Abstract Background and aims Meta-analyses of randomized control trials investigating the association between incident diabetes and statin use showed an increased risk of new-onset diabetes (NOD) ...from 9% to 13% associated with statins. However, short follow-up period, unpowered sample size, and lack of pre-specified diagnostic criteria for diabetes detection could be responsible of an underestimation of this risk. We conducted a meta-analysis of published observational studies to evaluate the association between statins use and risk of NOD. Methods and results PubMed, EMBASE and MEDLINE databases were searched from inception to June 30, 2016 for cohort and case–control studies with risk of NOD in users vs nonusers, on ≥1000 subjects followed-up for ≥1 year. Two review authors assessed study eligibility and risk of bias and undertook data extraction independently. Pooled estimates were calculated by a random-effects model and between-study heterogeneity was tested and measured by I2 index. Furthermore, stratified analyses and the evaluation of publication bias were performed. Finally, the meta-analysis included 20 studies, 18 cohort and 2 case–control studies. Overall, NOD risk was higher in statin users than nonusers (RR 1.44; 95% CI 1.31–1.58). High between-study heterogeneity (I2 = 97%) was found. Estimates for all single statins showed a class effect, from rosuvastatin (RR 1.61; 1.30–1.98) to simvastatin (RR 1.38; 1.19–1.61). Conclusions The present meta-analysis confirms and reinforces the evidence of a diabetogenic effect by statins utilization. These observations confirm the need of a rigorous monitoring of patients taking statins, in particular pre-diabetic patients or patients presenting with established risk factors for diabetes.
Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein ...that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis. NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association with a low dose of statin is of particular interest for patients experiencing statin-related side effects. The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events. To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß- lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation.
Abstract Background and aim Patients with systemic lupus erythematosus (SLE) have a higher prevalence of subclinical atherosclerosis and higher risk of cardiovascular (CV) events compared to the ...general population. The relative contribution of CV-, immune- and disease-related risk factors to accelerated atherogenesis in SLE is unclear. Methods and results Fifty SLE patients with long-lasting disease (mean age 44 ± 10 years, 86% female) and 50 sex- and age-matched control subjects were studied. Common carotid artery intima-media thickness (CCA-IMT) was used as a surrogate marker of atherosclerosis. We evaluated traditional and immune- and disease-related factors, assessed multiple T-cell subsets by 10-parameter-eight-colour polychromatic flow cytometry and addressed the effect of pharmacological therapies on CCA-IMT. In SLE patients, among several cardiometabolic risk factors, only high-density lipoprotein levels (HDL) and their adenosine triphosphate-binding cassette transporter 1 (ABCA-1)-dependent cholesterol efflux capacity were markedly reduced ( p < 0.01), whereas the CCA-IMT was significantly increased ( p = 0.03) compared to controls. CCA-IMT correlated with systolic blood pressure, low-density lipoprotein (LDL) cholesterol and body mass index (BMI), but not with disease activity and duration. The activated CD4+ HLA-DR+ and CCR5+ T-cell subsets were expanded in SLE patients. Patients under hydroxychloroquine (HCQ) therapy showed lower CCA-IMT (0.62 ± 0.08 vs. 0.68 ± 0.10 mm; p = 0.03) and better risk-factor profile and presented reduced circulating pro-atherogenic effector memory T-cell subsets and a parallel increased percentage of naïve T-cell subsets. Conclusion HDL represents the main metabolic parameter altered in SLE patients. The increased CCA-IMT in SLE patients may represent the net result of a process in which ‘classic’ CV risk factors give a continuous contribution, together with immunological factors (CD4+ HLA-DR+ T cells) which, on the contrary, could contribute through flares of activity of various degrees over time. Patients under HCQ therapy present a modified metabolic profile, a reduced T-cell activation associated with decreased subclinical atherosclerosis.
During infections or acute conditions high-density lipoproteins cholesterol (HDL-C) levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These ...changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity. The aim of this review is to provide an overview of the connection between HDL and immunity in atherosclerosis and beyond.
The comma-free codes and circular codes are two important classes of codes in code theory and in genetics. Fifty years ago before the discovery of the genetic code, a trinucleotide (triletter) ...comma-free code was proposed for associating the codons of genes with the amino acids of proteins. More recently, in the last ten years, trinucleotide circular codes have been identified statistically in different genomes. Here, we identify a relation between these two classes of trinucleotide codes by constructing a hierarchy of comma-free and circular codes.
To cite this article: Banfi C, Brioschi M, Lento S, Pirillo A, Galli S, Cosentino S, Tremoli E, Mussoni L. Statins prevent tissue factor induction by protease‐activated receptors 1 and 2 in human ...umbilical vein endothelial cells in vitro. J Thromb Haemost 2011; 9: 1608–19.
Summary. Background: Protease‐activated receptors (PARs) are G‐protein‐coupled receptors that function in hemostasis and thrombosis, as well as in the inflammatory and proliferative responses triggered by tissue injury. We have previously shown that PAR1 or PAR2 occupancy by specific PAR‐agonist peptides (PAR‐APs) induces tissue factor (TF) expression in human umbilical vein endothelial cells (HUVECs), where TF regulation by PAR1 (but not by PAR2) requires intact endothelial caveolin‐enriched membrane microdomains in which PAR1 and caveolin‐1 associate. Objectives: The aim of this study was to determine the effects of cholesterol‐lowering agents (statins) and cholesterol‐loading lipoprotein on PAR1‐AP‐mediated and PAR2‐AP‐mediated TF induction in HUVECs. Results: Statins completely prevented TF induction by PAR‐APs in an isoprenoid‐independent manner, induced the delocalization of PAR1 from caveolin‐enriched membrane microdomains without affecting PAR1 mRNA, and decreased PAR2 mRNA and protein levels. Statins also prevented PAR‐AP‐mediated extracellular signal‐related kinase 1/2 activation, which is crucial for TF induction. The redistribution of PAR1 is accompanied by the relocation of the membrane microdomain‐associated G‐protein α, caveolin‐1, and Src, which we previously showed to play a key role in signal transduction and TF induction. Conversely, cholesterol loading potently amplified PAR1‐AP‐induced TF, probably as a result of the increased abundance of PAR1 and the Src and G‐protein α signaling molecules in the caveolin‐1‐enriched fraction, without affecting PAR1 mRNA. Conclusions: As PARs have important functions in hemostasis, cancer, thrombosis, and inflammatory processes, our findings that statins prevent TF induction by PAR‐APs altering the membrane localization of PAR1 and the expression of PAR2 suggest that they may provide health benefits other than reducing atherosclerosis.
Varieties of comma-free codes Michel, Christian J.; Pirillo, Giuseppe; Pirillo, Mario A.
Computers & mathematics with applications (1987),
03/2008, Letnik:
55, Številka:
5
Journal Article
Recenzirano
Odprti dostop
New varieties of comma-free codes CFC of length 3 on the 4-letter alphabet are defined and analysed: self-complementary comma-free codes (CCFC),
C
3
comma-free codes (
C
3
CFC),
C
3
...self-complementary comma-free codes (
C
3
CCFC), self-complementary maximal comma-free codes (CMCFC),
C
3
maximal comma-free codes (
C
3
MCFC) and
C
3
self-complementary maximal comma-free codes (
C
3
CMCFC). New properties with words of length 3, 4, 5 and 6 in comma-free codes are used for the determination of growth functions in the studied code varieties.
The molecular mechanisms underlying the relationship between elevated plasma concentrations of triglyceride-rich lipoproteins and coronary artery disease remain uncertain. In the present work, we ...investigated the gene expression pattern and intracellular pathways in human endothelial cells incubated with very low density lipoproteins (VLDL). Moreover, as VLDL can enter the arterial wall and undergo oxidative modification, we compared the VLDL-induced expression pattern with the one of oxidised VLDL (Ox-VLDL).
Total RNA from endothelial cells incubated with 75 microg/ml VLDL or Ox-VLDL and total RNA from endothelial cells under basal conditions were hybridised to identical microarrays containing 8411 genes. Seven clusters of expression profiles were identified. This pattern was validated by quantitative real-time PCR of selected genes. The intracellular pathway involved in VLDL or Ox-VLDL mediated endothelial responses were also investigated.
VLDL predominantly activated the ERK1/2 pathway while P38 MAPK was the main target of Ox-VLDL. CREB and NF-kappa B were activated by both VLDL and Ox-VLDL. Real-time PCR demonstrated that VLDL induced matrix metalloproteinase-2 (5.47+/-1.74 fold), CD38 (2.38+/-0.23) and transforming growth factor-alpha (2.51+/-0.30) expression. Ox-VLDL was found to induce interleukin-15 (2.10+/-0.48) and macrophage migration inhibitory factor (3.19+/-0.07) expression. In addition, several genes implicated in endothelial cell activation and damage/proliferation were identified by the array analysis. Ox-VLDL was found to promote the generation of reactive oxygen species and exert a cytotoxic effect, while VLDL lacks these effects. These findings confirm the involvement of VLDL and Ox-VLDL in endothelial dysfunction and suggest new genes and molecular mechanisms involved in these actions.
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