Publications
49 results found
Maitre L, Lau C-HE, Vizcaino E, et al., 2017, Assessment of metabolic phenotypic variability in children's urine using H-1 NMR spectroscopy, Scientific Reports, Vol: 7, ISSN: 2045-2322
The application of metabolic phenotyping in clinical and epidemiological studies is limited by a poor understanding of inter-individual, intra-individual and temporal variability in metabolic phenotypes. Using 1H NMR spectroscopy we characterised short-term variability in urinary metabolites measured from 20 children aged 8–9 years old. Daily spot morning, night-time and pooled (50:50 morning and night-time) urine samples across six days (18 samples per child) were analysed, and 44 metabolites quantified. Intraclass correlation coefficients (ICC) and mixed effect models were applied to assess the reproducibility and biological variance of metabolic phenotypes. Excellent analytical reproducibility and precision was demonstrated for the 1H NMR spectroscopic platform (median CV 7.2%). Pooled samples captured the best inter-individual variability with an ICC of 0.40 (median). Trimethylamine, N-acetyl neuraminic acid, 3-hydroxyisobutyrate, 3-hydroxybutyrate/3-aminoisobutyrate, tyrosine, valine and 3-hydroxyisovalerate exhibited the highest stability with over 50% of variance specific to the child. The pooled sample was shown to capture the most inter-individual variance in the metabolic phenotype, which is of importance for molecular epidemiology study design. A substantial proportion of the variation in the urinary metabolome of children is specific to the individual, underlining the potential of such data to inform clinical and exposome studies conducted early in life.
Chatziioannou A, Georgiadis P, Hebels DG, et al., 2017, Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.
Sood D, Johnson N, Jain P, et al., 2017, CYP3A7*1C allele is associated with reduced levels of 2-hydroxylation pathway oestrogen metabolites, British Journal of Cancer, Vol: 116, Pages: 382-388, ISSN: 1532-1827
background: Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs.methods: We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS.results: In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 × 10−12; 2-hydroxyestradiol, P=2.7 × 10−7; 2-methoxyestrone, P=1.9 × 10−12; and 2-methoxyestradiol, P=0.0009). By contrast, 16α-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002).conclusions: The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2-hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16α-hydroxylation EMs in premenopausal women. To further characterise the association between parent oestrogens, EMs and subsequent risk of breast cancer, characterisation of additional genetic variants that influence oestrogen metabolism and large prospective studies of a broad spectrum of EMs will be required.
Siskos AP, Jain P, Romisch-Margl W, et al., 2016, Interlaboratory reproducibility of a targeted metabolomics platform for analysis of human serum and plasma, Analytical Chemistry, Vol: 89, Pages: 656-665, ISSN: 1086-4377
A critical question facing the field of metabolomics is whether data obtained from different centers can be effectively compared and combined. An important aspect of this is the interlaboratory precision (reproducibility) of the analytical protocols used. We analyzed human samples in six laboratories using different instrumentation but a common protocol (the AbsoluteIDQ p180 kit) for the measurement of 189 metabolites via liquid chromatography (LC) or flow injection analysis (FIA) coupled to tandem mass spectrometry (MS/MS). In spiked quality control (QC) samples 82% of metabolite measurements had an interlaboratory precision of <20%, while 83% of averaged individual laboratory measurements were accurate to within 20%. For 20 typical biological samples (serum and plasma from healthy individuals) the median interlaboratory coefficient of variation (CV) was 7.6%, with 85% of metabolites exhibiting a median interlaboratory CV of <20%. Precision was largely independent of the type of sample (serum or plasma) or the anticoagulant used but was reduced in a sample from a patient with dyslipidaemia. The median interlaboratory accuracy and precision of the assay for standard reference plasma (NIST SRM 1950) were 107% and 6.7%, respectively. Likely sources of irreproducibility were the near limit of detection (LOD) typical abundance of some metabolites and the degree of manual review and optimization of peak integration in the LC–MS/MS data after acquisition. Normalization to a reference material was crucial for the semi-quantitative FIA measurements. This is the first interlaboratory assessment of a widely used, targeted metabolomics assay illustrating the reproducibility of the protocol and how data generated on different instruments could be directly integrated in large-scale epidemiological studies.
Perng W, Oken E, Roumeliotaki T, et al., 2016, Leptin, acylcarnitine metabolites and development of adiposity in the Rhea mother-child cohort in Crete, Greece., Obesity Science and Practice, Vol: 2, Pages: 471-476, ISSN: 2055-2238
OBJECTIVE: This study aims to investigate relations of serum leptin at age 4 with development of adiposity and linear growth during 3 years of follow-up among 75 Greek children and to identify serum metabolites associated with leptin at age 4 and to characterize their associations with adiposity gain and linear growth. METHODS: Linear regression models that accounted for maternal age, education and gestational weight gain and child's age and sex were used to examine associations of leptin and leptin-associated metabolites measured at age 4 with indicators of adiposity and linear growth at age 7. RESULTS: Each 1-unit increment in natural log-(ln)-transformed leptin corresponded with 0.33 (95% CI: 0.10, 0.55) units greater body mass index-for-age z-score gain during follow-up. Likewise, higher levels of the leptin-associated metabolites methylmalonyl-carnitine and glutaconyl-carnitine corresponded with 0.14 (95% CI: 0.01, 0.27) and 0.07 (95% CI: -0.01, 0.16) units higher body mass index-for-age z-score gain, respectively. These relationships did not differ by sex or baseline weight status and were independent of linear growth. CONCLUSIONS: These findings suggest that leptin, methylmalonyl-carnitine and possibly glutaconyl-carnitine are associated with weight gain during early childhood. Future studies are warranted to confirm these findings in other populations.
Georgiadis P, Hebels DG, Valavanis I, et al., 2016, Omics for prediction of environmental health effects: blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking, Scientific Reports, Vol: 6, ISSN: 2045-2322
The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking (indicative estimates of sensitivity and positive predictive value 94% and 84%, respectively). Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment.
Valbuena GN, Rizzardini M, Cimini S, et al., 2015, Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis, Molecular Neurobiology, Vol: 53, Pages: 2222-2240, ISSN: 1559-1182
Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.
Miller JA, Pappan K, Thompson PA, et al., 2015, Plasma Metabolomic Profiles of Breast Cancer Patients after Short-term Limonene Intervention, CANCER PREVENTION RESEARCH, Vol: 8, ISSN: 1940-6207
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- Citations: 30
Chatziioannou AN, Siskos AP, Loxas D, et al., 2013, Transarterial Embolization with Sorafenib in Animal Livers: A Pharmacokinetics Study, JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY, Vol: 24, Pages: 1657-1663, ISSN: 1051-0443
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- Citations: 12
Katsila T, Siskos AP, Tamvakopoulos C, 2011, Peptide and protein drugs: The study of their metabolism and catabolism by mass spectrometry, MASS SPECTROMETRY REVIEWS, Vol: 31, Pages: 110-133, ISSN: 0277-7037
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- Citations: 56
Anderson R, Franch A, Castell M, et al., 2010, Liposomal encapsulation enhances and prolongs the anti-inflammatory effects of water-soluble dexamethasone phosphate in experimental adjuvant arthritis, Arthritis Research and Therapy, Vol: 12, Pages: 1-15, ISSN: 1478-6354
IntroductionThe objective of this study was to evaluate the efficacy of intravenous (i.v.) injection of liposomally encapsulated dexamethasone phosphate (DxM-P) in comparison to free DxM-P in rats with established adjuvant arthritis (AA). This study focused on polyethylene glycol (PEG)-free liposomes, to minimize known allergic reactions caused by neutral PEG-modified (PEG-ylated) liposomes.MethodsEfficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry.ResultsLiposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug.ConclusionsThis new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, wi
Siskos AP, Katsila T, Balafas E, et al., 2009, Simultaneous Absolute Quantification of the Glucose-Dependent Insulinotropic Polypeptides GIP<sub>1-42</sub> and GIP<sub>3-42</sub> in Mouse Plasma by LC/ESI-MS/MS: Preclinical Evaluation of DP-IV Inhibitors, JOURNAL OF PROTEOME RESEARCH, Vol: 8, Pages: 3487-3496, ISSN: 1535-3893
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- Citations: 12
Baerga-Ortiz A, Popovic B, Siskos AP, et al., 2006, Directed mutagenesis alters the stereochemistry of catalysis by isolated ketoreductase domains from the erythromycin polyketide synthase, CHEMISTRY & BIOLOGY, Vol: 13, Pages: 277-285, ISSN: 1074-5521
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- Citations: 87
Siskos AP, Baerga-Ortiz A, Bali S, et al., 2005, Molecular basis of Celmer's rules: Stereochemistry of catalysis by isolated ketoreductase domains from modular polyketide synthases, CHEMISTRY & BIOLOGY, Vol: 12, Pages: 1145-1153, ISSN: 1074-5521
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- Citations: 95
Hong H, Appleyard AN, Siskos AP, et al., 2005, Chain initiation on type I modular polyketide synthases revealed by limited proteolysis and ion-trap mass spectrometry, FEBS JOURNAL, Vol: 272, Pages: 2373-2387, ISSN: 1742-464X
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- Citations: 26
Weissman KJ, Hong H, Oliynyk M, et al., 2004, Identification of a phosphopantetheinyl transferase for erythromycin biosynthesis in <i>Saccharopolyspora erythraea</i>, CHEMBIOCHEM, Vol: 5, Pages: 116-125, ISSN: 1439-4227
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- Citations: 57
Siskos AP, Hill AM, 2003, A highly efficient synthesis of [1-<SUP>13</SUP>C, <SUP>18</SUP>O]- and [1-<SUP>13</SUP>C, <SUP>2</SUP>H<sub>2</sub>]-glycerol for the elucidation of biosynthetic pathways, TETRAHEDRON LETTERS, Vol: 44, Pages: 789-792, ISSN: 0040-4039
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- Citations: 9
Hill AM, Harris JP, Siskos AP, 1998, Investigation of glycerol incorporation into soraphen A, CHEMICAL COMMUNICATIONS, Pages: 2361-2362, ISSN: 1359-7345
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- Citations: 25
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