PubMed

Related Articles Effect of breadmaking process on in vitro gut microbiota parameters in irritable bowel syndrome. PLoS One. 2014;9(10):e111225 Authors: Costabile A, Santarelli S, Claus SP, Sanderson J, Hudspith BN, Brostoff J, Ward JL, Lovegrove A, Shewry PR, Jones HE, Whitley AM, Gibson GR Abstract A variety of foods have been implicated in symptoms of patients with Irritable Bowel Syndrome (IBS) but wheat products are most frequently cited by patients as a trigger. Our aim was to investigate the effects of breads, which were fermented for different lengths of time, on the colonic microbiota using in vitro batch culture experiments. A set of in vitro anaerobic culture systems were run over a period of 24 h using faeces from 3 different IBS donors (Rome Criteria-mainly constipated) and 3 healthy donors. Changes in gut microbiota during a time course were identified by fluorescence in situ hybridisation (FISH), whilst the small-molecular weight metabolomic profile was determined by NMR analysis. Gas production was separately investigated in non pH-controlled, 36 h batch culture experiments. Numbers of bifidobacteria were higher in healthy subjects compared to IBS donors. In addition, the healthy donors showed a significant increase in bifidobacteria (P<0.005) after 8 h of fermentation of a bread produced using a sourdough process (type C) compared to breads produced with commercial yeasted dough (type B) and no time fermentation (Chorleywood Breadmaking process) (type A). A significant decrease of δ-Proteobacteria and most Gemmatimonadetes species was observed after 24 h fermentation of type C bread in both IBS and healthy donors. In general, IBS donors showed higher rates of gas production compared to healthy donors. Rates of gas production for type A and conventional long fermentation (type B) breads were almost identical in IBS and healthy donors. Sourdough bread produced significantly lower cumulative gas after 15 h fermentation as compared to type A and B breads in IBS donors but not in the healthy controls. In conclusion, breads fermented by the traditional long fermentation and sourdough are less likely to lead to IBS symptoms compared to bread made using the Chorleywood Breadmaking Process. PMID: 25356771 [PubMed - indexed for MEDLINE]

Related Articles Mass spectrometry-based metabolite profiling in the mouse liver following exposure to ultraviolet B radiation. PLoS One. 2014;9(10):e109479 Authors: Park HM, Shon JC, Lee MY, Liu KH, Kim JK, Lee SJ, Lee CH Abstract Although many studies have been performed on the effects of ultraviolet (UV) radiation on the skin, only a limited number of reports have investigated these effects on non-skin tissue. This study aimed to describe the metabolite changes in the liver of hairless mice following chronic exposure to UVB radiation. We did not observe significant macroscopic changes or alterations in hepatic cholesterol and triglyceride levels in the liver of UVB-irradiated mice, compared with those for normal mice. In this study, we detected hepatic metabolite changes by UVB exposure and identified several amino acids, fatty acids, nucleosides, carbohydrates, phospholipids, lysophospholipids, and taurine-conjugated cholic acids as candidate biomarkers in response to UVB radiation in the mouse liver by using various mass spectrometry (MS)-based metabolite profiling including ultra-performance liquid chromatography-quadrupole time-of-flight (TOF)-MS, gas chromatography-TOF-MS and nanomate LTQ-MS. Glutamine exhibited the most dramatic change with a 5-fold increase in quantity. The results from altering several types of metabolites suggest that chronic UVB irradiation may impact significantly on major hepatic metabolism processes, despite the fact that the liver is not directly exposed to UVB radiation. MS-based metabolomic approach for determining regulatory hepatic metabolites following UV irradiation will provide a better understanding of the relationship between internal organs and UV light. PMID: 25275468 [PubMed - indexed for MEDLINE]

Gestational dating by metabolic profile at birth: A California cohort study. Am J Obstet Gynecol. 2015 Dec 11; Authors: Jelliffe-Pawlowski LL, Norton ME, Baer RJ, Santos N, Rutherford GW Abstract BACKGROUND: Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often under- or over-estimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications. OBJECTIVE: To evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (<37 weeks) from term births and to assign a specific gestational age in the preterm birth group. STUDY DESIGN: We evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11 to 20 weeks' gestation. Using training and testing subsets (divided in a ratio of 3 to 1) we evaluated the association between preterm birth, target newborn characteristics, acylcarnitines, amino acids, thyroid stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses (LDA) to create a linear function for preterm birth and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions. RESULTS: Along with birth weight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing preterm and term births. Using a LDA-derived linear function, we were able to sort preterm and term births accurately with sensitivities and specificities of 95% or more in both the training and testing subsets. Assignment of a specific week of gestation in those identified as preterm births resulted in the correct assignment of week +/-2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When preterm birth rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, preterm-birth rates were 7.15% versus 6.11% in the training subset and 7.31% versus 6.25% in the testing subset. CONCLUSION: When considered in combination with birth weight and hours of age at test, metabolic profile evaluated within eight days of birth appears to be a useful measure of preterm birth and, among those born preterm, of specific week of gestation +/-2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care. PMID: 26688490 [PubMed - as supplied by publisher]

Integrative drug efficacy assessment of Danggui and European Danggui using NMR-based metabolomics. J Pharm Biomed Anal. 2015 Dec 3;120:1-9 Authors: Zhang ZZ, Fan ML, Hao X, Qin XM, Li ZY Abstract Danggui (DG) is a commonly used herbal drug in traditional Chinese medicine, and usually adulterated with European Danggui (EDG) due to the increasing demand. In present study, global metabolic profiling with NMR coupled with integrative drug efficacy evaluation methods was performed to compare and discover underlying blood-enriching regulation mechanisms of DG and EDG on blood deficiency rats induced by acetyl phenylhydrazine (APH). Totally, the contents of 12 key metabolites in serum and 4 in urine of DG group, 7 in serum and 4 in urine of EDG group were significantly reversed in comparison with model group. DG was more effective than EDG as revealed by the relative distance, efficacy index and similarity analysis. The metabolism pathways analysis showed that the better effect of DG maybe related with the regulatory effect on valine, leucine and isoleucine biosynthesis, synthesis and degradation of ketone bodies, glycine, serine and threonine metabolism, as well as nicotinate and nicotinamide metabolism. The results presented here showed that metabolomic coupled with efficacy index and similarity analysis made it possible to disclose the subtle biological difference between DG and EDG, which highlight the potential of metabolomic approach to quantitatively compare the pharmacological effect of the herbal drugs. PMID: 26686769 [PubMed - as supplied by publisher]

The role of endothelial mechanosensitive genes in atherosclerosis and omics approaches. Arch Biochem Biophys. 2015 Dec 10; Authors: Simmons RD, Kumar S, Jo H Abstract Atherosclerosis is the leading cause of morbidity and mortality in the U.S., and is a multifactorial disease that preferentially occurs in regions of the arterial tree exposed to disturbed blood flow. The detailed mechanisms by which d-flow induces atherosclerosis involve changes in the expression of genes, epigenetic patterns, and metabolites of multiple vascular cells, especially endothelial cells. This review presents an overview of endothelial mechanobiology and its relation to the pathogenesis of atherosclerosis with special reference to the anatomy of the artery and the underlying fluid mechanics, followed by a discussion of a variety of experimental models to study the role of fluid mechanics and atherosclerosis. Various in vitro and in vivo models to study the role of flow in endothelial biology and pathobiology are discussed in this review. Furthermore, strategies used for the global profiling of the genome, transcriptome, miRNA-nome, DNA methylome, and metabolome, as they are important to define the biological and pathophysiological mechanisms of atherosclerosis. These "omics" approaches, especially those which derive data based on a single animal model, provide unprecedented opportunities to not only better understand the pathophysiology of atherosclerosis development in a holistic and integrative manner, but also to identify novel molecular and diagnostic targets. PMID: 26686737 [PubMed - as supplied by publisher]

Modulation of genetic clusters for synthesis of bioactive molecules in fungal endophytes: A review. Microbiol Res. 2016 Jan;182:125-40 Authors: Deepika VB, Murali TS, Satyamoorthy K Abstract Novel drugs with unique and targeted mode of action are very much need of the hour to treat and manage severe multidrug infections and other life-threatening complications. Though natural molecules have proved to be effective and environmentally safe, the relative paucity of discovery of new drugs has forced us to lean towards synthetic chemistry for developing novel drug molecules. Plants and microbes are the major resources that we rely upon in our pursuit towards discovery of novel compounds of pharmacological importance with less toxicity. Endophytes, an eclectic group of microbes having the potential to chemically bridge the gap between plants and microbes, have attracted the most attention due to their relatively high metabolic versatility. Since continuous large scale supply of major metabolites from microfungi and especially endophytes is severely impeded by the phenomenon of attenuation in axenic cultures, the major challenge is to understand the regulatory mechanisms in operation that drive the expression of metabolic gene clusters of pharmaceutical importance. This review is focused on the major regulatory elements that operate in filamentous fungi and various combinatorial multi-disciplinary approaches involving bioinformatics, molecular biology, and metabolomics that could aid in large scale synthesis of important lead molecules. PMID: 26686621 [PubMed - in process]

Neurometabolic roles of ApoE and Ldl-R in mouse brain. J Bioenerg Biomembr. 2015 Dec 21; Authors: Lee J, Choi J, Wong GW, Wolfgang MJ Abstract Polymorphisms in ApoE are highly correlated with the progression of neurodegenerative disease, in particular Alzheimer's disease. Little is known, however, about the role of ApoE or cholesterol metabolism on brain neurochemistry in general. To better understand the role of lipoprotein and cholesterol metabolism in the brain, we profiled 6 and 12-week old Apoe KO and Ldlr KO mouse models via unbiased metabolomics to determine which metabolites were affected at an early age to identify those that may play a role in triggering pathology later in life. Steady-state metabolomics revealed only subtle differences among Apoe KO, Ldlr KO and WT mouse brains. Ldlr KO mice exhibited alterations in metabolites involved in neurotransmitter, amino acid and cholesterol metabolism. In contrast, Apoe KO mice only showed subtle changes in amino acid and neurotransmitter metabolism. These subtle changes in a broad range of metabolites indicate that ApoE and Ldl-R alone may not play a significant role in these mouse models at an early age, but instead require the cumulative effect from different pathways that lead to dysfunction at a much later stage of life. PMID: 26686234 [PubMed - as supplied by publisher]

Lactobacillus and Leuconostoc volatilomes in cheese conditions. Appl Microbiol Biotechnol. 2015 Dec 19; Authors: Pogačić T, Maillard MB, Leclerc A, Hervé C, Chuat V, Valence F, Thierry A Abstract New strains are desirable to diversify flavour of fermented dairy products. The objective of this study was to evaluate the potential of Leuconostoc spp. and Lactobacillus spp. in the production of aroma compounds by metabolic fingerprints of volatiles. Eighteen strains, including five Lactobacillus species (Lactobacillus fermentum, Lactobacillus helveticus, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus sakei) and three Leuconostoc species (Leuconostoc citreum, Leuconostoc lactis, and Leuconostoc mesenteroides) were incubated for 5 weeks in a curd-based slurry medium under conditions mimicking cheese ripening. Populations were enumerated and volatile compounds were analysed by headspace trap gas chromatography-mass spectrometry (GC-MS). A metabolomics approach followed by multivariate statistical analysis was applied for data processing and analysis. In total, 12 alcohols, 10 aldehydes, 7 esters, 11 ketones, 5 acids and 2 sulphur compounds were identified. Very large differences in concentration of volatile compounds between the highest producing strains and the control medium were observed in particular for diacetyl, 2-butanol, ethyl acetate, 3-methylbutanol, 3-methylbutanoic acid and 2-methylbutanoic acid. Some of the characterized strains demonstrated an interesting aromatizing potential to be used as adjunct culture. PMID: 26685674 [PubMed - as supplied by publisher]

Related Articles Succinylome analysis reveals the involvement of lysine succinylation in metabolism in pathogenic Mycobacterium tuberculosis. Mol Cell Proteomics. 2015 Apr;14(4):796-811 Authors: Yang M, Wang Y, Chen Y, Cheng Z, Gu J, Deng J, Bi L, Chen C, Mo R, Wang X, Ge F Abstract Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, remains one of the most prevalent human pathogens and a major cause of mortality worldwide. Metabolic network is a central mediator and defining feature of the pathogenicity of Mtb. Increasing evidence suggests that lysine succinylation dynamically regulates enzymes in carbon metabolism in both bacteria and human cells; however, its extent and function in Mtb remain unexplored. Here, we performed a global succinylome analysis of the virulent Mtb strain H37Rv by using high accuracy nano-LC-MS/MS in combination with the enrichment of succinylated peptides from digested cell lysates and subsequent peptide identification. In total, 1545 lysine succinylation sites on 626 proteins were identified in this pathogen. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the central metabolism pathway. Site-specific mutations showed that succinylation is a negative regulatory modification on the enzymatic activity of acetyl-CoA synthetase. Molecular dynamics simulations demonstrated that succinylation affects the conformational stability of acetyl-CoA synthetase, which is critical for its enzymatic activity. Further functional studies showed that CobB, a sirtuin-like deacetylase in Mtb, functions as a desuccinylase of acetyl-CoA synthetase in in vitro assays. Together, our findings reveal widespread roles for lysine succinylation in regulating metabolism and diverse processes in Mtb. Our data provide a rich resource for functional analyses of lysine succinylation and facilitate the dissection of metabolic networks in this life-threatening pathogen. PMID: 25605462 [PubMed - indexed for MEDLINE]

Related Articles Douglas-fir seedlings exhibit metabolic responses to increased temperature and atmospheric drought. PLoS One. 2014;9(12):e114165 Authors: Jansen K, Du B, Kayler Z, Siegwolf R, Ensminger I, Rennenberg H, Kammerer B, Jaeger C, Schaub M, Kreuzwieser J, Gessler A Abstract In the future, periods of strongly increased temperature in concert with drought (heat waves) will have potentially detrimental effects on trees and forests in Central Europe. Norway spruce might be at risk in the future climate of Central Europe. However, Douglas-fir is often discussed as an alternative for the drought and heat sensitive Norway spruce, because some provenances are considered to be well adapted to drier and warmer conditions. In this study, we identified the physiological and growth responses of seedlings from two different Douglas-fir provenances to increased temperature and atmospheric drought during a period of 92 days. We analysed (i) plant biomass, (ii) carbon stable isotope composition as an indicator for time integrated intrinsic water use efficiency, (iii) apparent respiratory carbon isotope fractionation as well as (iv) the profile of polar low molecular metabolites. Plant biomass was only slightly affected by increased temperatures and atmospheric drought but the more negative apparent respiratory fractionation indicated a temperature-dependent decrease in the commitment of substrate to the tricarboxylic acid cycle. The metabolite profile revealed that the simulated heat wave induced a switch in stress protecting compounds from proline to polyols. We conclude that metabolic acclimation successfully contributes to maintain functioning and physiological activity in seedlings of both Douglas-fir provenances under conditions that are expected during heat waves (i.e. elevated temperatures and atmospheric drought). Douglas-fir might be a potentially important tree species for forestry in Central Europe under changing climatic conditions. PMID: 25436455 [PubMed - indexed for MEDLINE]

Related Articles ALLocator: an interactive web platform for the analysis of metabolomic LC-ESI-MS datasets, enabling semi-automated, user-revised compound annotation and mass isotopomer ratio analysis. PLoS One. 2014;9(11):e113909 Authors: Kessler N, Walter F, Persicke M, Albaum SP, Kalinowski J, Goesmann A, Niehaus K, Nattkemper TW Abstract Adduct formation, fragmentation events and matrix effects impose special challenges to the identification and quantitation of metabolites in LC-ESI-MS datasets. An important step in compound identification is the deconvolution of mass signals. During this processing step, peaks representing adducts, fragments, and isotopologues of the same analyte are allocated to a distinct group, in order to separate peaks from coeluting compounds. From these peak groups, neutral masses and pseudo spectra are derived and used for metabolite identification via mass decomposition and database matching. Quantitation of metabolites is hampered by matrix effects and nonlinear responses in LC-ESI-MS measurements. A common approach to correct for these effects is the addition of a U-13C-labeled internal standard and the calculation of mass isotopomer ratios for each metabolite. Here we present a new web-platform for the analysis of LC-ESI-MS experiments. ALLocator covers the workflow from raw data processing to metabolite identification and mass isotopomer ratio analysis. The integrated processing pipeline for spectra deconvolution "ALLocatorSD" generates pseudo spectra and automatically identifies peaks emerging from the U-13C-labeled internal standard. Information from the latter improves mass decomposition and annotation of neutral losses. ALLocator provides an interactive and dynamic interface to explore and enhance the results in depth. Pseudo spectra of identified metabolites can be stored in user- and method-specific reference lists that can be applied on succeeding datasets. The potential of the software is exemplified in an experiment, in which abundance fold-changes of metabolites of the l-arginine biosynthesis in C. glutamicum type strain ATCC 13032 and l-arginine producing strain ATCC 21831 are compared. Furthermore, the capability for detection and annotation of uncommon large neutral losses is shown by the identification of (γ-)glutamyl dipeptides in the same strains. ALLocator is available online at: https://allocator.cebitec.uni-bielefeld.de. A login is required, but freely available. PMID: 25426929 [PubMed - indexed for MEDLINE]

Related Articles Comparison of traditional and commercial vinegars based on metabolite profiling and antioxidant activity. J Microbiol Biotechnol. 2015 Feb;25(2):217-26 Authors: Jang YK, Lee MY, Kim HY, Lee S, Yeo SH, Baek SY, Lee CH Abstract Metabolite profiles of seven commercial vinegars and two traditional vinegars were performed by gas chromatography time-of-flight mass spectrometry with multivariate statistical analysis. During alcohol fermentation, yeast, nuruk, and koji were used as sugars for nutrients and as fermentation substrates. Commercial and traditional vinegars were significantly separated in the principal component analysis and orthogonal partial least square discriminant analysis. Six sugars and sugar alcohols, three organic acids, and two other components were selected as different metabolites. Target analysis by ultra-performance liquid chromatography quadruple-time-of-flight mass spectrometry and liquid chromatographyion trap-mass spectrometry/mass spectrometry were used to detect several metabolites having antioxidant activity, such as cyanidin-3-xylosylrutinoside, cyanidin-3-rutinoside, and quercetin, which were mainly detected in Rural Korean Black raspberry vinegar (RKB). These metabolites contributed to the highest antioxidant activity measured in RKB among the nine vinegars. This study revealed that MS-based metabolite profiling was useful in helping to understand the metabolite differences between commercial and traditional vinegars and to evaluate the association between active compounds of vinegar and antioxidant activity. PMID: 25293630 [PubMed - indexed for MEDLINE]

Related Articles Novel anti-microbial peptide SR-0379 accelerates wound healing via the PI3 kinase/Akt/mTOR pathway. PLoS One. 2014;9(3):e92597 Authors: Tomioka H, Nakagami H, Tenma A, Saito Y, Kaga T, Kanamori T, Tamura N, Tomono K, Kaneda Y, Morishita R Abstract We developed a novel cationic antimicrobial peptide, AG30/5C, which demonstrates angiogenic properties similar to those of LL-37 or PR39. However, improvement of its stability and cost efficacy are required for clinical application. Therefore, we examined the metabolites of AG30/5C, which provided the further optimized compound, SR-0379. SR-0379 enhanced the proliferation of human dermal fibroblast cells (NHDFs) via the PI3 kinase-Akt-mTOR pathway through integrin-mediated interactions. Furthermore SR-0379 promoted the tube formation of human umbilical vein endothelial cells (HUVECs) in co-culture with NHDFs. This compound also displays antimicrobial activities against a number of bacteria, including drug-resistant microbes and fungi. We evaluated the effect of SR-0379 in two different would-healing models in rats, the full-thickness defects under a diabetic condition and an acutely infected wound with full-thickness defects and inoculation with Staphylococcus aureus. Treatment with SR-0379 significantly accelerated wound healing when compared to fibroblast growth factor 2 (FGF2). The beneficial effects of SR-0379 on wound healing can be explained by enhanced angiogenesis, granulation tissue formation, proliferation of endothelial cells and fibroblasts and antimicrobial activity. These results indicate that SR-0379 may have the potential for drug development in wound repair, even under especially critical colonization conditions. PMID: 24675668 [PubMed - indexed for MEDLINE]

Knocking down mitochondrial iron transporter (MIT) reprograms primary and secondary metabolism in rice plants. J Exp Bot. 2015 Dec 17; Authors: Vigani G, Bashir K, Ishimaru Y, Lehmann M, Casiraghi FM, Nakanishi H, Seki M, Geigenberger P, Zocchi G, Nishizawa NK Abstract Iron (Fe) is an essential micronutrient for plant growth and development, and its reduced bioavailability strongly impairs mitochondrial functionality. In this work, the metabolic adjustment in the rice (Oryza sativa) mitochondrial Fe transporter knockdown mutant (mit-2) was analysed. Biochemical characterization of purified mitochondria from rice roots showed alteration in the respiratory chain of mit-2 compared with wild-type (WT) plants. In particular, proteins belonging to the type II alternative NAD(P)H dehydrogenases accumulated strongly in mit-2 plants, indicating that alternative pathways were activated to keep the respiratory chain working. Additionally, large-scale changes in the transcriptome and metabolome were observed in mit-2 rice plants. In particular, a strong alteration (up-/down-regulation) in the expression of genes encoding enzymes of both primary and secondary metabolism was found in mutant plants. This was reflected by changes in the metabolic profiles in both roots and shoots of mit-2 plants. Significant alterations in the levels of amino acids belonging to the aspartic acid-related pathways (aspartic acid, lysine, and threonine in roots, and aspartic acid and ornithine in shoots) were found that are strictly connected to the Krebs cycle. Furthermore, some metabolites (e.g. pyruvic acid, fumaric acid, ornithine, and oligosaccharides of the raffinose family) accumulated only in the shoot of mit-2 plants, indicating possible hypoxic responses. These findings suggest that the induction of local Fe deficiency in the mitochondrial compartment of mit-2 plants differentially affects the transcript as well as the metabolic profiles in root and shoot tissues. PMID: 26685186 [PubMed - as supplied by publisher]

Accumulated metabolites of hydroxybutyric acid serve as diagnostic and prognostic biomarkers of high-grade serous ovarian carcinomas. Cancer Res. 2015 Dec 18; Authors: Hilvo M, de Santiago I, Gopalacharyulu P, Schmitt WD, Budczies J, Kuhberg M, Dietel M, Aittokallio T, Markowetz F, Denkert C, Sehouli J, Frezza C, Darb-Esfahani S, Braicu EI Abstract Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition (EMT) gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities. PMID: 26685161 [PubMed - as supplied by publisher]

Metabolic profiling for the identification of huntington biomarkers by on-line solid-phase extraction capillary electrophoresis mass spectrometry combined with advanced data analysis tools. Electrophoresis. 2015 Dec 18; Authors: Pont L, Benavente F, Jaumot J, Tauler R, Alberch J, Ginés S, Barbosa J, Sanz-Nebot V Abstract In this work, an untargeted metabolomic approach based on sensitive analysis by on-line solid-phase extraction capillary electrophoresis mass spectrometry (SPE-CE-MS) in combination with multivariate data analysis is proposed as an efficient method for the identification of biomarkers of Huntington's disease (HD) progression in plasma. For this purpose, plasma samples from wild type (wt) and HD (R6/1) mice of different ages (8, 12 and 30 weeks), were analysed by C18 -SPE-CE-MS in order to obtain the characteristic electrophoretic profiles of low molecular mass compounds. Then, multivariate curve resolution alternating least squares (MCR-ALS) was applied to the multiple full scan MS data sets. This strategy permitted the resolution of a large number of metabolites being characterised by their electrophoretic peaks and their corresponding mass spectra. A total number of 29 compounds were relevant to discriminate between wt and HD plasma samples, as well as to follow-up the HD progression. The intracellular signalling was found to be the most affected metabolic pathway in HD mice after 12 weeks of birth, when mice already showed motor coordination deficiencies and cognitive decline. This fact agreed with the atrophy and dysfunction of specific neurons, loss of several types of receptors and changed expression of neurotransmitters. This article is protected by copyright. All rights reserved. PMID: 26685060 [PubMed - as supplied by publisher]

Comparative study of comprehensive gas chromatography-nitrogen chemiluminescence detection and gas chromatography-ion trap-tandem mass spectrometry for determining nicotine and carcinogen organic nitrogen compounds in thirdhand tobacco smoke. J Chromatogr A. 2015 Nov 17; Authors: Ramírez N, Vallecillos L, Lewis AC, Borrull F, Marcé RM, Hamilton JF Abstract Thirdhand tobacco smoke (THS) constitutes a poorly understood pathway of exposure of non-smokers, especially toddlers, to tobacco-related carcinogens. However, to date most of the carcinogens present in tobacco smoke have not been detected in THS and, therefore, the significance of THS health risk is still unknown. In this study, we have compared the performance of two analytical methods - one based on gas chromatography coupled to ion trap mass spectrometry detection (GC-IT-MS) and the other on comprehensive two-dimensional gas chromatography coupled to a nitrogen chemiluminescence detector (GC×GC-NCD) - for simultaneously determining, in settled house dust, the presence of 16 organic nitrogen carcinogens already detected in tobacco smoke. The target compounds included four aromatic amines, two nitrocompounds, eight N-nitrosamines and two tobacco-specific nitrosamines, as well as nicotine as a tobacco marker. Dust samples were extracted using in-cell clean up pressurized liquid extraction with silica as clean up sorbent and ethyl acetate as the organic solvent, with average recovery of 89%. Although GC-IT-MS, using chemical ionization with methanol and tandem MS, performed well, the optimized GC×GC-NCD gave lower limits of detection (from 4 to 22ngg(-1)) and better repeatability and reproducibility a low concentration levels (%RSD<8%) and, therefore, was applicable for determining these different groups of carcinogens without the need for derivatization prior to the GC analysis. The performance of the optimized PLE/GC×GC-NCD method was tested by quantifying the target compounds in house dust samples from smokers' and non-smokers' homes. The median carcinogen compounds detected was 3.8μgg(-1) and 1.1μgg(-1) in smokers' and non-smokers' house dust, respectively. In this study, we have detected highly carcinogenic aromatic amines and nitro compounds for the first time in settled house dust complementing the state of knowledge of THS composition and providing fresh evidence about THS health risks. PMID: 26684592 [PubMed - as supplied by publisher]

Prediction of Declining Renal Function and Albuminuria in Patients with Type 2 Diabetes by Metabolomics. J Clin Endocrinol Metab. 2015 Dec 18;:jc20153345 Authors: Solini A, Manca ML, Penno G, Pugliese G, Cobb JE, Ferrannini E Abstract CONTEXT: Renal disease in type 2 diabetes (T2DM) is associated with excess morbidity/mortality. While glomerular filtration rate (eGFR) and albuminuria are routine for assessing renal impairment, novel biomarkers could improve risk stratification and prediction. OBJECTIVE: To identify specific biomarkers of progression of renal dysfunction Design Prospective observational: Setting Academic diabetes clinics Patients: 286 T2DM patients (age 62±8 years, HbA1c 7.2±0.9%, eGFR 85±20 mL(.)min(-1.)1.73m(2)). INTERVENTIONS: None Main Outcome Measures: Progression of eGFR and albuminuria Results: We performed screening metabolomics in serum and urine samples by GC/MS and UPLC/MS/MS. Biomarker identification was performed by random forest using an eGFR cutoff of <60 or an albumin/creatinine (ACR) cutoff of ≥30 mg/g as response variables. At follow-up, eGFR had declined by 16 [9] (median [IQR]) mL(.)min(-1.)1.73m(2) and ACR had increased by 41 [135] mg/g in patients in the respective top quartile of changes from baseline. Clinical parameters (gender, age, fasting glucose, and baseline eGFR) predicted outcome with ROC=0.671. The 5 serum metabolites best correlated with either eGFR<60 or ACR≥30 at baseline were tested for their ability to improve clinical prediction. Sum of C-glycosyltryptophan, pseudouridine, and N-acetylthreonine (MetIndex) raised ROC to 0.739 (p<0.0001). eGFR decline was predicted by the top MetaIndex quartile (OR=5.48 [95%CI=2.23-14.47]. MetIndex also predicted ACR increase with an OR of 2.82[1.20-7.03] and a ROC of 0.750. Top urine metabolites did not add significant predictivity. CONCLUSIONS: A limited number of circulating intermediates of amino acid and nucleotide pathways carry clinically significant predictivity for deterioration of renal function in well-controlled T2DM. PMID: 26684276 [PubMed - as supplied by publisher]

Pro-inflammatory pattern of IgG1 Fc glycosylation in multiple sclerosis cerebrospinal fluid. J Neuroinflammation. 2015;12(1):235 Authors: Wuhrer M, Selman MH, McDonnell LA, Kümpfel T, Derfuss T, Khademi M, Olsson T, Hohlfeld R, Meinl E, Krumbholz M Abstract BACKGROUND: Immunoglobulin G (IgG) effector functions are regulated by the composition of glycans attached to a conserved N-glycosylation site in the Fc part. Intrathecal production of IgG, especially IgG1, is a hallmark of multiple sclerosis (MS), but nothing is known about IgG Fc glycosylation in MS and in cerebrospinal fluid (CSF) in general. METHODS: We applied mass spectrometry of tryptic Fc glycopeptides to analyze IgG Fc glycosylation (sialylation, galactosylation, fucosylation, and bisecting N-acetylglucosamine (GlcNAc)) in 48 paired CSF and serum samples from adult patients with MS or a first demyelinating event highly suggestive of MS (designated as MS cases), and from healthy volunteers and patients with other non-inflammatory diseases (control group). p values were adjusted for multiple testing. RESULTS: Our experiments revealed four main results. First, IgG1 glycosylation patterns were different in CSF vs. serum, in the MS group and even in control donors without intrathecal IgG synthesis. Second, in MS patients vs. controls, IgG1 glycosylation patterns were altered in CSF, but not in serum. Specifically, in CSF from the MS group, bisecting GlcNAc were elevated, and afucosylation and galactosylation were reduced. Elevated bisecting GlcNAc and reduced galactosylation are known to enhance IgG effector functions. Third, hypothesis-free regression analysis revealed that alterations of afucosylation and bisecting GlcNAc in CSF from MS cases peaked 2-3 months after the last relapse. Fourth, CSF IgG1 glycosylation correlated with the degree of intrathecal IgG synthesis and CSF cell count. CONCLUSIONS: The CNS compartment as well as the inflammatory milieu in MS affect IgG1 Fc glycosylation. In MS, the CSF IgG1 glycosylation has features that enhance Fc effector functions. PMID: 26683050 [PubMed - as supplied by publisher]

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