Metabolomics Profiling of Vitamin D Status in Relation to Dyslipidemia.

Vitamin D deficiency is a global disorder associated with several chronic illnesses including dyslipidemia and metabolic syndrome. The impact of this association with both dyslipidemia and vitamin D deficiency on metabolomics profile is not yet fully understood. This study analyses the metabolomics and lipidomic signatures in relation to vitamin D status and dyslipidemia. Metabolomics data were collected from Qatar Biobank database and categorized into four groups based on vitamin D and dyslipidemia status. Metabolomics multivariate analysis was performed using the orthogonal partial least square discriminate analysis (OPLS-DA) whilst linear models were used to assess the per-metabolite association with each of the four dyslipidemia/vitamin D combination groups. Our results indicate a high prevalence of vitamin D deficiency among the younger age group, while dyslipidemia was more prominent in the older group. A significant alteration of metabolomics profile was observed among the dyslipidemic and vitamin D deficient individuals in comparison with control groups. These modifications reflected changes in some key pathways including ceramides, diacylglycerols, hemosylceramides, lysophospholipids, phosphatidylcholines, phosphatidylethanol amines, and sphingomyelins. Vitamin D deficiency and dyslipidemia have a deep impact on sphingomyelins profile. The modifications were noted at the level of ceramides and are likely to propagate through downstream pathways

Author Correction: Metabolic GWAS of elite athletes reveals novel genetically-influenced metabolites associated with athletic performance

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Impact of phospholipids, surfactants and cholesterol selection on the performance of transfersomes vesicles using medical nebulizers for pulmonary drug delivery

The aim of this study is to formulate and optimize novel transfersome formulations for pulmonary drug delivery. Transfersome formulations (F1 – F18) were prepared by a thin-film method using three phospholipids (Soya phosphatidylcholine (SPC), Dimyristoly phosphatidylcholine (DMPC) and Hydrogenated soya phosphatidylcholine (HSPC)), in combination with three different surfactants (Tween 80, Span 80 and Span 20) with or without cholesterol, employing Beclomethasone dipropionate (BDP) as the model drug. Nano-transfersome formulations post-extrusion were delivered to a Two-stage Impinger (TSI) via three medical nebulizers (i.e. Air-jet, Ultrasonic and Vibrating mesh nebulizer). Based on the physicochemical properties, formulations F1 (SPC and Tween 80), F7 (DMPC and Tween 80) and F13 (HSPC and Tween 80) demonstrated significantly smaller VMD (162.34 ± 6.48, 198.66 ± 6.64, and 183.52 ± 7.34 nm), and significantly higher entrapment efficiency (97.56 ± 2.45, 95.67 ± 4.26 and 95.06 ± 3.38%). Based on nebulization performance, the Ultrasonic nebulizer exhibited the shortest nebulization time for formulations F1, F7 and F13 (i.e. 17.88 ± 2.45, 19.26 ± 2.04 and 19.59 ± 2.12 min), and higher output rate (212.04 ± 11.54, 194.61 ± 10.27 and 192.43 ± 9.84 mg/min), when compared to Air-jet and Vibrating mesh nebulizers. Irrespective of nebulizer type, significantly higher BDP deposition was observed in the lower stage of TSI for the F1 formulation (on average of 61%), whereas a higher amount of BDP was deposited in the upper stage of TSI using the F7 formulations (49%). Moreover, Formulation F1 in combination with Air-jet nebulizer demonstrated higher emitted dose (ED) and fine particle fraction (FPF) (82% and 83%), when compared to the counterpart formulations and nebulizer types investigated. This study has demonstrated that based on nebulizer performance, BDP deposition and formulation type; the F1 formulation in combination with an Air-jet nebulizer is most optimal for lower respiratory tract deposition, whereas the F7 formulation in combination with an Ultrasonic nebulizer is ideal for upper respiratory tract deposition

The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis.

PURPOSE: Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies. METHODS: The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system. RESULTS: The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10-9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036]. CONCLUSIONS: We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes

Primed T Cell Responses to Chemokines Are Regulated by the Immunoglobulin-Like Molecule CD31

CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naïve T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity

Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism

Background: The genetic predisposition to elite athletic performance has been a controversial subject due to the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n = 662) and low/moderate (n = 134) aerobic component. Replication of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P = 1.43 × 10−8, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA + AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82 × 10–05) including the testosterone precursor androstenediol (3beta,17beta) disulfate. Conclusions: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted

Leucine125Valine (Leu125Val) Gene Polymorphism of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) and Myocardial Infarction in Indian Population

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) has role in atherosclerotic plaque development as well as in thrombosis leading to myocardial infarction (MI). Present study was aimed to analyse the association of PECAM-1 Leu125Val gene polymorphism with MI in Indian population. Subjects included healthy individuals as control (N = 116) and MI patients (N = 100) divided into two groups; MI patients at presentation of the acute event (MI-Group-1, N = 46) and patients with recent event of MI stabilized with treatment 4.5 days from their symptoms (MI-Group-2, N = 54). The difference in the distribution of Leu125Val genotype frequencies of controls and patients did not reach statistical significance. However Leu allele frequency (0.57) was more associated with MI patients as compared to control (0.504). sPECAM-1 levels were significantly elevated in patients at acute event of MI (MI-Group-1) by 44.1% (P = 0.009) as compared to controls and by 95.2% (P = 0.001) as compared to stabilized MI patients (MI-Group-2)

ICAM-1 (Lys469Glu) and PECAM-1 (Leu125Val) polymorphisms in diffuse astrocytomas

Cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) play an important role in glioma invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphisms of ICAM-1 and PECAM-1 could be associated with glioma development and progression. Single-nucleotide polymorphism in codon 469 of ICAM-1 and codon 125 of PECAM-1 were examined in 158 patients with astrocytomas and 162 controls using polymerase chain reaction and restriction enzyme analysis. The distribution of PECAM-1 polymorphic genotypes in astrocytomas did not show any significant difference. However, a specific ICAM-1 genotype (G/G, corresponding to Lys469Glu) exhibited higher frequency in grade II astrocytomas compared to controls, grade III, and grade IV astrocytomas; suggesting that this polymorphism could be involved in the development of grade II astrocytomas.FAPESPFAEPACAPESLIC