Telomere shortening & metabolic/vascular diseases

Telomeres are specialized DNA-protein structures located at the ends of eukaryotic chromosomes whose length is progressively reduced in most somatic cells during ageing. Over the past decade, emerging evidence has shown that the telomeres are essential regulators of cellular life span and chromosome integrity in a dynamic fashion. By inducing genomic instability, replicative senescence and apoptosis, shortening of telomeres is thought to contribute to organismal ageing. While the aetiology of cardiovascular diseases and diabetes represent a complex interaction between various risk factors overlaid on different genetic backgrounds, the conventional risk factors often did not explain the inter-individual variability related to predisposition of disease states. This underscores the need for biological indicators of ageing in evaluating the aetiology of several age-related disorders, and recent studies indicate that telomere length could qualify as an ideal marker of biological ageing. Short telomeres have been detected in senescent endothelial cells and vascular smooth muscle cells from human atherosclerotic plaque as well as in myocardial tissue from patients with end-stage heart failure and cardiac hypertrophy. In addition, telomere shortening has been demonstrated in WBCs from patients with coronary heart disease, premature myocardial infarction, hypertension and diabetes mellitus. In this review, we discuss the telomere hypothesis of ageing as well as human studies that address the role of telomeres in cardiovascular, diabetes and other cardio-metabolic pathologies

Curcumin-induced inhibition of cellular reactive oxygen species generation: novel therapeutic implications

There is evidence for increased levels of circulating reactive oxygen species (ROS) in diabetics, as indirectly inferred by the findings of increased lipid peroxidation and decreased antioxidant status. Direct measurements of intracellular generation of ROS using fluorescent dyes also demonstrate an association of oxidative stress with diabetes. Although phenolic compounds attenuate oxidative stress-related tissue damage, there are concerns over toxicity of synthetic phenolic antioxidants and this has considerably stimulated interest in investigating the role of natural phenolics in medicinal applications. Curcumin (the primary active principle in turmeric, Curcuma longa Linn.) has been claimed to represent a potential antioxidant and antiinflammatory agent with phytonutrient and bioprotective properties. However there are lack of molecular studies to demonstrate its cellular action and potential molecular targets. In this study the antioxidant effect of curcumin as a function of changes in cellular ROS generation was tested. Our results clearly demonstrate that curcumin abolished both phorbol-12 myristate-13 acetate (PMA) and thapsigargin-induced ROS generation in cells from control and diabetic subjects. The pattern of these ROS inhibitory effects as a function of dose-dependency suggests that curcumin mechanistically interferes with protein kinase C (PKC) and calcium regulation. Simultaneous measurements of ROS and Ca2+ influx suggest that a rise in cytosolic Ca2+ may be a trigger for increased ROS generation. We suggest that the antioxidant and antiangeogenic actions of curcumin, as a mechanism of inhibition of Ca2+ entry and PKC activity, should be further exploited to develop suitable and novel drugs for the treatment of diabetic retinopathy and other diabetic complications

Mitophagy plays a central role in mitochondrial ageing

The mechanisms underlying ageing have been discussed for decades, and advances in molecular and cell biology of the last three decades have accelerated research in this area. Over this period, it has become clear that mitochondrial function, which plays a major role in many cellular pathways from ATP production to nuclear gene expression and epigenetics alterations, declines with age. The emerging concepts suggest novel mechanisms, involving mtDNA quality, mitochondrial dynamics or mitochondrial quality control. In this review, we discuss the impact of mitochondria in the ageing process, the role of mitochondria in reactive oxygen species production, in nuclear gene expression, the accumulation of mtDNA damage and the importance of mitochondrial dynamics and recycling. Declining mitophagy (mitochondrial quality control) may be an important component of human ageing

VFG – INDEX: A NOVEL GRAPH INDEXING METHOD

The latest advancements in science and technology have observed large quantity of complicated structures and schema less data such as proteins, circuits, images, Web, and XML documents which can be modeled into various types of which one of the most dominant now a days are graphs. This has caused Graph Mining, one of the budding areas of research happening throughout. In this paper, we investigate the various algorithms for Graph Indexing which makes use of Frequent Sub graph as a key term for indexing, of which one the most dominant is FG-index algorithm. This algorithm is tested with AIDS dataset and an improved algorithm is proposed for effective indexing

Novel pharmacotherapies in diabetic retinopathy: Current status and what's in the horizon?

The blood–retinal barrier (BRB) alteration is the hallmark feature of diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a potent vasopermeability factor that has been implicated in the pathogenesis of BRB alteration. Inflammation also plays a crucial role in this process with involvement of several chemokines and cytokines. Multiple anti-VEGF drugs are widely used as in the treatment of diabetic macular edema (DME) as well as proliferative diabetic retinopathy. Several clinical trials have proved the beneficial effects of these drugs in improvement of vision and prevention of vision loss. However, the response to anti-VEGF drugs in DME is not complete in a significant number of patients. The effect seems transient in this latter group, and many patients do not show complete resolution of fluid. Potential novel therapies targeting molecules beyond VEGF are being developed and examined in clinical trials

Relationship of body fat with insulin resistance and cardiometabolic risk factors among normal glucose-tolerant subjects

Background: The amount of body fat, rather than the amount of excess weight, determines the health risks of obesity, type 2 diabetes mellitus, and cardiovascular disease. Aims: To look at the association of body fat percentage with cardiometabolic risk factors in subjects with normal glucose tolerance (NGT). Settings and Design: Cross-section study from the Chennai Urban Rural Epidemiology Study. Materials and Methods: Body fat was measured by Beurer body fat analyzer. Metabolic syndrome (MS) was diagnosed based on modified ATPIII guidelines. Statistical Analysis: Student′s t test or one-way ANOVA (with Tukey′s HSD) was used to compare groups for continuous variables. Results: Body mass index, waist circumference, systolic and diastolic blood pressure, HOMA IR, serum cholesterol, and LDL cholesterol increased significantly with increasing tertiles of body fat (P<0.001). There was a linear increase in the percentage of body fat with increase in number of components of MS (no metabolic abnormality: 25±11, one metabolic abnormality: 28±10, two metabolic abnormalities: 33±8, and three and more metabolic abnormalities: 35±7) (P<0.001). Regression models showed significant association of body fat with MS after adjusting for age, gender, insulin resistance, and glycated hemoglobin (Odds ratio: 1.04, 95% confidence interval: 1.04 - 1.08, P<0.001). In linear regression analysis, body fat showed a significant association with insulin resistance after adjusting for age, gender, and glycated hemoglobin (β=0.030, P<0.001). Conclusions: A significant association exists between body fat, MS, and cardiometabolic risk factors even among subjects with NGT

Relationship of body fat with insulin resistance and cardiometabolic risk factors among normal glucose-tolerant subjects

Background: The amount of body fat, rather than the amount of excess weight, determines the health risks of obesity, type 2 diabetes mellitus, and cardiovascular disease. Aims: To look at the association of body fat percentage with cardiometabolic risk factors in subjects with normal glucose tolerance (NGT). Settings and Design : Cross-section study from the Chennai Urban Rural Epidemiology Study. Materials and Methods : Body fat was measured by Beurer body fat analyzer. Metabolic syndrome (MS) was diagnosed based on modified ATPIII guidelines. Statistical Analysis: Student's t test or one-way ANOVA (with Tukey's HSD) was used to compare groups for continuous variables. Results: Body mass index, waist circumference, systolic and diastolic blood pressure, HOMA IR, serum cholesterol, and LDL cholesterol increased significantly with increasing tertiles of body fat (P&lt;0.001). There was a linear increase in the percentage of body fat with increase in number of components of MS (no metabolic abnormality: 25&#177;11, one metabolic abnormality: 28&#177;10, two metabolic abnormalities: 33&#177;8, and three and more metabolic abnormalities: 35&#177;7) (P&lt;0.001). Regression models showed significant association of body fat with MS after adjusting for age, gender, insulin resistance, and glycated hemoglobin (Odds ratio: 1.04, 95% confidence interval: 1.04 - 1.08, P&#60;0.001). In linear regression analysis, body fat showed a significant association with insulin resistance after adjusting for age, gender, and glycated hemoglobin (&#946;=0.030, P&lt;0.001). Conclusions: A significant association exists between body fat, MS, and cardiometabolic risk factors even among subjects with NGT

Telomere shortening &amp; metabolic/vascular diseases

Telomeres are specialized DNA-protein structures located at the ends of eukaryotic chromosomes whose length is progressively reduced in most somatic cells during ageing. Over the past decade, emerging evidence has shown that the telomeres are essential regulators of cellular life span and chromosome integrity in a dynamic fashion. By inducing genomic instability, replicative senescence and apoptosis, shortening of telomeres is thought to contribute to organismal ageing. While the aetiology of cardiovascular diseases and diabetes represent a complex interaction between various risk factors overlaid on different genetic backgrounds, the conventional risk factors often did not explain the inter-individual variability related to predisposition of disease states. This underscores the need for biological indicators of ageing in evaluating the aetiology of several age-related disorders, and recent studies indicate that telomere length could qualify as an ideal marker of biological ageing. Short telomeres have been detected in senescent endothelial cells and vascular smooth muscle cells from human atherosclerotic plaque as well as in myocardial tissue from patients with end-stage heart failure and cardiac hypertrophy. In addition, telomere shortening has been demonstrated in WBCs from patients with coronary heart disease, premature myocardial infarction, hypertension and diabetes mellitus. In this review, we discuss the telomere hypothesis of ageing as well as human studies that address the role of telomeres in cardiovascular, diabetes and other cardio-metabolic pathologies

Subclinical inflammation/oxidation as revealed by altered gene expression profiles in subjects with impaired glucose tolerance and Type 2 diabetes patients

Although subclinical inflammation and oxidative stress are implicated in the aetiology of diabetes, there are hardly any studies in prediabetes. Therefore, we made an attempt to study the gene expression pattern of certain inflammatory/oxidative genes using lymphocytes from Type 2 diabetic patients, impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) subjects. Compared to NGT group, interleukin-6, tumor necrosis factor-α (TNF-α), p22Phox NADPH oxidase, and thioredoxin interacting protein (TXNIP) mRNA levels were higher and suppressor of cytokine signaling (SOCS-3) mRNA was lower in subjects with IGT and diabetes. The mean (±SE) levels of thiobarbituric acid reactive substances and protein carbonyl content were also elevated in glucose intolerant subjects. In multiple linear regression analysis, TXNIP and TNF-α showed a significant association with HbA1c even after adjusting for TBARS and PCO (TXNIP: β = 1.70, P < 0.01; TNF-α: β = 1.86, P < 0.01). Increased subclinical inflammation/oxidation is seen in Asian Indians with not only Type 2 diabetes but also IGT