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21.
Karen CM Moraes Lívia F Diniz Maria Terezinha Bahia 《Memórias do Instituto Oswaldo Cruz》2015,110(2):181-191
Chagas disease, caused by the intracellular protozoan Trypanosoma
cruzi, is a serious health problem in Latin America. During this
parasitic infection, the heart is one of the major organs affected. The pathogenesis
of tissue remodelling, particularly regarding cardiomyocyte behaviour after parasite
infection and the molecular mechanisms that occur immediately following parasite
entry into host cells are not yet completely understood. When cells are infected with
T. cruzi, they develop an inflammatory response, in which
cyclooxygenase-2 (COX-2) catalyses rate-limiting steps in the arachidonic acid
pathway. However, how the parasite interaction modulates COX-2 activity is poorly
understood. In this study, the H9c2 cell line was used as our model and we
investigated cellular and biochemical aspects during the initial 48 h of parasitic
infection. Oscillatory activity of COX-2 was observed, which correlated with the
control of the pro-inflammatory environment in infected cells. Interestingly,
subcellular trafficking was also verified, correlated with the control of Cox-2 mRNA
or the activated COX-2 protein in cells, which is directly connected with the
assemble of stress granules structures. Our collective findings suggest that in the
very early stage of the T. cruzi-host cell interaction, the parasite
is able to modulate the cellular metabolism in order to survives. 相似文献
22.
Cíntia Júnia Monteiro Suianne Letícia Antunes Mota Lívia de Figueiredo Diniz Maria Terezinha Bahia Karen CM Moraes 《Memórias do Instituto Oswaldo Cruz》2015,110(8):996-1002
Chagas disease, which is caused by the intracellular protozoanTrypanosoma
cruzi, is a serious health problem in Latin America. The heart is one of
the major organs affected by this parasitic infection. The pathogenesis of tissue
remodelling, particularly regarding cardiomyocyte behaviour after parasite infection,
and the molecular mechanisms that occur immediately following parasite entry into
host cells are not yet completely understood. Previous studies have reported that the
establishment of parasitism is connected to the activation of the
phosphatidylinositol-3 kinase (PI3K), which controls important steps in cellular
metabolism by regulating the production of the second messenger
phosphatidylinositol-3,4,5-trisphosphate. Particularly, the tumour suppressor PTEN is
a negative regulator of PI3K signalling. However, mechanistic details of the
modulatory activity of PTEN on Chagas disease have not been elucidated. To address
this question, H9c2 cells were infected with T. cruzi Berenice 62
strain and the expression of a specific set of microRNAs (miRNAs) were investigated.
Our cellular model demonstrated that miRNA-190b is correlated to the decrease of
cellular viability rates by negatively modulating PTEN protein expression in
T. cruzi-infected cells. 相似文献
23.
Anna Wolc Jesus Arango Petek Settar Janet E Fulton Neil P O'Sullivan Rudolf Preisinger David Habier Rohan Fernando Dorian J Garrick Jack CM Dekkers 《遗传、选种与进化》2011,43(1):23
Background
The predictive ability of genomic estimated breeding values (GEBV) originates both from associations between high-density markers and QTL (Quantitative Trait Loci) and from pedigree information. Thus, GEBV are expected to provide more persistent accuracy over successive generations than breeding values estimated using pedigree-based methods. The objective of this study was to evaluate the accuracy of GEBV in a closed population of layer chickens and to quantify their persistence over five successive generations using marker or pedigree information.Methods
The training data consisted of 16 traits and 777 genotyped animals from two generations of a brown-egg layer breeding line, 295 of which had individual phenotype records, while others had phenotypes on 2,738 non-genotyped relatives, or similar data accumulated over up to five generations. Validation data included phenotyped and genotyped birds from five subsequent generations (on average 306 birds/generation). Birds were genotyped for 23,356 segregating SNP. Animal models using genomic or pedigree relationship matrices and Bayesian model averaging methods were used for training analyses. Accuracy was evaluated as the correlation between EBV and phenotype in validation divided by the square root of trait heritability.Results
Pedigree relationships in outbred populations are reduced by 50% at each meiosis, therefore accuracy is expected to decrease by the square root of 0.5 every generation, as observed for pedigree-based EBV (Estimated Breeding Values). In contrast the GEBV accuracy was more persistent, although the drop in accuracy was substantial in the first generation. Traits that were considered to be influenced by fewer QTL and to have a higher heritability maintained a higher GEBV accuracy over generations. In conclusion, GEBV capture information beyond pedigree relationships, but retraining every generation is recommended for genomic selection in closed breeding populations. 相似文献24.
Background
A recent epidemiological study demonstrated a reduced risk of lung cancer mortality in breast cancer patients using antiestrogens. These and other data implicate a role for estrogens in lung cancer, particularly nonsmall cell lung cancer (NSCLC). Approximately 61% of human NSCLC tumors express nuclear estrogen receptor β (ERβ); however, the role of ERβ and estrogens in NSCLC is likely to be multifactorial. Here we tested the hypothesis that proteins interacting with ERβ in human lung adenocarcinoma cells that respond proliferatively to estradiol (E2) are distinct from those in non-E2-responsive cells.Methods
FLAG affinity purification of FLAG-ERβ-interacting proteins was used to isolate ERβ-interacting proteins in whole cell extracts from E2 proliferative H1793 and non-E2-proliferative A549 lung adenocarcinoma cell lines. Following trypsin digestion, proteins were identified using liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). Proteomic data were analyzed using Ingenuity Pathway Analysis. Select results were confirmed by coimmunoprecipitation.Results
LC-MS/MS identified 27 non-redundant ERβ-interacting proteins. ERβ-interacting proteins included hsp70, hsp60, vimentin, histones and calmodulin. Ingenuity Pathway Analysis of the ERβ-interacting proteins revealed differences in molecular and functional networks between H1793 and A549 lung adenocarcinoma cells. Coimmunoprecipitation experiments in these and other lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a gender-dependent manner and in response to E2 or EGF. BRCA1 interacted with ERβ in A549 cell lines and in human lung adenocarcinoma tumors, but not normal lung tissue.Conclusion
Our results identify specific differences in ERβ-interacting proteins in lung adenocarcinoma cells corresponding to ligand-dependent differences in estrogenic responses.25.
Background
Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity. 相似文献26.
Various proteases are involved in cancer progression and metastasis. In particular, gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, have been implicated to play a role in colon cancer progression and metastasis in animal models and patients. In the present review, the clinical relevance and the prognostic value of messenger ribonucleic acid (mRNA) and protein expression and proenzyme activation of MMP-2 and MMP-9 are evaluated in relation to colorectal cancer. Expression of tissue inhibitors of MMPs (TIMPs) in relation with MMP expression in cancer tissues and the relevance of detection of plasma or serum levels of MMP-2 and/or MMP-9 and TIMPs for prognosis are also discussed. Furthermore, involvement of MMP-2 and MMP-9 in experimental models of colorectal cancer is reviewed. In vitro studies have suggested that gelatinase is expressed in cancer cells but animal models indicated that gelatinase expression in non-cancer cells in tumors contributes to cancer progression. In fact, interactions between cancer cells and host tissues have been shown to modulate gelatinase expression in host cells. Inhibition of gelatinases by synthetic MMP inhibitors has been considered to be an attractive approach to block cancer progression. However, despite promising results in animal models, clinical trials with MMP inhibitors have been disappointing so far. To obtain more insight in the (patho)physiological functions of gelatinases, regulation of MMP-2 and MMP-9 expression is discussed. Mitogen activated protein kinase (MAPK) signalling has been shown to be involved in regulation of gelatinase expression in both cancer cells and non-cancer cells. Expression can be triggered by a variety of stimuli including growth factors, cytokines and extracellular matrix (ECM) components. On the other hand, MMP-2 and MMP-9 activity regulates bioavailability and activity of growth factors and cytokines, affects the immune response and is involved in angiogenesis. Because of the multifunctionality of gelatinases, it is unpredictable at what stage of cancer development and in which processes gelatinase activity is involved. Therefore, it is concluded that the use of MMP inhibitors to treat cancer should be considered carefully. 相似文献
27.
Wilma M Frederiks Jan van Marle Carel van Oven Begonya Comin-Anduix Marta Cascante 《The journal of histochemistry and cytochemistry》2006,54(1):47-52
Since the introduction of cyano-ditolyl-tetrazolium chloride (CTC), a tetrazolium salt that gives rise to a fluorescent formazan after reduction, it has been applied to quantify activity of dehydrogenases in individual cells using flow cytometry. Confocal laser scanning microscopy (CLSM) showed that the fluorescent formazan was exclusively localized at the surface of individual cells and not at intracellular sites of enzyme activity. In the present study, the technique has been optimized to localize activity of glucose-6-phosphate dehydrogenase (G6PD) intracellularly in individual cells. Activity was demonstrated in cultured fibrosarcoma cells in different stages of the cell cycle. Cells were incubated for the detection of G6PD activity using a medium containing 6% (w/v) polyvinyl alcohol, 5 mM CTC, magnesium chloride, sodium azide, the electron carrier methoxyphenazine methosulphate, NADP, and glucose-6-phosphate. Before incubation, cells were permeabilized with 0.025% glutaraldehyde. Fluorescent formazan was localized exclusively in the cytoplasm of fibrosarcoma cells. The amount of fluorescent formazan in cells increased linearly with incubation time when measured with flow cytometry and CLSM. When combining the Hoechst staining for DNA with the CTC method for the demonstration of G6PD activity, flow cytometry showed that G6PD activity of cells in S phase and G2/M phase is 27 +/- 4% and 43 +/- 4% higher, respectively, than that of cells in G1 phase. CLSM revealed that cells in all phases of mitosis as well as during apoptosis contained considerably lower G6PD activity than cells in interphase. It is concluded that posttranslational regulation of G6PD is responsible for this cell cycle-dependent activity. 相似文献
28.
van Welsem T Frederiks F Verzijlbergen KF Faber AW Nelson ZW Egan DA Gottschling DE van Leeuwen F 《Molecular and cellular biology》2008,28(11):3861-3872
Dot1 methylates histone H3 lysine 79 (H3K79) on the nucleosome core and is involved in Sir protein-mediated silencing. Previous studies suggested that H3K79 methylation within euchromatin prevents nonspecific binding of the Sir proteins, which in turn facilitates binding of the Sir proteins in unmethylated silent chromatin. However, the mechanism by which the Sir protein binding is influenced by this modification is unclear. We performed genome-wide synthetic genetic array (SGA) analysis and identified interactions of DOT1 with SIR1 and POL32. The synthetic growth defects found by SGA analysis were attributed to the loss of mating type identity caused by a synthetic silencing defect. By using epistasis analysis, DOT1, SIR1, and POL32 could be placed in different pathways of silencing. Dot1 shared its silencing phenotypes with the NatA N-terminal acetyltransferase complex and the conserved N-terminal bromo adjacent homology (BAH) domain of Sir3 (a substrate of NatA). We classified all of these as affecting a common silencing process, and we show that mutations in this process lead to nonspecific binding of Sir3 to chromatin. Our results suggest that the BAH domain of Sir3 binds to histone H3K79 and that acetylation of the BAH domain is required for the binding specificity of Sir3 for nucleosomes unmethylated at H3K79. 相似文献
29.
Background
Immune response pathways have been relatively well-conserved across animal species, with similar systems in both mammals and invertebrates. Interestingly, honey bees have substantially reduced numbers of genes associated with immune function compared with solitary insect species. However, social species such as honey bees provide an excellent environment for pathogen or parasite transmission with controlled environmental conditions in the hive, high population densities, and frequent interactions. This suggests that honey bees may have developed complementary mechanisms, such as behavioral modifications, to deal with disease. 相似文献30.
Wenhui Nie Beiyuan Fu Patricia CM O'Brien Jinhuan Wang Weiting Su Alongkoad Tanomtong Vitaly Volobouev Malcolm A Ferguson-Smith Fengtang Yang 《BMC biology》2008,6(1):18