Leptin, one of the major adipokines, is a pleiotropic hormone whose plasma levels rise with the increase in adipose tissue. Leptin has a dual role as a hormone and a cytokine. As a hormone, it plays ...a critical role in regulating appetite, growth, energy and bone metabolism. As a cytokine, leptin participates in the enhancement of some pro-infammatory responses. Increasing leptin concentrations in serum in obese patients signifcantly contributes to the low-grade infammatory state that makes those subjects more prone to develop insulin resistance, type 2 diabetes, cardiovascular and autoimmune diseases 1.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), ...insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Reactive oxygen species (ROS) are reactive intermediates of molecular oxygen that act as important second messengers within the cells; however, an imbalance between generation of reactive ...ROS and antioxidant defense systems represents the primary cause of endothelial dysfunction, leading to vascular damage in both metabolic and atherosclerotic diseases. Endothelial activation is the first alteration observed, and is characterized by an abnormal pro-inflammatory and pro-thrombotic phenotype of the endothelial cells lining the lumen of blood vessels. This ultimately leads to reduced nitric oxide (NO) bioavailability, impairment of the vascular tone and other endothelial phenotypic changes collectively termed endothelial dysfunction(s). This review will focus on the main mechanisms involved in the onset of endothelial dysfunction, with particular focus on inflammation and aberrant ROS production and on their relationship with classical and non-classical cardiovascular risk factors, such as hypertension, metabolic disorders, and aging. Furthermore, new mediators of vascular damage, such as microRNAs, will be discussed. Understanding mechanisms underlying the development of endothelial dysfunction is an important base of knowledge to prevent vascular damage in metabolic and cardiovascular diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Reactive oxygen species (ROS) are highly reactive chemical species containing oxygen, controlled by both enzymatic and nonenzymatic antioxidant defense systems. In the heart, ROS play an important ...role in cell homeostasis, by modulating cell proliferation, differentiation, and excitation-contraction coupling. Oxidative stress occurs when ROS production exceeds the buffering capacity of the antioxidant defense systems, leading to cellular and molecular abnormalities, ultimately resulting in cardiac dysfunction. In this review, we will discuss the physiological sources of ROS in the heart, the mechanisms of oxidative stress-related myocardial injury, and the implications of experimental studies and clinical trials with antioxidant therapies in cardiovascular diseases.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
GLP-1 receptor agonists (GLP-1RA) and SGLT2 inhibitors (SGLT2i) have been associated with improved glycemic control, body weight loss and favorable changes in cardiovascular risk factors and ...outcomes. We conducted a systematic review and meta-analysis to evaluate the effects of the addition of GLP-1RA to SGLT2i in patients with type 2 diabetes mellitus and inadequate glycemic control. Six databases were searched until March 2019. Randomized controlled trials (RCT) with a follow-up of at least 24 weeks reporting on HbA1c, body weight, systolic blood pressure, lipids, achievement of HbA1c < 7%, requirement of rescue therapy due to hyperglycemia and hypoglycemic events were selected. Four RCTs were included. Compared to SGLT2i, the GLP-1RA/SGLT2i combination was associated with greater reduction in HbA1c (-0.74%), body weight (-1.61 kg), and systolic blood pressure (-3.32 mmHg). A higher number of patients achieved HbA1c < 7% (RR = 2.15), with a lower requirement of rescue therapy (RR = 0.37) and similar incidence of hypoglycemia. Reductions in total and LDL cholesterol were found. The present review supports treatment intensification with GLP-1RA in uncontrolled type 2 diabetes on SGLT2i. This drug regimen could provide improved HbA1c control, together with enhanced weight loss and blood pressure and lipids control.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Operating system (OS) containers enabling the microservice-oriented architecture are becoming popular in the context of Cloud services. Containers provide the ability to create lightweight and ...portable runtime environments that decouple the application requirements from the characteristics of the underlying system. Services built on containers have a small resource footprint in terms of processing, storage, memory and network, allowing a more dense deployment environment. While the performance of such containers is addressed in few previous studies, understanding the failure-repair behavior of the containers remains unexplored. In this paper, from an availability point of view, we propose and compare different configuration models for deploying a containerized software system. Inspired by Google Kubernetes, a container management system, these configurations are characterized with a failure response and migration service. We develop novel non-state-space (i.e., fault tree) and state-space (i.e., stochastic reward net) analytic models for container availability analysis. Analytical as well as simulative solutions are obtained for the developed models. Our analysis provides insights on k out-of N availability and sensitivity of system availability for key system parameters. Finally, we build an open-source software tool powered by these models. The tool helps a Cloud administrator to assess the availability of a containerized system and to conduct a what-if analysis based on user-provided parameters and configurations.
The histone deacetylases SIRT1 and SIRT2 have been shown to be involved in the differentiation of rodent adipocyte precursors. In light of the differences in gene expression and metabolic function of ...visceral (V) and subcutaneous (S) adipose tissue (AT) and their resident cells, the aim of this study was to investigate the role of SIRT1 and SIRT2 in the differentiation of adipose stem cells (ASCs) isolated from SAT and VAT biopsies of nondiabetic obese and nonobese individuals.
Human ASCs were isolated from paired SAT and VAT biopsies obtained from 83 nonobese and 92 obese subjects and were differentiated in vitro. Adipogenesis was evaluated by analyzing the lipid deposition using an image processing software, and gene expression by RT-qPCR. SIRT1 and SIRT2 protein expression was modified by using recombinant adenoviral vectors.
Visceral but not subcutaneous ASCs from obese subjects showed an intrinsic increase in both adipogenesis and lipid accumulation when compared with ASCs from nonobese subjects, and this was associated with reduced SIRT1 and SIRT2 mRNA and protein levels. Moreover, adipose tissue mRNA levels of SIRT1 and SIRT2 showed an inverse correlation with BMI in the visceral but not subcutaneous depot. Overexpression of SIRT1 or SIRT2 in visceral ASCs from obese subjects resulted in inhibition of adipocyte differentiation, whereas knockdown of SIRT1 or SIRT2 in visceral ASCs from nonobese subjects enhanced this process. Changes in SIRT1 or SIRT2 expression and adipocyte differentiation were paralleled by corresponding changes in PPARG, CEBPA, and other genes marking terminal adipocyte differentiation.
SIRT1 and SIRT2 modulate the differentiation of human ASC. Reduced expression of SIRT1 and SIRT2 may enhance the differentiation capacity of visceral ASC in human obesity, fostering visceral adipose tissue expansion.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The widespread increase in life expectancy is accompanied by an increased prevalence of features of physical frailty. Signs and symptoms may include sarcopenia and osteopenia, reduced exercise ...capacity, and diminished sense of well-being. The pathogenesis of age-associated sarcopenia and osteopenia is multifactorial, and hormonal decline may be a contributing factor. Aging is associated with a progressive decrease in GH secretion, and more than 30% of elderly people have circulating IGF1 levels below the normal range found in the young. GH acts directly on target tissues, including skeletal muscle and bone among many others, but many effects are mediated indirectly by circulating (liver-derived) or locally produced IGF1. Aging is also associated with reduced insulin sensitivity which, in turn, may contribute to the impairment of IGF1 action. Recent experimental evidence suggests that besides the age-dependent decline in GH and IGF1 serum levels, the dysregulation of GH and IGF1 actions due to impairment of the post-receptor signaling machinery may contribute to the loss of muscle mass and osteopenia. This article will focus on the molecular mechanisms of impaired GH and IGF1 signaling and action in aging, and their role in the pathogenesis of sarcopenia and osteoporosis.
Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the ...abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•A framework for task scheduling policies in a large-scale distributed cloud.•A mathematical formulation driven by real system requirements.•Model with: FIFO queue, tasks with deadlines, the actual ...load on the machines.•Application of the distributed Alternating Direction Method of Multipliers (ADMM).
The ever increasing request of computational resources has shifted the computing paradigm towards solutions where less computation is performed locally. The most widely adopted approach nowadays is represented by cloud computing. With the cloud, users can transparently access to virtually infinite resources with the same aptitude of using any other utility. Next to the cloud, the volunteer computing paradigm has gained attention in the last decade, where the spared resources on each personal machine are shared thanks to the users’ willingness to cooperate. Cloud and volunteer paradigms have been recently seen as companion technologies to better exploit the use of local resources. Conversely, this scenario places complex challenges in managing such a large-scale environment, as the resources available on each node and the presence of the nodes online are not known a-priori. The complexity further increases in presence of tasks that have an associated Service Level Agreement specified, e.g., through a deadline. Distributed management solutions have then be advocated as the only approaches that are realistically applicable.
In this paper, we propose a framework to allocate tasks according to different policies, defined by suitable optimization problems. Then, we provide a distributed optimization approach relying on the Alternating Direction Method of Multipliers (ADMM) for one of these policies, and we compare it with a centralized approach. Results show that, when a centralized approach can not be adopted in a real environment, it could be possible to rely on the good suboptimal solutions found by the ADMM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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