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Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m²) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (-30 ± 20 mg/dL; p = 0.012), LDL cholesterol (-31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (-14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention., info:eu-repo/semantics/published

Background and aims Saturated free fatty acids (SFAs) can induce lipotoxicity in different cells. No studies have investigated the effects of SFA in circulating angiogenic cells (CACs), which play a key role in endothelial repair processes. The aim of the study was to assess the effects of SFAs, specifically stearic acid (SA), on viability and function of CACs and to investigate potential underlying molecular mechanisms. Methods CACs were isolated from healthy subjects by established methods. CACs were incubated with BSA-complexed stearate (100 μM) to assess the time course (from 8 to 24 h exposure) of the effects on viability and apoptosis (activation of caspases 3/7), angiogenic function (tube formation assay), pro-inflammatory cytokine (IL-1β, IL-6, IL-8, MCP-1 and TNFα) gene expression (qPCR) and secretion (ELISA), activation of MAPK (JNK, p38 and Erk1/2) by Western blot and endoplasmic reticulum (ER) stress marker (CHOP, BIP, ATF4, XBP-1 and sXBP-1) gene expression by qPCR. Results Stearic acid activates effector caspases in CACs in a dose- and time-dependent manner. SA also impairs CAC function and increases pro-inflammatory molecule (IL-1β, IL-6, IL-8, MCP-1 and TNFα) gene expression and secretion in CACs starting from 3 h of incubation. The activation of JNK by SA mediates pro-inflammatory response, but it may be not necessary for apoptosis. Moreover, SA induces the expression of ER stress markers across the three branches of the ER stress response. Conclusions In humans, both function and viability of CACs are exquisitely vulnerable to physiologic concentrations of stearate; lipotoxic impairment of endothelial repair processes may be implicated in vascular damage caused by SFAs.

Macrophages, a heterogeneous and ubiquitous cell population representing up to 15% of the cellular content of different types of tissue, are the principal cell mediators in response to pathogens, inflammation process, tissue homeostasis and repair and play a pivotal role in atherosclerosis and insulin resistance because of their capacity to be the major source of inflammatory cytokines, which can function through paracrine and endocrine mechanisms. Recently, differently activated macrophage populations have been described, depending on a large variety of microenvironmental signals, and it is now recognized that their activation plays a crucial role in the development and progression of atherosclerosis. There is good evidence of the ability of conjugated linoleic acids and polyphenolic compounds to modulate inflammation in experimental models involving macrophages. This observation leaves room to the intriguing hypothesis that macrophage polarization could represent one of the unifying mechanisms through which specific food components can exert anti-inflammatory effects in humans, contributing to the prevention of chronic diseases strongly linked to inflammation, such as atherosclerosis. Future studies should be addressed to substantiate this hypothesis, investigating whether or not physiological concentrations of food-derived metabolites can perturb macrophage activation in vitro. On the in vivo side, the evaluation of macrophage populations in tissues, however complex, should be included among the analyses performed in observational and intervention studies, in order to understand if macrophage activation is involved in the anti-inflammatory activity of a specific dietary regimen.

The number of Endothelial Progenitor Cells (EPCs) is considered a novel marker of cardiovascular (CV) disease. It is not clear which are the main determinants of EPC number in apparently healthy subjects in the absence of overt clinical CV or metabolic abnormalities. We evaluated the main clinical determinants of EPC levels in a population of healthy subjects with normal glucose tolerance.EPC number was determined in 122 healthy subjects (73M/49F;36.6 ± 8yrs). Blood samples were collected to test biochemical variables. OGTT was performed and insulin resistance/compensatory hyperinsulinemia was defined according to fasting plasma insulin (FPI) levels. EPCs were identified as cells co-expressing CD133/CD34/KDR antigens by flow-cytometry. CD133(+)/KDR(+) count inversely correlated with BMI (rho=-0.18;p 0.05), waist circumference (-0.2;0.05), diastolic (-0.23;0.01) and systolic blood pressure (-0.21;0.05), uric acid (-0.24;0.005), PAI-1 (-0.197;0.05) and FPI (-0.2;0.05) and directly correlated with HDL cholesterol (0.182;0.05). CD34(+)/CD133(+)/KDR(+) count inversely correlated with uric acid (-0.28;0.005) and FPI (-0.2;0.05). EPC number was lower in males (p 0.05) and gender was the only independent predictor of EPC count (p 0.05). By dividing the population in four subgroups based on gender and insulin resistance, CD133(+)/KDR(+) levels were lower in insulin resistant compared to insulin sensitive males (p 0.05) with no differences in females.The male gender is an independent predictor of low EPC levels in healthy subjects. This might contribute to explaining the higher CV risk in males compared to pre-menopausal age-matched females. In this study a reduced EPC number seems to be associated with insulin resistance in male subjects.

BackgroundMacrophages are a heterogeneous cell population which in response to the cytokine milieu polarize in either classically activated macrophages (M1) or alternatively activated macrophages (M2). This plasticity makes macrophages essential in regulating inflammation, immune response and tissue remodeling and a novel therapeutic target in inflammatory diseases such as atherosclerosis. The aim of the study was to describe the transcriptomic profiles of differently polarized human macrophages to generate new hypotheses on the biological function of the different macrophage subtypes.Methods and resultsPolarization of circulating monocytes/macrophages of blood donors was induced in vitro by IFN-γ and LPS (M1), by IL-4 (M2a), and by IL-10 (M2c). Unstimulated cells (RM) served as time controls. Gene expression profile of M1, M2a, M2c and RM was assessed at 6, 12 and 24h after polarization with Whole Human Genome Agilent Microarray technique. When compared to RM, M1 significantly upregulated pathways involved in immunity and inflammation, whereas M2a did the opposite. Conversely, decreased and increased expression of mitochondrial metabolism, consistent with insulin resistant and insulin sensitive patterns, was seen in M1 and M2a, respectively. The time sequence in the expression of some pathways appeared to have some specific bearing on M1 function. Finally, canonical and non-canonical Wnt genes and gene groups, promoting inflammation and tissue remodeling, were upregulated in M2a compared to RM.ConclusionOur data in in vitro polarized human macrophages: 1. confirm and extend known inflammatory and anti-inflammatory gene expression patterns; 2. demonstrate changes in mitochondrial metabolism associated to insulin resistance and insulin sensitivity in M1 and M2a, respectively; 3. highlight the potential relevance of gene expression timing in M1 function; 4. unveil enhanced expression of Wnt pathways in M2a suggesting a potential dual (pro-inflammatory and anti-inflammatory) role of M2a in inflammatory diseases.

Insulin resistance is considered to be a pathogenetic mechanism in several and diverse diseases (e.g. type 2 diabetes, atherosclerosis) often antedating them in apparently healthy subjects. The aim of this study is to investigate with a microarray based approach whether IR per se is characterized by a specific pattern of gene expression. For this purpose we analyzed the transcriptomic profile of peripheral blood mononuclear cells in two groups (10 subjects each) of healthy individuals, with extreme insulin resistance or sensitivity, matched for BMI, age and gender, selected within the MultiKnowledge Study cohort (n = 148). Data were analyzed with an ad-hoc rank-based classification method. 321 genes composed the gene set distinguishing the insulin resistant and sensitive groups, within which the "Adrenergic signaling in cardiomyocytes" KEGG pathway was significantly represented, suggesting a pattern of increased intracellular cAMP and Ca2+, and apoptosis in the IR group. The same pathway allowed to discriminate between insulin resistance and insulin sensitive subjects with BMI >25, supporting his role as a biomarker of IR. Moreover, ASCM pathway harbored biomarkers able to distinguish healthy and diseased subjects (from publicly available data sets) in IR-related diseases involving excitable cells: type 2 diabetes, chronic heart failure, and Alzheimer's disease. The altered gene expression profile of the ASCM pathway is an early molecular signature of IR and could provide a common molecular pathogenetic platform for IR-related disorders, possibly representing an important aid in the efforts aiming at preventing, early detecting and optimally treating IR-related diseases.

Background and aims Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. Methods and results LTL was determined in 82 healthy subjects (49M/33F; age37 ± 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD ( t = 2.70; p = 0.009), age ( r = −0.238; p = 0.032), waist circumference ( r = −0.256; p = 0.02), triglycerides ( r = −0.218; p = 0.049), PAI-1 ( r = −0.288; p = 0.009) and directly correlated with HDL-cholesterol ( r = 0.316; p = 0.004) and EPC number ( r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD ( p = 0.013), EPC count ( p = 0.003), and HDL-cholesterol ( p = 0.017) were independently associated with LTL ( r = 0.62). Conclusion LTL is independently associated to CV risk factors also in healthy young adults.

Due to their recently discovered plasticity, macrophages could be an important target in the treatment and prevention of atherosclerosis, and it is of interest that quercetin has been shown to modulate inflammation in humans through mechanisms involving macrophages. The aim of this work was to investigate the effect of quercetin-3-O-glucuronide (Q3GA), a major circulating human metabolite of quercetin, on gene expression in differently polarized human macrophages. Classical (M1) and alternative (M2a) macrophages were exposed to Q3GA (500 nM). Gene expression was monitored after incubation periods of 6, 12 and 24 h. M1 and M2a macrophages maintained their respective traits. Q3GA did not affect M1 macrophages in the promotion of a defense response, which remains the principal characteristic of this type of activation, but it was able to reduce the transcription of genes involved in inflammation, such as pro-inflammatory interleukins and enzymes involved in oxidative stress responses. Exposure of M2a to Q3GA elicited an improvement in anti-inflammatory features resulting from further down-regulation of pro-inflammatory genes. Thus, Q3GA is a potential anti-atherogenic metabolite, enhancing the anti-inflammatory properties of M2a macrophages and modulating immune response effects in the presence of pro-inflammatory stimuli.