Neutrophil aging exacerbates high fat diet induced metabolic alterations.

Background: High fat diet (HFD) chronically hyper-activates the myeloid cell precursors, but whether it affects the neutrophil aging is unknown.

Purpose: We characterized how HFD impacts neutrophil aging, infiltration in metabolic tissues and if this aging, in turn, modulates the development of metabolic alterations. We immunophenotyped neutrophils and characterized the metabolic responses in physiology (wild-type mice, WT) and in mice with constitutively aged neutrophils (MRP8 driven conditional deletion of CXCR4; herein CXCR4fl/flCre+) or with constitutively fresh neutrophils (MRP8 driven conditional deletion of CXCR2; CXCR2fl/flCre+), following 20 weeks of HFD feeding (45 % kcal from fat).

The High Fat Diet Impacts the Plasticity between Fresh and Aged Neutrophils.

Metabolic alterations induced by unhealthy lifestyles, including obesity and insulin resistance are often associated with increased innate immune response and chronic inflammation. Cholesterol has been identified as a key metabolite driving the activation of the inflammasome and the "epigenetic memory" in long-term living hematopoietic stem cells. In addition to these mechanisms, the physiological aging of short-living neutrophils is a relevant modifier of their immune competency, as while they egress from medullary niches as "fresh", fully competent, cells, they turn into "aged", disarmed cells, when they extravasate into peripheral tissues to fight against pathogens or they reach the spleen for disposal.

Targeted Plasma Proteomics to Predict the Development of Carotid Plaques.

Background: Cardiovascular risk stratification in primary prevention is a clinical challenge. We recently identified a large set of circulating proteins improving the risk prediction for cardiovascular events. We now evaluate which of these proteins predicts the development of subclinical carotid atherosclerosis (SCA) in primary cardiovascular prevention.

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations.

Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.

Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues.

Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment.

Molecular Immune-Inflammatory Connections between Dietary Fats and Atherosclerotic Cardiovascular Disease: Which Translation into Clinics?

Current guidelines recommend reducing the daily intake of dietary fats for the prevention of ischemic cardiovascular diseases (CVDs). Avoiding saturated fats while increasing the intake of mono- or polyunsaturated fatty acids has been for long time the cornerstone of dietary approaches in cardiovascular prevention, mainly due to the metabolic effects of these molecules. However, recently, this approach has been critically revised.

A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice.

Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37.

Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation.

Aim: The long pentraxin PTX3 plays a non-redundant role during acute myocardial infarction, atherosclerosis and in the orchestration of tissue repair and remodeling during vascular injury, clotting and fibrin deposition. The aim of this work is to investigate the molecular mechanisms underlying the protective role of PTX3 during arterial thrombosis.

Methods And Results: PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant reduction in carotid artery blood flow following FeCl3 induced arterial thrombosis (-80.

Normative values for carotid intima media thickness and its progression: Are they transferrable outside of their cohort of origin?

Background: The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations.

Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.

Background: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.

Methods: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease.

Pitavastatin - pharmacological profile from early phase studies.

Pitavastatin has been designed as a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with a novel cyclopropyl moiety that results in several differences compared to other statins. These include effective inhibition of cholesterol synthesis and increased lipoprotein lipase expression at lower doses than other statins, and significant high-density lipoprotein-cholesterol and apolipoprotein A1-elevating activity that persists with time. The safety, tolerability and pharmacokinetics of pitavastatin and its major metabolite, pitavastatin lactone, have been investigated in a variety of patient groups with similar results, which suggests dosage adjustments are not required for gender, age or race.

Averting a pandemic health crisis in Europe by 2020: what physicians need to know regarding cholesterol management.

Background: Cardiovascular disease (CVD) represents a major cause of premature death, disability, and escalating healthcare costs throughout Europe. According to a recent report by the Stockholm Network (an independent European 'think tank'), major political, economic, social, and medical changes are urgently needed with respect to cholesterol management to help prevent CVD.

Methods: To identify key cholesterol management issues that practitioners should consider to help prevent an impending European health crisis, our collective experience of policies and practices relating to CVD and cholesterol management in our respective countries was consolidated and used to develop this commentary.

A stable isotope method using a [(2)H(5)]glycerol bolus to measure very low density lipoprotein triglyceride kinetics in humans.

We have developed a method using a bolus of [(2)H(5)]glycerol to determine parameters of VLDL-triglyceride (VLDL-TG) turnover and have compared the data to that obtained using simultaneously a bolus of [2-(3)H]glycerol in six young normolipidemic men. No measurable enrichment was found after 12 h for [(2)H(5)]glycerol; therefore, we could only perform a monoexponential analysis of its data. No differences in fractional catabolic rate (FCR) were seen when comparing the multicompartmental modeling of [2-(3)H]glycerol data (modeled over 48 h) either to the monoexponential analyses of the [2-(3)H]glycerol or that of the [(2)H(5)]glycerol data.

Diabetes and atherosclerosis--a lipoprotein perspective.

Atherosclerosis is the most frequent complication of diabetes. It affects all major vascular beds. The metabolic derangements that occur in diabetes may underlie many of the reasons for this.

The Diabetes Atherosclerosis Intervention Study (DAIS): a study conducted in cooperation with the World Health Organization. The DAIS Project Group.

The incidence of coronary artery disease is greatly increased in those with diabetes mellitus. The largest number of those who have coronary artery disease have non-insulin-dependent diabetes (NIDDM). Lipoprotein abnormalities have been identified among the several risk factors that could account for this increase in atherosclerosis.

Morphological aspects of endothelial cell-monocyte interactions in culture.

Monocytes obtained from the blood of healthy volunteers were added to cultures of bovine aortic endothelial cells (BAEC) at increasing time intervals (from 1 h to 24 h). Cultures of BAEC without the added blood elements were used as controls. The ultrastructural features of cellular interactions were studied by transmission electron microscopy.