Syntheses and antitumor activities of N′1,N′3-dialkyl-N′1,N′3-di-(alkylcarbonothioyl) malonohydrazide: The discovery of elesclomol

A series of N′¹,N′³-dialkyl-N′¹,N′³-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure–activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.     

Cloning,expression and characterization of d-aminoacylase from Achromobacter xylosoxidans subsp. denitrificans ATCC 15173

d-Aminoacylase catalyzes the conversion of N-acyl-d-amino acids to d-amino acids and fatty acids. The aim of this study was to identify the d-aminoacylase gene from Achromobacter xylosoxidans subsp. denitrificans ATCC 15173 and investigate the biochemical characterization of the enzyme. A previously uncharacterized d-aminoacylase gene (ADdan) from this organism was cloned and sequenced. The open reading frame (ORF) of ADdan was 1467 bp in size encoding a 488-amino acid polypeptide. ADdan, with a high amino acid similarity to N-acyl-d-aspartate amidohydrolase from Alcaligenes A6, showed relatively low sequence similarities to other characterized d-aminoacylases. The recombinant ADdan protein was expressed in Escherichia coli BL21 (DE3) using pET-28a with a T7 promoter. The enzyme was purified in a single chromatographic step using nickel affinity gel column. The molecular mass of the expressed protein, calculated by SDS–PAGE, was about 52 kDa. The purified ADdan showed optimal activity at pH 8.0 and 50 °C, and was stable at pH 6.0–8.0 and up to 45 °C. Its activity was inhibited by Cu²⁺, Fe²⁺, Ca²⁺, Mn²⁺, Ni²⁺, Zn²⁺ and Hg²⁺, whereas Mg²⁺ had no significant influence on this recombinant d-aminoacylase. This is the first report on the characterization of d-aminoacylase with activity towards both N-acyl derivatives of neutral d-amino acids and N-acyl-d-aspartate. The characteristics of ADdan could prove to be of interest in industrial production of d-amino acids.     

Novel nanoimaging approach: Antibodious polymeric nanolabel for intracellular alpha‐fetoprotein targeted monitoring

This study describes preparation and use of novel labeled and antibodious polymeric nanolabels (anti‐alpha fetoprotein cross‐linked nanolabels) as an immunogenic and semisynthetic nanolabel with potential prognostic and therapeutic roles for hepatoma cancer. Specificity, uptake, and binding efficiencies of the nanolabel have been examined in a human hepatosarcoma cell line HepG2, a human colorectal cell line DLD‐1, and a mouse myoblast cell line C2. Labeling of the cells has been performed by treating live and fixed cells with varying concentrations of the nanolabels and then, the cells have been examined under a fluorescence microscope. In addition, all cell lines have also been labeled using FITC‐conjugated nanotrastuzumab to compare the results obtained with those of the binding of the FITC‐nanoanti‐alpha fetoprotein nanolabels. Results show that FITC‐conjugated anti‐alpha fetoprotein cross‐linked nanolabels have been taken up by both live and fixed cells and have efficiently and specifically labeled HepG2 cells at a quite low concentration. Taken all together, the results indicate that the novel targeted nanoimaging tools and technique demonstrated their ability to detect the distribution of the nanolabels as probes in hepatoma cells. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29: 472–479, 2013     

Neural plasticity in high-level visual cortex underlying object perceptual learning

With intensive training, human can achieve impressive behavioral improvement on various perceptual tasks. This phenomenon, termed perceptual learning, has long been considered as a hallmark of the plasticity of sensory neural system. Not surprisingly, high-level vision, such as object perception, can also be improved by perceptual learning. Here we review recent psychophysical, electrophysiological, and neuroimaging studies investigating the effects of training on object selective cortex, such as monkey inferior temporal cortex and human lateral occipital area. Evidences show that learning leads to an increase in object selectivity at the single neuron level and/or the neuronal population level. These findings indicate that high-level visual cortex in humans is highly plastic and visual experience can strongly shape neural functions of these areas. At the end of the review, we discuss several important future directions in this area.     

N-Substituted Benzyl Matrinic Acid Derivatives Inhibit Hepatitis C Virus (HCV) Replication through Down-Regulating Host Heat-Stress Cognate 70 (Hsc70) Expression

Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD₅₀>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.     

Low-Grade Albuminuria Is Associated with Metabolic Syndrome and Its Components in Middle-Aged and Elderly Chinese Population

Background

Micro-albuminuria has been well established as one of the risk factors of metabolic syndrome (MetS). However, the association of MetS and its components with low-grade albuminuria among those with normal urinary albumin excretion has not been clearly elucidated in Chinese population.

Methodology and Findings

A cross-sectional study was conducted among 9,579 participants with normal urinary albumin excretion, who were recruited from Jia Ding District, Shanghai, China. The single-void first morning urine sample was collected for urinary albumin and creatinine measurements, and urinary albumin-to-creatinine ratio (UACR) was calculated as urinary albumin divided by creatinine. Low-grade albuminuria was classified as sex-specific upper UACR quartile in this population. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence of MetS and its components increased across the UACR quartiles (all P _trend <0.01). A multivariable adjusted logistic regression analysis revealed that the prevalence of MetS was gradually elevated according to the UACR quartiles (adjusted odds ratios [ORs] were 1.14, 1.24 and 1.59 for UACR quartiles 2, 3 and 4, compared with the lowest quartile; P _trend<0.0001). In the further stratified logistic regression analyses, the associations between low-grade albuminuria and MetS were significant in both sex strata (male and female), both age strata (<60 and ≥60 years), both body mass index strata (<24 and ≥24 kg/m²), and both diabetes strata (yes and no). Compared to the lowest UACR quartile, the participants in the highest quartile of UACR had the highest prevalence of central obesity (OR = 1.43; 95%CI = 1.25–1.63), high blood pressure (OR = 1.64; 95%CI = 1.43–1.87), hyperglycemia (OR = 1.52; 95%CI = 1.30–1.78) and high triglycerides (OR = 1.19; 95%CI = 1.04–1.37).

Conclusions and Significance

Low-grade albuminuria was significantly associated with the increasing prevalence of MetS and its components in the middle-aged and elderly Chinese population with normal urinary albumin excretion.     

The Differential Antiviral Activities of Chicken Interferon α (ChIFN-α) and ChIFN-β are Related to Distinct Interferon-Stimulated Gene Expression

Chicken interferon α (ChIFN-α) and ChIFN-β are type I IFNs that are important antiviral cytokines in the innate immune system. In the present study, we identified the virus-induced expression of ChIFN-α and ChIFN-β in chicken fibroblast DF-1 cells and systematically evaluated the antiviral activities of recombinant ChIFN-α and ChIFN-β by cytopathic-effect (CPE) inhibition assays. We found that ChIFN-α exhibited stronger antiviral activity than ChIFN-β in terms of inhibiting the replication of vesicular stomatitis virus, Newcastle disease virus and avian influenza virus, respectively. To elucidate the mechanism of differential antiviral activities between the two ChIFNs, we measured the relative mRNA levels of IFN-stimulated genes (ISGs) in IFN-treated DF-1 cells by real-time PCR. ChIFN-α displayed greater induction potency than ChIFN-β on several ISGs encoding antiviral proteins and MHC-I, whereas ChIFN-α was less potent than ChIFN-β for inducing ISGs involved in signaling pathways. In conclusion, ChIFN-α and ChIFN-β presented differential induction potency on various sets of ISGs, and the stronger antiviral activity of ChIFN-α is likely attributed to the greater expression levels of downstream antiviral ISGs.     

Erythropoietin Inhibits Gluconeogenesis and Inflammation in the Liver and Improves Glucose Intolerance in High-Fat Diet-Fed Mice

Erythropoietin (EPO) has multiple biological functions, including the modulation of glucose metabolism. However, the mechanisms underlying the action of EPO are still obscure. This study is aimed at investigating the potential mechanisms by which EPO improves glucose tolerance in an animal model of type 2 diabetes. Male C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks and then treated with EPO (HFD-EPO) or vehicle saline (HFD-Con) for two week. The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. Therefore, our data indicated that EPO treatment improved glucose intolerance by inhibiting gluconeogenesis and inflammation in the livers of HFD-fed mice.