Search results for " Ly"

2020

Tumor-necrosis-factor-alpha-induced protein 3 (TNFAIP3), or A20, is a ubiquitin-modifying protein and negative regulator of canonical nuclear factor κB (NF-κB) signaling. Several single-nucleotide polymorphisms in TNFAIP3 are associated with autoimmune diseases, suggesting a role in tissue inflammation. While the role of A20 in peripheral immune cells has been well investigated, less is known about its role in the central nervous system (CNS). Here, we show that microglial A20 is crucial for maintaining brain homeostasis. Without microglial A20, CD8+ T cells spontaneously infiltrate the CNS and acquire a viral response signature. The combination of infiltrating CD8+ T cells and activated A2…

Assessment in vitro of cytogenetic and genotoxic effects of propolis on human lymphocytes

2012

We evaluated the genetic damage by ethanolic extract of propolis (EEP) induced to human lymphocytes which were exposed to increasing concentrations (0–2000 μg ml−1). The results indicated that EEP reduced significantly the mitotic index (MI) and proliferation index (PI) when high concentrations of EEP were used. Sister chromatid exchange (SCE) rates indicated that EEP could have genotoxic effects at high concentrations. Exposure of the cells to the amount of ethanol used as solvent did not alter either the MI and cell proliferation kinetics (CPK), or the rate of SCE. The results showed: (a) statistical increase in the percentage the cells with CAs and in the frequency of SCE at the highest …

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemi…

2016

Abstract Background Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methods Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptak…

Protonation effects on the UV/Vis absorption spectra of imatinib: A theoretical and experimental study

2014

An experimental and theoretical investigation of protonation effects on the UV/Vis absorption spectra of imatinib showed systematic changes of absorption depending on the pH, and a new absorption band appeared below pH 2. These changes in the UV/Vis absorption spectra were interpreted using quantum chemical calculations. The geometry of various imatinib cations in the gas phase and in ethanol solution was optimized with the DFT/B3LYP method. The resultant geometries were compared to the experimentally determined crystal structures of imatinib salts. The semi-empirical ZINDO-CI method was employed to calculate the absorption lines and electronic transitions. Our study suggests that the forma…

Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML).

2004

Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferat…

Molecular and structural characterization of fluorescent human parvovirus B19 virus-like particles

2005

Although sharing a T = 1 icosahedral symmetry with other members of the Parvoviridae family, it has been suggested that the fivefold channel of the human parvovirus B19 VP2 capsids is closed at its outside end. To investigate the possibility of placing a relatively large protein moiety at this site of B19, fluorescent virus-like particles (fVLPs) of B19 were developed. The enhanced green fluorescent protein (EGFP) was inserted at the N-terminus of the structural protein VP2 and assembly of fVLPs from this fusion protein was obtained. Electron microscopy revealed that these fluorescent protein complexes were very similar in size when compared to wild-type B19 virus. Further, fluorescence cor…

Design and development of heterologous competitive immunoassays for the determination of boscalid residues

2014

Boscalid is a modern agrochemical belonging to the so-called chemical class of succinate dehydrogenase inhibitor fungicides. With the aim of developing rapid analytical screening methods for this relevant compound, we herein report the synthesis of new boscalid mimics and the study of their suitability for the production of polyclonal antibodies. Aliphatic spacer arms equivalent in length and composition were tethered at two different aromatic rings of the target molecular structure. These haptens, besides being used for immunization, were employed in the development of heterologous competitive enzyme-linked immunosorbent assays (cELISAs) in order to improve assay detectability. Direct and …

Single-Molecule FRET Reveals a Cooperative Effect of Two Methyl Group Modifications in the Folding of Human Mitochondrial tRNALys

2011

Summary Using a combination of advanced RNA synthesis techniques and single molecule spectroscopy, the deconvolution of individual contributions of posttranscriptional modifications to the overall folding and stabilization of human mitochondrial tRNA Lys is described. An unexpected destabilizing effect of two pseudouridines on the native tRNA folding was evidenced. Furthermore, the presence of m 2 G10 alone does not facilitate the folding of tRNA Lys , but a stabilization of the biologically functional cloverleaf shape in conjunction with the principal stabilizing component m 1 A9 exceeds the contribution of m 1 A alone. This constitutes an unprecedented cooperative effect of two nucleotide…

Dynamic Effects on Reaction Rates in a Michael Addition Catalyzed by Chalcone Isomerase. Beyond the Frozen Environment Approach

2008

We present a detailed microscopic study of the dynamics of the Michael addition reaction leading from 6'-deoxychalcone to the corresponding flavanone. The reaction dynamics are analyzed for both the uncatalyzed reaction in aqueous solution and the reaction catalyzed by Chalcone Isomerase. By means of rare event simulations of trajectories started at the transition state, we have computed the transmission coefficients, obtaining 0.76 +/- 0.04 and 0.87 +/- 0.03, in water and in the enzyme, respectively. According to these simulations, the Michael addition can be seen as a formation of a new intramolecular carbon-oxygen bond accompanied by a charge transfer essentially taking place from the nu…

Structural Characterization of Set1 RNA Recognition Motifs and their Role in Histone H3 Lysine 4 Methylation

2006

Departament de Bioquimica iBiologia Molecular, Universitatde Valencia, C/Dr Moliner 50,46100, Burjassot, SpainThe yeast Set1 histone H3 lysine 4 (H3K4) methyltransferase contains, inaddition to its catalytic SET domain, a conserved RNA recognition motif(RRM1). We present here the crystal structure and the secondary structureassignment in solution of the Set1 RRM1. Although RRM1 has the expectedβαββαβ RRM-fold, it lacks the typical RNA-binding features of thesemodules. RRM1 is not able to bind RNA by itself in vitro, but a constructcombining RRM1 with a newly identified downstream RRM2 specificallybinds RNA. Invivo,H3K4 methylation isnot affectedbyapoint mutation inRRM2 that preserves Set1 s…