Altered blood gene expression of tumor-related genes (PRKCB, BECN1 and CDKN2A) in Alzheimer's disease

Alzheimer's disease (AD) is the most common of the neurodegenerative diseases. Recent diagnostic criteria have defined a preclinical disease phase during which neuropathological substrates are thought to be present in the brain. There is an urgent need to find measurable alterations in this phase as well as a good peripheral biomarker in the blood. We selected a cohort of 100 subjects (controls = 47; preclinical AD = 11; patients with AD = 42) and analyzed whole blood expression of 20 genes by quantitative polymerase chain reaction. The selected genes belonged to calcium-signaling, senescence and autophagy, and mitochondria/oxidative stress pathways. Additionally, two genes associated with an increased risk of developing AD (CLU and BIN1) were also analyzed. We detected significantly different gene expressions of BECN1 and PRKCB between the control and the AD groups; and, of CDKN2A between the control and the preclinical AD groups. Notably, these three genes are also considered tumor suppressor (CDKN2A and BECN1) or tumor promoter (PRKCB) genes. Gene-gene expression Pearson correlations were computed separately for controls and patients with AD. The significant correlations (p<0.001) were represented in a network analysis with Cytoscape tool, which suggested an uncoupling of mitochondriarelated genes in AD group. Whole blood is emerging as a valuable tissue in the study of the physiopathology of AD

Improving assessment of lipoprotein profile profile in type 1 diabetes by 1H NMR spectrometry

Patients with type 1 diabetes (T1D) present increased risk of cardiovascular disease (CVD). The aim of this study is to improve the assessment of lipoprotein profile in patients with T1D by using a robust developed method 1H nuclear magnetic resonance spectroscopy (1H NMR), for further correlation with clinical factors associated to CVD. Thirty patients with T1D and 30 non-diabetes control (CT) subjects, matched for gender, age, body composition (DXA, BMI, waist/hip ratio), regular physical activity levels and cardiorespiratory capacity (VO2peak), were analyzed. Dietary records and routine lipids were assessed. Serum lipoprotein particle subfractions, particle sizes, and cholesterol and triglycerides subfractions were analyzed by 1H NMR. It was evidenced that subjects with T1D presented lower concentrations of small LDL cholesterol, medium VLDL particles, large VLDL triglycerides, and total triglycerides as compared to CT subjects. Women with T1D presented a positive association with HDL size (p<0.005; R = 0.601) and large HDL triglycerides (p<0.005; R = 0.534) and negative (p<0.005; R = -0.586) to small HDL triglycerides. Body fat composition represented an important factor independently of normal BMI, with large LDL particles presenting a positive correlation to total body fat (p<0.005; R = 0.505), and total LDL cholesterol and small LDL cholesterol a positive correlation (p<0.005; R = 0.502 and R = 0.552, respectively) to abdominal fat in T1D subjects; meanwhile, in CT subjects, body fat composition was mainly associated to HDL subclasses. VO2peak was negatively associated (p<0.005; R = -0.520) to large LDL-particles only in the group of patients with T1D. In conclusion, patients with T1D with adequate glycemic control and BMI and without chronic complications presented a more favourable lipoprotein profile as compared to control counterparts. In addition, slight alterations in BMI and/or body fat composition showed to be relevant to provoking alterations in lipoproteins profiles. Finally, body fat composition appears to be a determinant for cardioprotector lipoprotein profile

Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators

Collagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts. In order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays. We found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases

Altered blood gene expression of tumor-related genes (PRKCB, BECN1 and CDKN2A) in Alzheimer's disease

Alzheimer's disease (AD) is the most common of the neurodegenerative diseases. Recent diagnostic criteria have defined a preclinical disease phase during which neuropathological substrates are thought to be present in the brain. There is an urgent need to find measurable alterations in this phase as well as a good peripheral biomarker in the blood. We selected a cohort of 100 subjects (controls = 47; preclinical AD = 11; patients with AD = 42) and analyzed whole blood expression of 20 genes by quantitative polymerase chain reaction. The selected genes belonged to calcium-signaling, senescence and autophagy, and mitochondria/oxidative stress pathways. Additionally, two genes associated with an increased risk of developing AD (CLU and BIN1) were also analyzed. We detected significantly different gene expressions of BECN1 and PRKCB between the control and the AD groups; and, of CDKN2A between the control and the preclinical AD groups. Notably, these three genes are also considered tumor suppressor (CDKN2A and BECN1) or tumor promoter (PRKCB) genes. Gene-gene expression Pearson correlations were computed separately for controls and patients with AD. The significant correlations (p<0.001) were represented in a network analysis with Cytoscape tool, which suggested an uncoupling of mitochondriarelated genes in AD group. Whole blood is emerging as a valuable tissue in the study of the physiopathology of AD

Network models of lipoproteins and clinical variables in control subjects and in T1D subjects.

<p>Control (1A) and T1D subjects (1B). Integration of datasets was accomplished with the Cytoscape tool (<a href="http://www.cytoscape.org/" target="_blank">www.cytoscape.org</a>), which constructs and displays correlation networks between components (p-value < 0.005 and thresholds R > ± 0.5 for clinical variables, and R > ± 0.7 for lipoprotein variables). Continuous lines represent positive correlations, and dashed lines represent negative associations. Grey spheres represent clinical variables; in red, LDL related lipoproteins; in green, HDL lipoproteins; in blue, VLDL lipoproteins; and in purple, total triglycerides. Orange circles mark the variables that are reduced in T1D subjects.</p

Statistical analysis of covariance contrasting lipid and lipoprotein data from subjects with type 1 diabetes and control subjects.

<p>^a lipoprotein subfraction determined by LipoProfile</p><p>^b lipoproteins subfraction determined PLS regression</p><p>^c lipoprotein determined by conventional determinations</p><p>Covariates considered: age, gender, active smoking, waist/hip ratio, total fat percentage by DXA and VO_2peak</p><p>* FC: Fold change. Negative values correspond to lower concentrations found in T1D.</p><p>Statistical analysis of covariance contrasting lipid and lipoprotein data from subjects with type 1 diabetes and control subjects.</p

Diet components by dietary records in subjects with type 1 diabetes and controls.

<p>No statistical differences between groups, based on Student T-test, except for total carbohydrate intake.</p><p>Diet components by dietary records in subjects with type 1 diabetes and controls.</p

Clinical characteristics of subjects with type 1 diabetes and controls.

<p>MET: Metabolic Equivalent of Task. 1 MET = 3.5 ml O₂·kg⁻¹·min⁻¹. No statistical differences between groups, based on Chi-square and Student T-test.</p><p>Clinical characteristics of subjects with type 1 diabetes and controls.</p