine clearance increased significantly from day 3 after kidney transplantation and stabilized thereafter. Plasma concentration of 4β-hydroxycholesterol was elevated significantly on days 90 and 180 after kidney transplantation. In conclusion, this study suggests the recovery of CYP3A activity with improvement in renal function after kidney transplantation in patients with ESRD.     

Brugia pahangi: Immunization with early L3 ES alters parasite migration,and reduces microfilaremia and lymphatic lesion formation in gerbils (Meriones unguiculatus)

Previous studies have shown that intradermally (ID) injected Brugia pahangi L3s migrate through various tissues and into the lymphatics of gerbils in a distinct pattern. Excretory/secretory products (ES) produced at the time of invasion of B. pahangi are likely to be important in this early migration phase of the parasite life cycle in their rodent host. Hence, early L3 ES was collected from 24 h in vitro cultures of B. pahangi L3 larvae and used in immunization experiments to investigate the effect of immunity to early L3 ES on worm migration, survival and development of B. pahangi. Immunization of gerbils with ES in RIBI adjuvant produced antibodies to numerous ES proteins eliciting a strong humoral response to ES and indirect fluorescent antibody (IFA) assay using anti-ES serum recognized the ES proteins on the surface of B. pahangi L3 larvae. Following ES immunization, gerbils were challenged either ID or intraperitoneally (IP) with 100 L3s of B. pahangi and euthanized at 3 or 106 days post inoculation (DPI). Immunization with early ES slowed the migration of ID inoculated L3 at 3 DPI and significantly altered the locations of adult worms at 106 DPI. Immunization did not induce protection in any treatment group. However, immunized animals had significantly fewer microfilariae per female worm suggesting the antigens in ES are important in microfilariae development or survival in the host. The number of lymphatic granulomas was also significantly reduced in ES immunized animals. It is important to note that microfilariae serve as a nidus in these granulomas. Our results shows immunization with early Brugia malayi L3 ES alters the worm migration, affects circulating microfilarial numbers and reduces lymphatic granulomas associated with B. pahangi infection in gerbils.     

Trypanosoma rangeli: An alkaline ecto-phosphatase activity is involved with survival and growth of the parasite

The aim of this work was to investigate whether an alkaline ecto-phosphatase activity is present in the surface of Trypanosoma rangeli. Intact short epimastigote forms were assayed for ecto-phosphatase activity to study kinetics and modulators using β-glycerophosphate (β-GP) and p-nitrophenyl phosphate (pNPP) as substrates. Its role in parasite development and differentiation was also studied. Competition assays using different proportions of β-GP and pNPP evidenced the existence of independent and non-interacting alkaline and acid phosphatases. Hydrolysis of β-GP increased progressively with pH, whereas the opposite was evident using pNPP. The alkaline enzyme was inhibited by levamisole in a non-competitive fashion. The Ca²⁺ present in the reaction medium was enough for full activity. Pretreatment with PI-PLC decreased the alkaline but not the acid phosphatase evidence that the former is catalyzed by a GPI-anchored enzyme, with potential intracellular signaling ability. β-GP supported the growth and differentiation of T. rangeli to the same extent as high orthophosphate (P_i). Levamisole at the IC₅₀ spared significantly parasite growth when β-GP was the sole source of P_i and stopped it in the absence of β-GP, indicating that the alkaline enzyme can utilize phosphate monoesters present in serum. These results demonstrate the existence of an alkaline ecto-phosphatase in T. rangeli with selective requirements and sensitivity to inhibitors that participates in key metabolic processes in the parasite life cycle.     

Properties of Brush Border Vesicles Isolated from Rat Kidney Cortex by Calcium Precipitation

Brush border membrane vesicles were isolated from rat kidney cortex by differential centrifugation in the presence of 10 mM calcium. Their properties were compared to brush border vesicles isolated by free-flow electrophoresis. By the calcium precipitation method membrane vesicles were obtained in a shorter time with a similar enrichment of brush border marker enzymes (11- to 12-fold for alkaline phosphatase and maltase), with a similarly reduced activity of the marker enzyme for basal-lateral plasma membranes and an almost identical protein composition as revealed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The transport properties of the two membrane preparations for D-glucose, L-phenylalanine, and phosphate are essentially the same; there is some indication for a lower sodium permeability of the vesicles prepared by the calcium precipitation method. The latter vesicles were also shown to exhibit sodium gradient stimulated uptake of L-glutamate.     

鲤鱼汤对阿霉素肾病大鼠肾组织TGF-β1及下游因子表达的影响

本研究探讨鲤鱼汤利尿消肿拮抗肾纤维化保护肾脏的分子机制。阿霉素6.2 mg/kg尾静脉单次注射制备ADRN模型,2 W后干预连续7 W。检测尿、血生化指标,光镜电镜观察肾组织形态变化,免疫组化检测转化生长因子β1(TGF-β1)及下游因子表达。结果发现模型组较对照组12 h尿量(12 h-Uv)减少,血白蛋白(Alb)降低,肾小球硬化指数(GSI)及间质损伤指数(TII)升高,肾组织Smad7表达下调,转化生TGF-β1、成纤维细胞特异性蛋白-1(FSP-1)、I型胶原(Col-I)表达上调;鲤鱼汤组较模型组12 h-Uv增加,血Alb升高,GSI及TII下降,肾组织Smad7表达上调,TGF-β1、FSP-1、Col-Ⅰ表达下调。表明鲤鱼汤的肾保护作用至少部分与其利尿消肿、调节TGF-β1/Smad7信号通路、抑制上皮细胞转分化(EMT)及细胞外基质沉积(ECM)有关。