•Use of a statistical approach to link lipidomic patterns with dietary data to identify biomarkers.•Identification of key dietary factors that influence the lipidome in a free-living ...population.•Identification of specific biomarkers of dietary fat intake, alcohol consumption and fish intake.
Reliable dietary assessments are essential when attempting to understand the complex links between diet and health. Traditional methods for collecting dietary exposure can be unreliable, therefore there is an increasing interest in identifying biomarkers to provide a more accurate measurement. Metabolomics is a technology that offers great promise in this area. The aim of this study was to use a multivariate statistical strategy to link lipidomic patterns with dietary data in an attempt to identify dietary biomarkers. We assessed the relationship between lipidomic profiles and dietary data in volunteers (n=34) from the Metabolic Challenge Study (MECHE). Principal component analysis (PCA), linear regression and receiver operating characteristic (ROC) analysis were used to (1) reduce the lipidomic data into lipid patterns (LPs), (2) investigate relationships between these patterns and dietary data and (3) identify biomarkers of dietary intake. Our study identified a total of 6 novel LPs. LP1 was highly predictive of dietary fat intake (area under the curve AUC=0.82). A random forest (RF) classification model used to discriminate between low and high consumers resulted with an error rate of >10%, with a panel of six metabolites identified as the most predictive. LP4 was highly predictive of alcohol intake (AUC=0.81) with lysophosphatidylcholine alkyl C18:0 (LPCeC18:0) identified as a potential biomarker of alcohol consumption. LP6 had a reasonably good ability to predict dietary fish intake (AUC=0.76), with lysophosphatidylethanolamine acyl C18:2 (LPEaC18:2) phoshatidylethanolamine diaclyl C38:4 (PEaaC38:4) identified as potential biomarkers. The identification of these LPs and specific biomarkers will help in better classifying a persons dietary intake and in turn will improve the assessment of the relationship between diet and disease. Linking these LPs and specific biomarkers with health parameters will be an important future step.
•A classic twin study approach to modelling variation in lipid mediators including oxylipins, endocannabinoids, bile acids and steroids.•Heritable lipid mediators included 12-HETE, 12-HEPE, 14-HDoHE ...and DHEA.•12-LOX derived lipid mediators are highly heritable.•Environment contributes to a large proportion of variation for the majority of profiled lipid mediators.
Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism. This study recruited 138 monozygotic (MZ) and dizygotic (DZ) twins aged 18–65 years and measured serum oxylipins, endocannabinoids, bile acids and steroids using liquid chromatography mass-spectrometry (LC-MS). In this classic twin design, the similarities and differences between MZ and DZ twins are modelled to estimate the contribution of genetic and environmental influences to variation in lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxyeicosatetraenoic acid 0.70 (95% CI: 0.12,0.82), 12-hydroxyeicosatetraenoic acid 0.73 (95% CI: 0.30,0.83) and 14‑hydroxy-docosahexaenoic acid 0.51 (95% CI: 0.07,0.71), along with the endocannabinoid docosahexaenoy-lethanolamide 0.52 (95% CI: 0.15,0.72). For others such as 13-hydroxyoctadecatrienoic acid and lithocholic acid the contribution of environment to variation was stronger. With increased understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends pre-existing knowledge of the genetic and environmental influences on the human lipidome.
The threshold of toxicological concern (TTC) has been used for the safety assessment of packaging migrants and flavouring agents that occur in food. The approach compares the estimated oral intake ...with a TTC value derived from chronic oral toxicity data for structurally-related compounds. Application of the TTC approach to cosmetic ingredients and impurities requires consideration of whether route-dependent differences in first-pass metabolism could affect the applicability of TTC values derived from oral data to the topical route. The physicochemical characteristics of the chemical and the pattern of cosmetic use would affect the long-term average internal dose that is compared with the relevant TTC value. Analysis has shown that the oral TTC values are valid for topical exposures and that the relationship between the external topical dose and the internal dose can be taken into account by conservative default adjustment factors. The TTC approach relates to systemic effects, and use of the proposed procedure would not provide an assessment of any local effects at the site of application. Overall the TTC approach provides a useful additional tool for the safety evaluation of cosmetic ingredients and impurities of known chemical structure in the absence of chemical-specific toxicology data.
Attitudes towards healthy eating were explored according to dietary, lifestyle and socio-demographic correlates in a random sample of 1256 Irish adults. Data were obtained from an Irish ...cross-sectional survey (1997–1999). A self-administered questionnaire was used to obtain attitudinal information. Food consumption was estimated using a 7-d food diary. A majority of the sample had a positive attitude or motivation towards their healthy eating behaviour. Those who perceived their own eating habits to be healthy were more likely to comply with current dietary guidelines than those who did not. Females, increasing age, higher social class, tertiary education, non-smokers, lower body-weights and increased recreational activity were associated with a lower odds ratio (OR) for having a negative attitude towards their healthy eating behaviour. An increased intake (g/d) of breakfast cereals, vegetables, fruit and poultry dishes were associated with decreased OR for negative attitudes towards their healthy eating behaviour, while an increased intake of high-calorie beverages (g/d) was associated with an increased OR. It can be concluded that attitudes or motivation towards eating healthily was related to measured dietary and lifestyle behaviour in this sample. Future research is warranted to devise appropriate methods of instituting attitude change towards dietary behaviour in certain subgroups of the population.
Low n-3 polyunsaturated fatty acid (PUFA) status may be associated with neuro-degenerative disorders, in particular Alzheimer's disease, which has been associated with poor dietary fish or n-3 PUFA ...intake, and low docosahexaenoic acid (DHA) status. The present case–control study used an established biomarker of n-3 PUFA intake (serum cholesteryl ester-fatty acid composition) to determine n-3 PUFA status in patients with Alzheimer's disease, who were free-living in the community. All cases fulfilled the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for Alzheimer's disease. Detailed neuropsychological testing and neuroimaging established the diagnosis in all cases. The subjects (119 females and twenty-nine males) aged 76·5 (SD 6·6) YEARS HAD A CLINICAL DEMENTIA RATING (CDR) OF 1 (sd 0·62) and a mini mental state examination (MMSE) score of 19·5 (sd 4·8). The control subjects (thirty-six females and nine males) aged 70 (sd 6·0) years were not cognitively impaired (defined as MMSE score <24): they had a mean MMSE score of 28·9 (sd 1·1). Serum cholesteryl ester-eicosapentaenoic acid and DHA levels were significantly lower (P<0·05 and P<0·001 respectively) in all MMSE score quartiles of patients with Alzheimer's disease compared with control values. Serum cholesteryl ester-DHA levels were progressively reduced with severity of clinical dementia. DHA levels did not differ in patients with Alzheimer's disease across age quartiles: all were consistently lower than in control subjects. Step-wise multiple regression analysis showed that cholesteryl ester-DHA and total saturated fatty acid levels were the important determinants of MMSE score and CDR. It remains to be determined whether low DHA status in Alzheimer's disease is a casual factor in the pathogenesis and progression of Alzheimer's disease.
BACKGROUND Characterization of the normal degree of physiological variation in the metabolomic profiles of healthy humans is a necessary step in the development of metabolomics as both a clinical ...research and diagnostic tool. This study investigated the effects of the menstrual cycle on 1H nuclear magnetic resonance (NMR) derived metabolomic profiles of urine and plasma from healthy women. METHODS In this study, 34 healthy women were recruited and a first void urine and fasting blood sample were collected from each woman at four different time points during one menstrual cycle. Serum hormone levels were used in combination with the menstrual calendar to classify the urine and plasma samples into five different phases i.e. menstrual, follicular, periovulatory, luteal and premenstrual. The urine and plasma samples were analysed using 1H NMR spectroscopy and subsequent data were analysed using principal component analysis (PCA) and partial least squares discriminant analysis. RESULTS PCA of the urine spectra showed no separation of samples based on the phases of the menstrual cycle. Multivariate analysis of the plasma spectra showed a separation of the menstrual phase and the luteal phase samples (R2 = 0.61, Q2 = 0.41). Subsequent analysis revealed a significant decrease in levels of glutamine, glycine, alanine, lysine, serine and creatinine and a significant increase in levels of acetoacetate and very low density lipoprotein (VLDL CH2) during the luteal phase. CONCLUSIONS These results establish a need to control for metabolic changes that occur in plasma due to the menstrual cycle in the design of future metabolomic studies involving premenopausal women.
Background: Excessive energy intake and obesity lead to the metabolic syndrome (MetS). Dietary saturated fatty acids (SFAs) may be particularly detrimental on insulin sensitivity (SI) and on other ...components of the MetS. Objective: This study determined the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with MetS. Design: A free-living, single-blinded dietary intervention study. Subjects and Methods: MetS subjects (n=417) from eight European countries completed the randomized dietary intervention study with four isoenergetic diets distinct in fat quantity and quality: high-SFA; high-monounsaturated fatty acids and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) (1.2 g per day) or placebo for 12 weeks. SI estimated from an intravenous glucose tolerance test (IVGTT) was the primary outcome measure. Lipid and inflammatory markers associated with MetS were also determined. Results: In weight-stable subjects, reducing dietary SFA intake had no effect on SI, total and low-density lipoprotein cholesterol concentration, inflammation or blood pressure in the entire cohort. The LFHCC n-3 PUFA diet reduced plasma triacylglycerol (TAG) and non-esterified fatty acid concentrations (P<0.01), particularly in men. Conclusion: There was no effect of reducing SFA on SI in weight-stable obese MetS subjects. LC n-3 PUFA supplementation, in association with a low-fat diet, improved TAG-related MetS risk profiles.
The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based ...phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5β1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.
The use of metabolomic based techniques to aid oocyte and embryo selection has gained attention in recent years. Previous work from our laboratory has demonstrated that the (1)H NMR-based metabolic ...profile of follicular fluid correlates with oocyte developmental potential. Patients undergoing IVF at the Merrion Fertility Clinic had follicular fluid collected at the time of oocyte retrieval. The fatty acid composition of follicular fluid from follicles where oocytes fertilised and developed into multi-cell embryos (n=15) and from oocytes that fertilised normally but failed to cleave (n=9) (cleaved vs non-cleaved) was compared. Statistical analysis was performed on the data using univariate and multivariate techniques. Analysis of the fatty acid composition revealed that there were nine fatty acids significantly different between follicular fluid from the cleaved and the non-cleaved sample groups. Of particular interest were the higher concentration of total saturated (P=0.03) and the lower concentration of total polyunsaturated fatty acids in the non-cleaved sample group (P=0.001). Random forest classification models were used to predict successful cleavage in follicular fluid samples producing models with errors rates of <10%. Receiver operating characteristic analysis demonstrated that the model had good predictability with an area under the curve of 0.96. The panel of fatty acid biomarkers identified in this study indicates that the fatty acid composition of follicular fluid may be more predictive in comparison to other previously identified biomarkers. Following validation in a larger cohort, these biomarkers may have the potential to be used in fertility clinics to aid the selection of oocytes in the future.
Proteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing ...pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples.
Beta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible.
Twenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p ≤ 0.01). Receiver operator characteristic curves determined the protein panels to have excellent discrimination between low and high beta-cell function. Linear regression analysis determined that beta-endorphin and IL-17F have strong associations with beta-cell function/HOMA-IR, β = 0.039 (p = 0.005) and β = -0.027 (p = 0.013) respectively. Calcineurin and CRTAM were strongly associated with the disposition index (β = 0.005 and β = 0.005 respectively, p = 0.012). In vitro experiments confirmed that IL-17F modulated insulin secretion in the BRIN-BD11 cell line, with the lower concentration of 10 ng/mL significantly increasing glucose stimulated insulin secretion (p = 0.043).
Early detection of compromised beta-cell function could allow for implementation of nutritional and lifestyle interventions before progression to type 2 diabetes.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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