20 research outputs found
Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells
Background: Advanced glycation end products (AGEs), the final products of the Maillard reaction, have been shown to impair endothelial proliferation and function, thus contributing to endothelial cell injury present in diabetes, inflammatory and cardiovascular diseases. Endoplasmic reticulum (ER) stress triggered under hyperglycemic, hypoxic and oxidative conditions has been implicated in endothelial dysfunction through activation of the unfolded protein response (UPR). The present study investigates the role of AGEs in ER stress induction in human aortic endothelial cells exposed to variable AGE treatments.
Methods: Human aortic endothelial cells (HAEC) were treated with increasing concentrations (100, 200 μg/mL) of AGE-bovine serum albumin (AGE-BSA) at different time-points (24, 48, 72 h). The induction of ER stress and the involved UPR components were investigated on mRNA and protein levels. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously.
Results: AGEs administration significantly reduced HAEC proliferation in a time- and dose-dependent manner. An immediate induction of the ER chaperones GRP78, GRP94 and the transcriptional activator, XBP-1 was observed at 24 h and 48 h. A later induction of the phospho-lF2α and proapoptotic transcription factor CHOP was observed at 48 h and 72 h, being correlated with elevated early apoptotic cell numbers at the same time-points.
Conclusions: The present study demonstrates that AGEs directly induce ER stress in human aortic endothelial cells, playing an important role in endothelial cell
apoptosis. Targeting AGEs signaling pathways in order to alleviate ER stress may prove of therapeutic potential to endothelial dysfunction-related disorders
DoctorEye: A clinically driven multifunctional platform, for accurate processing of tumors in medical images
Copyright @ Skounakis et al.This paper presents a novel, open access interactive platform for 3D medical image analysis, simulation and visualization, focusing in oncology images. The platform was developed through constant interaction and feedback from expert clinicians integrating a thorough analysis of their requirements while having an ultimate goal of assisting in accurately delineating tumors. It allows clinicians not only to work with a large number of 3D tomographic datasets but also to efficiently annotate multiple regions of interest in the same session. Manual and semi-automatic segmentation techniques combined with integrated correction tools assist in the quick and refined delineation of tumors while different users can add different components related to oncology such as tumor growth and simulation algorithms for improving therapy planning. The platform has been tested by different users and over large number of heterogeneous tomographic datasets to ensure stability, usability, extensibility and robustness with promising results. AVAILABILITY: THE PLATFORM, A MANUAL AND TUTORIAL VIDEOS ARE AVAILABLE AT: http://biomodeling.ics.forth.gr. It is free to use under the GNU General Public License
Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer
The polycystins PC1 and PC2 are emerging as major players in
mechanotransduction, a process that influences all steps of the
invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate
cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and
quantitative real-time PCR and FACS analyses were employed to
investigate the effect of polycystin overexpression in colorectal cancer
(CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation
was evaluated through an MTT assay. In vitro data were analyzed by
Student’s t-test. HT29 human xenografts were treated with anti-PC1
(extracellular domain) inhibitory antibody and analyzed via
immunohistochemistry to determine the in vivo role of PC1 in CRC.
Clinical significance was assessed by examining PC1 and PC2 protein
expression in CRC patients (immunohistochemistry). In vivo and clinical
data were analyzed by non-parametric tests, Kaplan-Meier curves,
log-rank test and Cox model. All statistical tests were two-sided. PC1
overexpression promotes epithelial-to-mesenchymal transition (EMT) in
HCT116 cells, while PC2 overexpression results in upregulation of the
mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell
proliferation in CRC cells inducing tumor necrosis and suppressing EMT
in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression
associates with adverse pathological parameters, including invasiveness
and mucinous carcinomas. Moreover, PC1 overexpression appears as an
independent prognostic factor of reduced recurrence-free survival (HR =
1.016, p = 0.03) and lowers overall survival probability, while aberrant
PC2 expression predicts poor overall survival (p = 0.0468). These
results support, for the first time, a direct link between
mechanosensing polycystins (PC1 and PC2) and CRC progression.
What’s new? The behavior of cancer cells is regulated in part by
mechanical stimuli. Key to the mechanosensing properties of cells are
the epithelial polycystins PC1 and PC2, which the present study links to
the progression of colorectal cancer (CRC). In vitro experiments show
that overexpression of PC1 and PC2 are associated with aggressive CRC
phenotype, while clinical analyses associate PC1 overexpression with
poor recurrence-free survival and aberrant PC2 expression with poor
overall survival. The data imply that the two polycystins are of
clinical relevance in CRC, with potential roles as targets for the
prevention of invasion and metastasis
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The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape