Metabolic syndrome predicts vascular changes in whole body magnetic resonance imaging in patients with long standing diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Although diabetic patients have an increased rate of cardio-vascular events, there is considerable heterogeneity with respect to cardiovascular risk, requiring new approaches to individual cardiovascular risk factor assessment. In this study we used whole body-MR-angiography (WB-MRA) to assess the degree of atherosclerosis in patients with long-standing diabetes and to determine the association between metabolic syndrome (MetS) and atherosclerotic burden.</p> <p>Methods</p> <p>Long standing (≥10 years) type 1 and type 2 diabetic patients (n = 59; 31 males; 63.3 ± 1.7 years) were examined by WB-MRA. Based on the findings in each vessel, we developed an overall score representing the patient's vascular atherosclerotic burden (MRI-score). The score's association with components of the MetS was assessed.</p> <p>Results</p> <p>The median MRI-score was 1.18 [range: 1.00-2.41] and MetS was present in 58% of the cohort (type 2 diabetics: 73%; type 1 diabetics: 26%). Age (p = 0.0002), HDL-cholesterol (p = 0.016), hypertension (p = 0.0008), nephropathy (p = 0.0093), CHD (p = 0.001) and MetS (p = 0.0011) were significantly associated with the score. Adjusted for age and sex, the score was significantly (p = 0.02) higher in diabetics with MetS (1.450 [1.328-1.572]) compared to those without MetS (1.108 [0.966-1.50]). The number of MetS components was associated with a linear increase in the MRI-score (increase in score: 0.09/MetS component; r²= 0.24, p = 0.038). Finally, using an established risk algorithm, we found a significant association between MRI-score and 10-year risk for CHD, fatal CHD and stroke.</p> <p>Conclusion</p> <p>In this high-risk diabetic population, WB-MRA revealed large heterogeneity in the degree of systemic atherosclerosis. Presence and number of traits of the MetS are associated with the extent of atherosclerotic burden. These results support the perspective that diabetic patients are a heterogeneous population with increased but varying prevalence of atherosclerosis and risk.</p

Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

Proliferation of smooth muscle cells (SMCs) during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT), indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT

Oxidative Stress Accumulates in Adipose Tissue during Aging and Inhibits Adipogenesis

Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction

mTOR-Dependent Oxidative Stress Regulates oxLDL-Induced Trained Innate Immunity in Human Monocytes

Introduction: Cells of the innate immune system particularly monocytes and macrophages have been recognized as pivotal players both during the initial insult as well as the chronic phase of atherosclerosis. It has recently been shown that oxidized low-density lipoprotein (oxLDL) induces a long-term pro-inflammatory response in monocytes due to epigenetic and metabolic reprogramming, an emerging new concept called trained innate immunity. Changes in the cellular redox state are crucial events in the regulation of many physiologic functions in macrophages including transcription, differentiation and inflammatory response. Here we have analyzed the role of reactive oxygen species (ROS) in regulating this proinflammatory monocyte priming in response to oxLDL-treatment.Methods and Results: Human monocytes were isolated and incubated with oxLDL for 24 h. After 5 days of resting, oxLDL treated cells produced significantly more inflammatory cytokines upon restimulation with the TLR2-agonist Pam3cys. Furthermore, oxLDL incubation induced persistent mTOR activation, ROS formation, HIF1α accumulation and HIF1α target gene expression, while pharmacologic mTOR inhibition or siRNA mediated inhibition of the mTORC1 subunit Raptor prevented ROS formation and proinflammatory priming. mTOR dependent ROS formation was associated with increased expression of NAPDH oxidases and necessary for the emergence of the primed phenotype as antioxidant treatment blocked oxLDL priming. Inhibition of cytosolic ROS formation could also block mTOR activation and HIF1α accumulation suggesting a positive feedback loop between mTOR and cytosolic ROS. Although mitochondrial ROS scavenging did not block HIF1α-accumulation at an early time point (24 h), it was persistently reduced on day 6. Therefore, mitochondrial ROS formation appears to occur initially downstream of the mTOR-cytoROS-HIF1α feedback loop but seems to be a crucial factor that controls the long-term activation of the mTOR-HIF1α-axis.Conclusion: In summary, our data demonstrate that mTOR dependent ROS production controls the oxLDL-induced trained innate immunity phenotype in human monocyte derived macrophages. Pharmacologic modulation of these pathways might provide a potential approach to modulate inflammation, associated with aberrant monocyte activation, during atherosclerosis development

LXR&alpha; Regulates oxLDL-Induced Trained Immunity in Macrophages

Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXR&alpha; but not LXR&beta;. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNF&alpha; promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXR&alpha; and LXR&beta; genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXR&alpha; blocked the oxLDL-induced inflammatory response, while knock-down of LXR&beta; had no effect. We demonstrate a specific and novel role of the LXR&alpha; isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation

Substantiation of efficiency of managerial solutions in enterprise competitiveness management (based on the materials of LLC “Polisan” Pro- duction Company)

Кваліфікаційна робота ступеня бакалавр напряму підготовки 0306 Менеджмент, НТУ «Дніпровська політехніка», Дніпро, 2020. Об’єкт розроблення – процес управління конкурентоспроможністю підприємства. Мета кваліфікаційної роботи – обґрунтування теоретичних, методичних основ і прикладних аспектів управління конкурентоспроможністю підприємства і розробка заходів щодо її підвищення. Основні результати кваліфікаційної роботи бакалавра полягають у такому: досліджено теоретично-методологічні основи управління конкурентоспроможністю підприємства; проаналізовано господарську діяльність ТОВ «ВП «Полісан»; виконано конкурентний аналіз сил ринку лакофарбових матеріалів в Україні; оцінено конкурентну позицію підприємства; досліджено ризики діяльності виробників лакофарбової продукції; виконано оцінку значущості впливу факторів внутрішніх ризиків на конкурентоспроможність підприємства; розроблено заходи щодо підвищення конкурентоспроможності підприємства та обґрунтовано їх ефективністьКваліфікаційна робота ступеня бакалавр напряму підготовки 0306 Менеджмент, НТУ «Дніпровська політехніка», Дніпро, 2020. Об’єкт розроблення – процес управління конкурентоспроможністю підприємства. Мета кваліфікаційної роботи – обґрунтування теоретичних, методичних основ і прикладних аспектів управління конкурентоспроможністю підприємства і розробка заходів щодо її підвищення. Основні результати кваліфікаційної роботи бакалавра полягають у такому: досліджено теоретично-методологічні основи управління конкурентоспроможністю підприємства; проаналізовано господарську діяльність ТОВ «ВП «Полісан»; виконано конкурентний аналіз сил ринку лакофарбових матеріалів в Україні; оцінено конкурентну позицію підприємства; досліджено ризики діяльності виробників лакофарбової продукції; виконано оцінку значущості впливу факторів внутрішніх ризиків на конкурентоспроможність підприємства; розроблено заходи щодо підвищення конкурентоспроможності підприємства та обґрунтовано їх ефективніст

Altered Cellular Metabolism Drives Trained Immunity

Exposing innate immune cells to an initial insult induces a long-term proinflammatory response due to metabolic and epigenetic alterations which encompass an emerging new concept called trained immunity. Recent studies provide novel insights into mechanisms centered on metabolic reprogramming which induce innate immune memory in hematopoietic stem cells and monocytes

Semi-active control of a methalic scalled frame with a MR damper: numerical and experimental research

The need of vibration control has been spreading in tha last two decades to new application fields such as in the dynamic response of civil engineering structures. In this specific field a promising new technology for control of structural vibrations is based on the use of magneto-rheological (MR) fluid devices in the so-called MR dampers. The present work describes part of the R&D on using a semi-active structural control technique in a civil engineering experimental model frame equipped with a MR damper, developed within COVICOCEPAD project approved in the framework of Eurocores program S3T. Some results are provided associated with the calibration of a MR damper at FEUP as well as on the experimental modal indentification of the dynamic properties os a small-scale metallic frame, without and wich inclusion of a specific MR device. Some numerical results of the controlled frame under simulated earthquakes are given, to be later compared with the experimental results of such frame installed in a Quanser shaking table