PubMed

Related Articles Associations of multiple lipoprotein and apolipoprotein measures with worsening of glycemia and incident type 2 diabetes in 6607 non-diabetic Finnish men. Atherosclerosis. 2015 May;240(1):272-7 Authors: Fizelova M, Miilunpohja M, Kangas AJ, Soininen P, Kuusisto J, Ala-Korpela M, Laakso M, Stančáková A Abstract OBJECTIVE: We investigated the association of various lipoprotein traits, apolipoproteins and their ratios with the deterioration of glycemia, incident type 2 diabetes, insulin resistance and insulin secretion in a large population-based Metabolic Syndrome Men (METSIM) Study. RESEARCH DESIGN AND METHODS: The METSIM Study includes 10,197 Finnish men, aged 45-73 years, and examined in 2005-2010. From 6607 non-diabetic participants without statin treatment at baseline, 386 developed incident type 2 diabetes during a 5.9-year follow-up. A total of 3330 non-diabetic participants without statin treatment had both baseline and follow-up visit data, and were included in statistical analyses of the worsening of glycemia. RESULTS: Compared to single lipid and lipoprotein measurements, lipoprotein and apolipoprotein ratios were better predictors of the glucose area under the curve and incident type 2 diabetes after adjustment for confounding factors. The apolipoprotein B/LDL cholesterol ratio was the strongest predictor of the worsening of glycemia, whereas the apolipoprotein A1/HDL cholesterol ratio was the strongest predictor of incident type 2 diabetes. The associations of lipoprotein traits, apolipoproteins and their ratios with insulin sensitivity were stronger than those with insulin secretion. CONCLUSIONS: The apolipoprotein B/LDL cholesterol and apolipoprotein A1/HDL cholesterol ratios were the strongest predictors of the worsening of glycemia and incident type 2 diabetes, respectively. PMID: 25818853 [PubMed - indexed for MEDLINE]

Related Articles The relations between metabolic variations and genetic evolution of different species. Anal Biochem. 2015 May 15;477:105-14 Authors: Li Z, Lin C, Xu J, Wu H, Feng J, Huang H Abstract Metabonomics has been applied in many bio-related scientific fields. Nevertheless, some animal research works are shown to fail when they are extended to humans. Therefore, it is essential to figure out suitable animal modeling to mimic human metabolism so that animal findings can serve humans. In this study, two kinds of commonly selected body fluids, serum and urine, from humans and various experimental animals were characterized by integration of nuclear magnetic resonance (NMR) spectroscopy with multivariate statistical analysis to identify the interspecies metabolic differences and similarities at a baseline physiological status. Our results highlight that the dairy cow and pig may be an optimal choice for transportation and biodistribution studies of drugs and that the Kunming (KM) mouse model may be the most effective for excretion studies of drugs, whereas the Sprague-Dawley (SD) rat could be the most suitable candidate for animal modeling under overall considerations. The biochemical pathways analyses further provide an interconnection between genetic evolution and metabolic variations, where species evolution most strongly affects microbial biodiversity and, consequently, has effects on the species-specific biological substances of biosynthesis and corresponding biological activities. Knowledge of the metabolic effects from species difference will enable the construction of better models for disease diagnosis, drug metabolism, and toxicology research. PMID: 25728943 [PubMed - indexed for MEDLINE]

Related Articles High-throughput quantitative and qualitative analysis of microsomal incubations by cocktail analysis with an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer system. Bioanalysis. 2015;7(6):671-83 Authors: Backfisch G, Reder-Hilz B, Hoeckels-Messemer J, Angstenberger J, Sydor J, Laplanche L, Schulz M Abstract BACKGROUND: Metabolite identification studies are very resource intensive and also are rarely performed in early discovery. Here, we report the validation of an ultraperformance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) platform for generating high-throughput stability data with structure elucidation in a single injection. MATERIALS & METHODS: Tandem mass spectrometry spectra were obtained for quantitative analysis using a generic information-dependent acquisition method from pooled microsomal samples incubated at low compound concentrations. RESULTS: A good correlation was observed between clearance determined using UPLC-HRMS and UPLC-triple-quadrupole analysis. Structural elucidation performed with MassMetaSite™ (Molecular Discovery, Perugia, Italy) software identified 85% of the major metabolites of eight marketed drugs and over 100 internal compounds under these conditions. CONCLUSION: For the first time, a high-throughput quantitative-qualitative workflow was established using a cocktail approach for sample analysis with UPLC-HRMS in order to enable metabolite identification in early discovery projects. PMID: 25517264 [PubMed - indexed for MEDLINE]

Mannose metabolism in recombinant CHO cells and its effect on IgG glycosylation. Biotechnol Bioeng. 2016 Jan 1; Authors: Slade PG, Caspary RG, Nargund S, Huang CJ Abstract Understanding the causes of high-mannose (HM) glycosylation of recombinant IgG in CHO cells would facilitate the production of therapeutics. CHO cells grown with mannose as the major carbon source demonstrated a dramatic increase in total HM glycosylation in recombinant IgG, with no effect on cell growth, viability or titer. Quantitative metabolomics and (13) C flux analysis were used to explore the mechanism for increased HM glycosylation and understand the metabolism of mannose in CHO cells. It was demonstrated that mannose was a good carbon source for CHO cell growth and IgG production, readily entering both glycolysis and the TCA Cycle. Previous mechanisms for increased HM glycosylation during antibody production have been attributed to changes in pH, osmolality, increased specific productivity, and nutrient limitation. The results from this study propose a novel mechanism where an increased carbon flux in the GDP-mannose synthetic pathway increased the intracellular concentration of mannose-containing metabolites. The abnormally high concentration of mannose and mannose-metabolites were shown to inhibit α-mannosidase activity and it was proposed that this inhibition in the ER and Golgi caused the production of IgG with increased high-mannose glycosylation. This article is protected by copyright. All rights reserved. PMID: 26724786 [PubMed - as supplied by publisher]

Related Articles Sequencing the exposome: A call to action. Toxicol Rep. 2016;3:29-45 Authors: Jones DP Abstract The exposome is a complement to the genome that includes non-genetic causes of disease. Multiple definitions are available, with salient points being global inclusion of exposures and behaviors, and cumulative integration of associated biologic responses. As such, the concept is both refreshingly simple and dauntingly complex. This article reviews high-resolution metabolomics (HRM) as an affordable approach to routinely analyze samples for a broad spectrum of environmental chemicals and biologic responses. HRM has been successfully used in multiple exposome research paradigms and is suitable to implement in a prototype universal exposure surveillance system. Development of such a structure for systematic monitoring of environmental exposures is an important step toward sequencing the exposome because it builds upon successes of exposure science, naturally connects external exposure to body burden and partitions the exposome into workable components. Practical results would be repositories of quantitative data on chemicals according to geography and biology. This would support new opportunities for environmental health analysis and predictive modeling. Complementary approaches to hasten development of exposome theory and associated biologic response networks could include experimental studies with model systems, analysis of archival samples from longitudinal studies with outcome data and study of relatively short-lived animals, such as household pets (dogs and cats) and non-human primates (common marmoset). International investment and cooperation to sequence the human exposome will advance scientific knowledge and also provide an important foundation to control adverse environmental exposures to sustain healthy living spaces and improve prediction and management of disease. PMID: 26722641 [PubMed - as supplied by publisher]

Related Articles Making sense of blood-based proteomics and metabolomics in psychiatric research. Int J Neuropsychopharmacol. 2015 Dec 30; Authors: Guest PC, Guest FL, Martins-de-Souza D Abstract This manuscript describes the basics of proteomic and metabolic profiling of blood serum and plasma from patients with psychiatric disorders. It will also explain the rationale behind the use of these body fluids due to need for user friendly and rapid tests in the clinic with simple sampling procedures. It has emerged over the last 15 years or so that psychiatric disorders are whole body diseases and the bloodstream is a means of molecular transport and therefore provides a conduit for two way communication with the brain. Here we also describe some of the basic biomarker findings from studies of serum or plasma from patients with psychiatric disorders like schizophrenia, major depression and bipolar disorder. Finally, we will discuss potential future advancements in this area which includes the development of held devices containing miniature proteomic and metabolic assays which can be used for facilitating diagnosis in a point-of-care setting and yield results in less than 15 minutes from a single drop of blood. PMID: 26721951 [PubMed - as supplied by publisher]

Related Articles Cigarette smoking behaviour and blood metabolomics. Int J Epidemiol. 2015 Dec 31; Authors: Gu F, Derkach A, Freedman ND, Landi MT, Albanes D, Weinstein SJ, Mondul AM, Matthews CE, Guertin KA, Xiao Q, Zheng W, Shu XO, Sampson JN, Moore SC, Caporaso NE Abstract BACKGROUND: Identifying circulating metabolites related to cigarette smoking may provide insight into the biological mechanisms of smoking-related diseases and the nature of addiction. However, previous studies are limited, generally small, and have largely targeted a priori metabolites. METHODS: We examined associations between cigarette smoking and metabolites using an untargeted metabolomics approach in 892 men and women from four studies including participants from Italy, USA, China and Finland. We examined associations between individual log-transformed metabolites and two key smoking phenotypes (current smoking status and cigarettes per day [cig/day]) using linear regression. Fixed-effect meta-analysis was used to combine results across studies. Strict Bonferroni thresholds were used as our significance criteria. We further examined associated metabolites with other metrics of smoking behaviuor (current versus former, former versus never, smoking duration and years since quitting) in the US study. RESULTS: We identified a total of 25 metabolites associated with smoking behaviours; 24 were associated with current smoking status and eight with cig/day. In addition to three well-established nicotine metabolites (cotinine, hydroxycotinine, cotinine N-oxide), we found an additional 12 xenobiotic metabolites involved in benzoatic (e.g. 3-ethylphenylsulphate) or xanthine metabolism (e.g. 1-methylurate), three amino acids (o-cresol sulphate, serotonin, indolepropionate), two lipids (scyllo-inositol, pregnenolone sulphate), four vitamins or cofactors [e.g. bilirubin (Z,Z)], and one carbohydrate (oxalate). CONCLUSIONS: We identified associations between cigarette smoking and a diverse range of metabolites. Our findings, with further validation in future studies, have implications regarding aetiology and study design of smoking-related diseases. PMID: 26721601 [PubMed - as supplied by publisher]

Related Articles Emerging Systems Biology Approaches in Nanotoxicology: Towards a Mechanism-Based Understanding of Nanomaterial Hazard and Risk. Toxicol Appl Pharmacol. 2015 Dec 22; Authors: Costa PM, Fadeel B Abstract Engineered nanomaterials are being developed for a variety of technological applications. However, the increasing use of nanomaterials in society has led to concerns about their potential adverse effects on human health and the environment. During the first decade of nanotoxicological research, the realization has emerged that effective risk assessment of the multitudes of new nanomaterials would benefit from a comprehensive understanding of their toxicological mechanisms, which is difficult to achieve with traditional, low-throughput, single end-point oriented approaches. Therefore, systems biology approaches are being progressively applied within the nano(eco)toxicological sciences. This novel paradigm implies that the study of biological systems should be integrative resulting in quantitative and predictive models of nanomaterial behaviour in a biological system. To this end, global 'omics' approaches with which to assess changes in genes, proteins, metabolites, etc are deployed allowing for computational modelling of the biological effects of nanomaterials. Here, we highlight omics and systems biology studies in nanotoxicology, aiming towards the implementation of a systems nanotoxicology and mechanism-based risk assessment of nanomaterials. PMID: 26721310 [PubMed - as supplied by publisher]

The metabolic fingerprint of p,p'-DDE and HCB exposure in humans. Environ Int. 2015 Dec 22;88:60-66 Authors: Salihovic S, Ganna A, Fall T, Broeckling CD, Prenni JE, van Bavel B, Lind PM, Ingelsson E, Lind L Abstract BACKGROUND: Dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) are organochlorine pesticides with well-known endocrine disrupting properties. Exposure to p,p'-DDE and HCB concerns human populations worldwide and has been linked to metabolic disorders such as obesity and type 2 diabetes, but details about these associations in humans from the general population are largely unknown. OBJECTIVES: We investigated the associations between p,p'-DDE and HCB exposure and global metabolomic profiles in serum samples from 1016 participants from the Swedish population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. METHODS: HCB and p,p'-DDE levels were determined using gas chromatography coupled to high-resolution mass spectrometry (GC-HRMS). Metabolite levels were determined by using a non-targeted metabolomics approach with ultra-performance liquid chromatography coupled to time-of- flight mass spectrometry (UPLC-TOFMS). Association analyses were performed using multivariate linear regression. RESULTS: We found circulating levels of p,p-DDE and HCB to be significantly associated with circulating levels of 16 metabolites following adjustment for age, sex, education level, exercise habits, smoking, energy intake, and alcohol intake. The majority of the 16 metabolites belong to lipid metabolism pathways and include fatty acids, glycerophospholipids, sphingolipids, and glycerolipids. Overall, p,p'-DDE and HCB levels were found to be correlated to different metabolites, which suggests that different metabolic fingerprints may be related to circulating levels of these two pesticides. CONCLUSIONS: Our findings establish a link between human exposure to organochlorine pesticides and metabolites of key metabolic processes mainly related to human lipid metabolism. PMID: 26720637 [PubMed - as supplied by publisher]

SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst. 2016 Jan;108(1) Authors: Saxena N, Maio N, Crooks DR, Ricketts CJ, Yang Y, Wei MH, Fan TW, Lane AN, Sourbier C, Singh A, Killian JK, Meltzer PS, Vocke CD, Rouault TA, Linehan WM Abstract BACKGROUND: Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds. METHODS: In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations. RESULTS: We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4 ± 63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation.Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylatorphenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines. CONCLUSIONS: These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes. PMID: 26719882 [PubMed - in process]

Identification of a multiprotein reductive dehalogenase complex in Dehalococcoides mccartyi strain CBDB1 suggests a protein-dependent respiratory electron transport chain obviating quinone involvement. Environ Microbiol. 2015 Dec 31; Authors: Kublik A, Deobald D, Hartwig S, Schiffmann CL, Andrades A, von Bergen M, Sawers RG, Adrian L Abstract Dehalococcoides mccartyi strain CBDB1 is an obligate organohalide-respiring bacterium using only hydrogen as electron donor and halogenated organics as electron acceptor. Here, we studied proteins involved in the respiratory chain under non-denaturing conditions. Using Blue Native gel electrophoresis (BN-PAGE), gel filtration and ultrafiltration an active dehalogenating protein complex with a molecular mass of 250-270 kDa was identified. The active subunit of reductive dehalogenase (RdhA) co-localized with a complex iron-sulfur molybdoenzyme (CISM) subunit (CbdbA195) and an iron-sulfur cluster containing subunit (CbdbA131) of the hydrogen uptake hydrogenase (Hup). No co-localization between the catalytically active subunits of hydrogenase and reductive dehalogenase was found. By two-dimensional BN/SDS-PAGE the stability of the complex towards detergents was assessed, demonstrating stepwise disintegration with increasing detergent concentrations. Chemical cross-linking confirmed the presence of a higher molecular mass reductive dehalogenase protein complex composed of RdhA, CISM I and Hup hydrogenase and proved to be a potential tool for stabilizing protein-protein interactions of the dehalogenating complex prior to membrane solubilization. Taken together, the identification of the respiratory dehalogenase protein complex and the absence of indications for quinone participation in the respiration suggest a quinone-independent protein-based respiratory electron transfer chain in D. mccartyi. PMID: 26718631 [PubMed - as supplied by publisher]

Related Articles Gene expression mapping of histone deacetylases and co-factors, and correlation with survival time and 1H-HRMAS metabolomic profile in human gliomas. Sci Rep. 2015;5:9087 Authors: Dali-Youcef N, Froelich S, Moussallieh FM, Chibbaro S, Noël G, Namer IJ, Heikkinen S, Auwerx J Abstract Primary brain tumors are presently classified based on imaging and histopathological techniques, which remains unsatisfaying. We profiled here by quantitative real time PCR (qRT-PCR) the transcripts of eighteen histone deacetylases (HDACs) and a subset of transcriptional co-factors in non-tumoral brain samples from 15 patients operated for epilepsia and in brain tumor samples from 50 patients diagnosed with grade II oligodendrogliomas (ODII, n = 9), grade III oligodendrogliomas (ODIII, n = 22) and glioblastomas (GL, n = 19). Co-factor transcripts were significantly different in tumors as compared to non-tumoral samples and distinguished different molecular subgroups of brain tumors, regardless of tumor grade. Among all patients studied, the expression of HDAC1 and HDAC3 was inversely correlated with survival, whereas the expression of HDAC4, HDAC5, HDAC6, HDAC11 and SIRT1 was significantly and positively correlated with survival time of patients with gliomas. (1)H-HRMAS technology revealed metabolomically distinct groups according to the expression of HDAC1, HDAC4 and SIRT1, suggesting that these genes may play an important role in regulating brain tumorigenesis and cancer progression. Our study hence identified different molecular fingerprints for subgroups of histopathologically similar brain tumors that may enable the prediction of outcome based on the expression level of co-factor genes and could allow customization of treatment. PMID: 25791281 [PubMed - indexed for MEDLINE]

An unbiased metabolomic investigation of the Alzheimer's disease brain points to a dysregulation of the mitochondrial aspartate metabolism. J Proteome Res. 2015 Dec 30; Authors: Paglia G, Stocchero M, Cacciatore S, Lai S, Angel PM, Alam MT, Keller M, Ralser M, Astarita G Abstract Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n=21) and age-matched controls (n=19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of the mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing a dysregulation of the mitochondrial aspartate metabolism and supporting future venues of investigation. PMID: 26717242 [PubMed - as supplied by publisher]

Metabolomic Elucidation of the Effects of Curcumin on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis. PLoS One. 2015;10(12):e0145539 Authors: Ahn JK, Kim S, Hwang J, Kim J, Lee YS, Koh EM, Kim KH, Cha HS Abstract Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by synovial inflammation and joint disability. Curcumin is known to be effective in ameliorating joint inflammation in RA. To obtain new insights into the effect of curcumin on primary fibroblast-like synoviocytes (FLS, N = 3), which are key effector cells in RA, we employed gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS)-based metabolomics. Metabolomic profiling of tumor necrosis factor (TNF)-α-stimulated and curcumin-treated FLS was performed using GC/TOF-MS in conjunction with univariate and multivariate statistical analyses. A total of 119 metabolites were identified. Metabolomic analysis revealed that metabolite profiles were clearly distinct between TNF-α-stimulated vs. the control group (not stimulated by TNF-α or curcumin). Treatment of FLS with curcumin showed that the metabolic perturbation by TNF-α could be reversed to that of the control group to a considerable extent. Curcumin-treated FLS had higher restoration of amino acid and fatty acid metabolism, as indicated by the prominent metabolic restoration of intermediates of amino acid and fatty acid metabolism, compared with that observed in TNF-α-stimulated FLS. In particular, the abundance of glycine, citrulline, arachidonic acid, and saturated fatty acids in TNF-α-stimulated FLS was restored to the control level after treatment with curcumin, suggesting that the effect of curcumin on preventing joint inflammation may be elucidated with the levels of these metabolites. Our results suggest that GC/TOF-MS-based metabolomic investigation using FLS has the potential for discovering the mechanism of action of curcumin and new targets for therapeutic drugs in RA. PMID: 26716989 [PubMed - as supplied by publisher]

Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal. PLoS One. 2015;10(12):e0146152 Authors: Li X, Guo Y, Yan W, Snyder MP, Li X Abstract OBJECTIVE: Metformin, a leading drug used to treat diabetic patients, is reported to benefit bone homeostasis under hyperglycemia in animal models. However, both the molecular targets and the biological pathways affected by metformin in bone are not well identified or characterized. The objective of this study is to investigate the bioengergeric pathways affected by metformin in bone marrow cells of mice. MATERIALS AND METHODS: Metabolite levels were examined in bone marrow samples extracted from metformin or PBS -treated healthy (Wild type) and hyperglycemic (diabetic) mice using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. We applied an untargeted high performance LC-MS approach which combined multimode chromatography (ion exchange, reversed phase and hydrophilic interaction (HILIC)) and Orbitrap-based ultra-high accuracy mass spectrometry to achieve a wide coverage. A multivariate clustering was applied to reveal the global trends and major metabolite players. RESULTS: A total of 346 unique metabolites were identified, and they are grouped into distinctive clusters that reflected general and diabetes-specific responses to metformin. As evidenced by changes in the TCA and urea cycles, increased catabolism and nitrogen waste that are commonly associated with diabetes were rebalanced upon treatment with metformin. In particular, we found glutamate and succinate whose levels were drastically elevated in diabetic animals were brought back to normal levels by metformin. These two metabolites were further validated as the major targets of metformin in bone marrow stromal cells. CONCLUSION: Overall using limited sample size, our study revealed the metabolic pathways modulated by metformin in bones which have broad implication in our understanding of bone remodeling under hyperglycemia and in finding therapeutic interventions in mammals. PMID: 26716870 [PubMed - as supplied by publisher]

Longitudinal Metabolomic Profiling of Amino Acids and Lipids across Healthy Pregnancy. PLoS One. 2015;10(12):e0145794 Authors: Lindsay KL, Hellmuth C, Uhl O, Buss C, Wadhwa PD, Koletzko B, Entringer S Abstract Pregnancy is characterized by a complexity of metabolic processes that may impact fetal development and ultimately, infant health outcomes. However, our understanding of whole body maternal and fetal metabolism during this critical life stage remains incomplete. The objective of this study is to utilize metabolomics to profile longitudinal patterns of fasting maternal metabolites among a cohort of non-diabetic, healthy pregnant women in order to advance our understanding of changes in protein and lipid concentrations across gestation, the biochemical pathways by which they are metabolized and to describe variation in maternal metabolites between ethnic groups. Among 160 pregnant women, amino acids, tricarboxylic acid (TCA) cycle intermediates, keto-bodies and non-esterified fatty acids were detected by liquid chromatography coupled with mass spectrometry, while polar lipids were detected through flow-injected mass spectrometry. The maternal plasma concentration of several essential and non-essential amino acids, long-chain polyunsaturated fatty acids, free carnitine, acetylcarnitine, phosphatidylcholines and sphingomyelins significantly decreased across pregnancy. Concentrations of several TCA intermediates increase as pregnancy progresses, as well as the keto-body β-hydroxybutyrate. Ratios of specific acylcarnitines used as indicators of metabolic pathways suggest a decreased beta-oxidation rate and increased carnitine palmitoyltransferase-1 enzyme activity with advancing gestation. Decreasing amino acid concentrations likely reflects placental uptake and tissue biosynthesis. The absence of any increase in plasma non-esterified fatty acids is unexpected in the catabolic phase of later pregnancy and may reflect enhanced placental fatty acid uptake and utilization for fetal tissue growth. While it appears that energy production through the TCA cycle increases as pregnancy progresses, decreasing patterns of free carnitine and acetylcarnitine as well as increased carnitine palmitoyltransferase-1 rate and β-hydroxybutyrate levels suggest a concomitant upregulation of ketogenesis to ensure sufficient energy supply in the fasting state. Several differences in metabolomic profiles between Hispanic and non-Hispanic women demonstrate phenotypic variations in prenatal metabolism which should be considered in future studies. PMID: 26716698 [PubMed - as supplied by publisher]

Fatty acid binding protein 5 (FABP5) modulates docosahexaenoic acid (DHA)-induced recovery in rats undergoing spinal cord injury. J Neurotrauma. 2015 Dec 30; Authors: Figueroa JD, Illan MS, Licero J, Cordero K, Miranda JD, De Leon M Abstract Omega-3 polyunsaturated fatty acids (n-3 PUFAs) promote functional recovery in rats undergoing spinal cord injury (SCI). However, the precise molecular mechanism coupling n-3 PUFAs to neurorestorative responses is not well understood. The objective of the present study was to determine the spatiotemporal expression of the fatty acid binding protein 5 (FABP5) following contusive SCI and to investigate whether this protein plays a role in n-3 PUFAs-mediated functional recovery after SCI. We found that SCI resulted in a robust spinal cord upregulation in the FABP5 mRNA levels (556 ± 187 %) and protein expression (518 ± 195 %) when compared to sham-operated rats at 7 days post-injury (dpi). This upregulation coincided with significant alterations in the metabolism of fatty acids in the injured spinal cord, as revealed by metabolomics-based lipid analyses. In particular, we found increased levels of the n-3 series PUFAs, particularly docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA; 20:5 n-3) at 7 dpi. Animals consuming a diet rich in DHA and EPA exhibited a significant upregulation in FABP5 mRNA levels at 7 dpi. Immunofluorescence showed low basal FABP5 immunoreactivity (IR) in the spinal cord ventral gray matter NeuN+ neurons of sham-operated rats. SCI resulted in a robust induction of FABP5 in glial (GFAP+, APC+, and NG2+) and precursor cells (DCX+, nestin+). We found that continuous intrathecal administration of FABP5 silencing with small interfering RNA (2 μg) impaired spontaneous open-field locomotion after SCI. Further, FABP5 siRNA administration hindered the beneficial effects of DHA to ameliorate functional recovery at 7 dpi. Altogether, our findings suggest that FABP5 may be an important player in the promotion of cellular uptake, transport, and/or metabolism of DHA following SCI. Given the beneficial roles of n-3 PUFAs in ameliorating functional recovery, we propose that FABP5 in an important contributor to basic repair mechanisms in the injured spinal cord. PMID: 26715431 [PubMed - as supplied by publisher]

An in vitro metabolomics approach to identify hepatotoxicity biomarkers in human L02 liver cells treated with pekinenal, a natural compound. Anal Bioanal Chem. 2015 Dec 29; Authors: Shi J, Zhou J, Ma H, Guo H, Ni Z, Duan J, Tao W, Qian D Abstract An in vitro cell metabolomics study was performed on human L02 liver cells to investigate the toxic biomarkers of pekinenal from the herb Euphorbia pekinensis Rupr. Pekinenal significantly induced L02 cell damage, which was characterised by necrosis and apoptosis. Metabolomics combined with data pattern recognition showed that pekinenal significantly altered the profiles of more than 1299 endogenous metabolites with variable importance in the projection (VIP) > 1. Further, screening correlation coefficients between the intensities of all metabolites and the extent of L02 cell damage (MTT) identified 12 biomarker hits: ten were downregulated and two were upregulated. Among these hits, LysoPC(18:1(9Z)/(11Z)), PC(22:0/15:0) and PC(20:1(11Z)/14:1(9Z)) were disordered, implying the initiation of inflammation and cell damage. Several fatty acids (FAs) (3-hydroxytetradecanedioic acid, pivaloylcarnitine and eicosapentaenoyl ethanolamide) decreased due to fatty acid oxidation. Dihydroceramide and Cer(d18:0/14:0) were also altered and are associated with apoptosis. Additional examination of the levels of intracellular reactive oxygen species (ROS) and two eicosanoids (PGE2, PGF2α) in the cell supernatant confirmed the fatty acid oxidation and arachidonic acid metabolism pathways, respectively. In summary, cell metabolomics is a highly efficient approach for identifying toxic biomarkers and helping understand toxicity mechanisms and predict herb-induced liver injury. Graphical Abstract ᅟ. PMID: 26715247 [PubMed - as supplied by publisher]

Advances in the microbial etiology and pathogenesis of early childhood caries. Mol Oral Microbiol. 2015 Dec 30; Authors: Hajishengallis E, Parsaei Y, Klein MI, Koo H Abstract Early childhood caries (ECC) is one of the most prevalent infectious diseases affecting children worldwide. ECC is an aggressive form of dental caries, which left untreated, can result in rapid and extensive cavitation in teeth (rampant caries) that is painful and costly to treat. Furthermore, it affects mostly children from impoverished background, and thus constitutes a major challenge in public health. The disease is a prime example of the consequences arising from complex, dynamic interactions between microorganisms, host and diet, leading to the establishment of highly pathogenic (cariogenic) biofilms. To date, there are no effective methods to identify those at risk of developing ECC or control the disease in affected children. Recent advances in deep-sequencing technologies, novel imaging methods and (meta)proteomics-metabolomics approaches provide an unparalleled potential to reveal new insights to illuminate our current understanding about the etiology and pathogenesis of the disease. In this concise review, we provide a broader perspective about the etiology and pathogenesis of ECC based on previous and current knowledge on biofilm matrix, microbial diversity and host-microbe interactions which could have direct implications for developing new approaches for improved risk assessment and prevention of this devastating and costly childhood health condition. This article is protected by copyright. All rights reserved. PMID: 26714612 [PubMed - as supplied by publisher]

Related Articles Cadmium chloride inhibits lactate gluconeogenesis in mouse renal proximal tubules: An in vitro metabolomic approach with (13)C NMR. Toxicol Lett. 2015 Nov 4;238(3):45-52 Authors: Faiz H, Boghossian M, Martin G, Baverel G, Ferrier B, Conjard-Duplany A Abstract Using isolated mouse renal proximal tubules incubated with lactate as substrate, we have found that the addition of 1-50 μM cadmium chloride (CdCl2) caused a concentration-dependent decrease in lactate utilization, in glucose production and in the cellular level of ATP, coenzyme A, acetyl-coenzyme A and glutathione (reduced and oxidized forms). Combining enzymatic and (13)C NMR measurements in a cellular metabolomic approach, we have shown that, in the presence of 10 μM CdCl2, fluxes through the key-enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were greatly depressed by cadmium. This was accompanied by a reduction in fluxes through the enzymes of the tricarboxylic acid cycle. Comparing the mouse and human renal metabolic responses to cadmium, it is interesting to observe that the mouse renal proximal tubule was much more sensitive than the human renal proximal tubule to the adverse effects of CdCl2. As far as renal gluconeogenesis is concerned, the mouse seems to be an appropriate and convenient animal model to study the mechanism of cadmium nephrotoxicity. However, the data obtained in the mouse should be extrapolated to humans with caution because the inhibition of fluxes through the enzymes of the tricarboxylic acid cycle in mouse tubules were not observed in human tubules. PMID: 26235813 [PubMed - indexed for MEDLINE]