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Arabkhari M.,University of Toronto | Bunda S.,University of Toronto | Wang Y.,University of Toronto | Wang A.,University of Toronto | And 2 more authors.
Glycobiology | Year: 2010

We recently established that the subunit of cell surfaceresiding elastin receptor, neuraminidase-1 (Neu1), can desialylate adjacent insulin-like growth factor 1 receptors (IGF-1R) of arterial smooth muscle cells, thereby quenching their proliferative response to insulin-like growth factor II. In this study, we explored whether Neu1 would also desialylate the insulin receptors (IR), as well as the IGF-1R on rat skeletal L6 myoblasts, and whether desialylation of IR and IGF-1R would affect a netproliferativeeffectofinsulin. First, we found that physiological (0.5-1 nM) and high therapeutic (10 nM) insulin concentrations induced a modest increase in proliferation rate of cultured L6 myoblasts. While IR kinase inhibitor could abolish the mitogenic effect of these insulin concentrations, the observed more pronounced proliferative response to supraphysiological concentration (100 nM) of insulin could be eliminated only by specific inhibition of IGF-1R. Then, we found that treatment of L6 cells with mouse-derived Neu1 or with Clostridium perfringens neuraminidase caused desialylation of IR, which coincided with a significant increase of their proliferative response to lower (0.5-10 nM) concentrations of insulin. In contrast, experimental desialylation of IGF-1R coincided with elimination of the heightened proliferative response of L6 myoblasts to 100 nM insulin. Importantly, we also found that inhibition of endogenous Neu1 abolished the increase in proliferation of L6 cells induced by 1 and 10 nM of insulin, but amplified the proliferative effect of 100 nM insulin. We therefore conclude that desialylation of both IR and IGF-1R by Neu1 controls the net proliferative response of skeletal myoblasts to insulin. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Herman K.M.,McGill University | Sabiston C.M.,University of Toronto | Mathieu M.-E.,University of Montreal | Mathieu M.-E.,Sainte Justine Research Center | And 2 more authors.
Preventive Medicine | Year: 2014

Objectives: Sedentary behavior (SB) is distinct from physical inactivity. Children's guidelines recommend ≤. 2. h/day screen time and ≥. 60. min/day moderate-to-vigorous physical activity (MVPA). This study describes SB in children at elevated risk of obesity, including the possibility of high SB in otherwise active children. Methods: Participants were 534 children from Quebec, Canada, aged 8-10. years with ≥. 1 obese parent in 2005-2008. SB and MVPA were measured by accelerometer and specific SBs by self-report, and height and weight were directly measured. Results: Overweight/obese children were significantly more sedentary overall and reported higher screen time than normal weight children. About 19% of boys and 46% of girls met screen time but not PA guidelines; 28% of boys and 5% of girls met PA but not screen time guidelines. About 46% of overweight/obese children met neither guideline (32% normal weight); only 5% overweight/obese children met both (21% normal weight). Reported behaviors contributed 60%-80% of total SB time; the most sedentary children had the most unaccounted for SB time. Conclusions: Overweight/obese children are more sedentary overall and report higher screen time than normal weight children. Public health efforts targeting PA and SB in children must consider sex and weight status while being cognizant that being sufficiently active is not exclusive of high levels of SB. © 2014 Elsevier Inc.

Pshezhetsky A.V.,Sainte Justine Research Center | Pshezhetsky A.V.,University of Montreal | Pshezhetsky A.V.,McGill University | Hinek A.,University of Toronto
Glycoconjugate Journal | Year: 2011

Terminal sialic acid residues are found in abundance in glycan chains of glycoproteins and glycolipids on the surface of all live cells forming an outer layer of the cell originally known as glycocalyx. Their presence affects the molecular properties and structure of glycoconjugates, modifying their function and interactions with other molecules. Consequently, the sialylation state of glycoproteins and glycolipids has been recognized as a critical factor modulating molecular recognitions inside the cell, between the cells, between the cells and the extracellular matrix, and between the cells and certain exogenous pathogens. Sialyltransferases that attach sialic acid residues to the glycan chains in the process of their initial synthesis were thought to be mainly responsible for the creation and maintenance of a temporal and spatial diversity of sialylated moieties. However, the growing evidence also suggests that in mammalian cells, at least equally important roles belong to sialidases/neuraminidases, which are located on the cell surface and in intracellular compartments, and may either initiate the catabolism of sialoglycoconjugates or just cleave their sialic acid residues, and thereby contribute to temporal changes in their structure and functions. The current review summarizes emerging data demonstrating that neuraminidase 1 (NEU1), well known for its lysosomal catabolic function, can be also targeted to the cell surface and assume the previously unrecognized role as a structural and functional modulator of cellular receptors. © Springer Science+Business Media, LLC 2011.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8–12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.The Pharmacogenomics Journal advance online publication, 8 September 2015; doi:10.1038/tpj.2015.63. © 2015 Macmillan Publishers Limited

Patten S.A.,Sainte Justine Research Center | Moldovan F.,University of Montreal
Medical Hypotheses | Year: 2011

Adolescent idiopathic scoliosis (AIS) is a condition characterized by a three-dimensional structural deformity of the spine. It is the most common type of spine deformity occurring in children aged 10 to maturity. Although the etiology of AIS still remains unknown, the role of genetic factors in the development of idiopathic scoliosis is widely accepted. However, to date no causative genes of AIS have been identified. Recently, the semicircular canals, which are part of the inner ear, were found to be morphologically abnormal in idiopathic scoliosis patients. Here we hypothesized that genetic predisposition to inner ear anomalies in AIS patients may be a strong factor in the generation of idiopathic scoliosis. The proposed idea is that gene defects could impair the development of the semicircular canals. A malformation of semicircular canals might affect the transmission of sensory signal about rotational movement of the body to the central nervous system; leading to an alteration in the neuronal circuit of balance. This will in turn affect body posture and results in the initiation of the curvature of the spine. This hypothesis may provide new insights in the understanding of the pathophysiologic mechanisms of idiopathic scoliosis. It can also offer hopes for potential early prediction of scoliosis. © 2010.

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