Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity

Obesity leading to hyperlipidaemia and atherosclerosis is recognised to induce morphological and metabolic changes in many tissues. However, both hyperlipidaemia and atherosclerosis can occur in the absence of obesity. The impact of the latter scenario on skeletal muscle and liver is not understood sufficiently. In this regard, we used the Apolipoprotein E-deficient (ApoE-/-) mouse model, an established model of hyperlipidaemia and atherosclerosis, that does not become obese when subjected to a high-fat diet, to determine the impact of Western-type diet (WD) and ApoE deficiency on skeletal muscle morphological, metabolic and biochemical properties. To establish the potential of therapeutic targets, we further examined the impact of Nox2 pharmacological inhibition on skeletal muscle redox biology. We found ectopic lipid accumulation in skeletal muscle and the liver, and altered skeletal muscle morphology and intramuscular triacylglycerol fatty acid composition. WD and ApoE deficiency had a detrimental impact in muscle metabolome, followed by perturbed gene expression for fatty acid uptake and oxidation. Importantly, there was enhanced oxidative stress in the skeletal muscle and development of liver steatosis, inflammation and oxidative protein modifications. Pharmacological inhibition of Nox2 decreased reactive oxygen species production and protein oxidative modifications in the muscle of ApoE-/- mice subjected to a Western-type diet. This study provides key evidence to better understand the pathophysiology of skeletal muscle in the context of hyperlipidaemia and atherosclerosis and identifies Nox2 as a potential target for attenuating oxidative stress in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia

Insulin Resistance Impairs Circulating Angiogenic Progenitor Cell Function and Delays Endothelial Regeneration

OBJECTIVE Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration. RESEARCH DESIGN AND METHODS We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion. RESULTS IRKO mice, although glucose tolerant, had fewer circulating Sca-1+/Flk-1+ APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor–stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit+ bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial repair. CONCLUSIONS Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals

Novel Paracrine Action of Endothelium enhances Glucose Uptake in Muscle and Fat

Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell production of superoxide and a simultaneous reduction in availability of the vasoprotective signalling radical, nitric oxide (NO). We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to insulin like growth factor-1 (IGF-1) mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in endothelial cells in vivo. Methods and Results: We generated mice expressing mutant IGF-1 receptors (mIGF-1R), which form non-functioning hybrid receptors with native insulin receptors (IR) and IGF-1R, directed to endothelial cells under control of the Tie2 promoter-enhancer. Despite endothelial cell insulin and IGF-1 resistance, mutant IGF-1R endothelial cell over-expressing mice (mIGFREO) had enhanced insulin and IGF-1 mediated systemic glucose disposal, lower fasting free fatty acids and triglycerides. In hyperinsulinaemic-euglycaemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased NADPH oxidase 4 (Nox4) expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO endothelial cells generated increased hydrogen peroxide (H2O2), with no increase in superoxide. Treatment with catalase, a dismutase restored insulin tolerance to wild type levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favourable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H2O2 generation mediating enhanced whole-body insulin sensitivity

Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell–specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling

Insulinlike Growth Factor-Binding Protein-1 Improves Vascular Endothelial Repair in Male Mice in the Setting of Insulin Resistance

Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor–binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance

Factors That Influence on Preschoolers' Language in Cognitive Development

Preschool children's language is just an evolving period and they have already learned a lot of words in their native language until 5 and 6 years old. Children are actively involved in observing others and interaction with their peers and encouraging of adults to speak can help to improve language development. There are some factors which impact on language acquisition of children such as family interaction, peers' influence and watching television. We discussed these factors in our article

Directions for the Effective Use of Innovative Strategies in the Management of Industrial Enterprises

The article considers the features of planning of innovative development of the enterprise. Presents the basic components of the system of strategic planning on the basis of innovation with the investment component. Are the technology choices of strategy of innovative development of the enterprise? Justifies the principles on which to base the development of the strategy of innovative development. &nbsp

Factors Affect Creative Thinking of Preschoolers in Cognitive Development

The creativity is one of the best tools which are given by God to discover new things in any field of life. How the creativity may be improved? There are so many ways and methods to reach the creativity. The first thing is upgrade creative thinking and other thinking ways from early development of child. By this study we tried to analyze 4-5 years old preschoolers' creative thinking and we have learned children who illustrated high and low result what things influence on their thinking. To conclude that not to stimulate to think creatively and not to work with children and some our national customs and tradition may cause children to be convergent thinkers

Training Children's Attention By Playing Games Intellectual

Many factors have a positive and negative impact on the child's development. The National games of Uzbek peoples have a significant impact on the growth of child are undermining today. Instead of playing physical activities, children are currently opting to play games related to computers, cell phones and other techniques. In fact, the computers or other technological games may boost child's mental abilities. However, it has many negative effects on the child development. In addition, throughout technical games, the child will not be physical active and it will negatively influence on physical development. In recent years, children have been forgetting to play national games. We made an effort to identify positive effects of playing game on training children's attention