PubMed

6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates heptatocellular carcinoma in rats with NMR-based metabolic perturbations. Future Sci OA. 2017 Aug;3(3):FSO202 Authors: Kumar P, Singh AK, Raj V, Rai A, Maity S, Rawat A, Kumar U, Kumar D, Prakash A, Guleria A, Saha S Abstract AIM: 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) was synthesized and evaluated for in-vivo antiproliferative action in diethylnitrosamine-induced hepatocarcinogenic rats. MATERIALS & METHODS: The antiproliferative effect of M1 was assessed by various biochemical parameters, histopathology of liver and HPLC analysis. Proton nuclear magnetic resonance-based serum metabolic study was implemented on rat sera to explore the effects of M1 on hepatocellular carcinoma-induced metabolic alterations. RESULTS: M1 showed protective action on liver and restored the arrangement of liver tissues in normal proportion. HPLC analysis displayed a good plasma drug concentration after its oral administration. Score plots of partial least squares discriminate analysis models exhibited that M1 therapy ameliorated hepatocellular carcinoma-induced metabolic alterations which signified its antiproliferative potential. CONCLUSION: M1 manifested notable antiproliferative profile, and warrants further investigation for future anticancer therapy. PMID: 28884001 [PubMed]

Lipidomics of human umbilical cord serum: identification of unique sterol sulfates. Future Sci OA. 2017 Aug;3(3):FSO193 Authors: Wood PL, Siljander H, Knip M Abstract AIM: There are currently limited lipidomics data for human umbilical cord blood. Therefore, the lipidomes of cord sera from six newborns and sera from six nonpregnant females were compared. MATERIALS & METHODS: Sera lipidomics analyses were conducted using a high-resolution mass spectrometry analytical platform. RESULTS: Cord serum contained a diverse array of glycerophospholipids, albeit generally at lower concentrations than monitored in adult serum. The unexpected observations were that cord serum contained several neurosteroid sulfates and bile acid sulfates that were not detectable in adult serum. CONCLUSION: Our data are the first to demonstrate that cord serum contains bile acid sulfates that are synthesized early in the hydroxylase, neutral and acidic pathways of primary bile acid biosynthesis and support previous publications of cord blood perfluoralkyl toxins in newborns. PMID: 28883994 [PubMed]

Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study. BMJ Open Respir Res. 2017;4(1):e000183 Authors: Zhao YD, Yin L, Archer S, Lu C, Zhao G, Yao Y, Wu L, Hsin M, Waddell TK, Keshavjee S, Granton J, de Perrot M Abstract INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic pathways in IPF contribute to disease pathogenesis. METHODS: Metabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls. RESULTS: Specific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control. CONCLUSIONS: Our results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF. PMID: 28883924 [PubMed]

Metabolomic profiling for identification of metabolites and relevant pathways for taurine in hepatic stellate cells. World J Gastroenterol. 2017 Aug 21;23(31):5713-5721 Authors: Deng X, Liang XQ, Lu FG, Zhao XF, Fu L, Liang J Abstract AIM: To develop a reliable and simple method to identify important biological metabolites and relevant pathways for taurine in hepatic stellate cells (HSCs), in order to provide more data for taurine therapy. METHODS: All the biological samples were analyzed by using high-performance liquid chromatography-time electrospray ionization/quadrupole-time of flight mass spectrometry. Principal component analysis and partial least squares discriminant analysis were used to identify statistically different metabolites for taurine in HSCs, and metabolomic pathway analysis was used to do pathway analysis for taurine in HSCs. The chemical structure of the related metabolites and pathways was identified by comparing the m/z ratio and ion mode with the data obtained from free online databases. RESULTS: A total of 32 significant differential endogenous metabolites were identified, which may be related to the mechanism of action of taurine in HSCs. Among the seven relevant pathways identified, sphingolipid metabolism pathway, glutathione metabolism pathway and thiamine metabolism pathway were found to be the most important metabolic pathways for taurine in HSCs. CONCLUSION: This study showed that there were distinct changes in biological metabolites of taurine in HSCs and three differential metabolic pathways including sphingolipid pathway, glutathione pathway and thiamine metabolism pathway might be of key importance in mediating the mechanism of action of taurine in HSCs. PMID: 28883696 [PubMed - in process]

Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats. Eur J Pharm Sci. 2017 Sep 04;: Authors: van den Brink WJ, Elassaiss-Schaap J, Gonzalez-Amoros B, Harms AC, van der Graaf PH, Hankemeier T, de Lange ECM Abstract The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride. Remoxipride (vehicle, 0.7 or 3.5mg/kg) was administered to rats. Endogenous metabolites were analyzed in plasma using a biogenic amine platform and PKPD models were derived for each single metabolite. These models were clustered on basis of proximity between their PKPD parameter estimates, and PKPD models were subsequently fitted for the individual clusters. Finally, the metabolites were evaluated for being significantly affected by remoxipride. In total 44 metabolites were detected in plasma, many of them showing a dose dependent decrease from baseline. We identified 6 different clusters with different time and dose dependent responses and 18 metabolites were revealed as potential biomarker. The glycine, serine and threonine pathway was associated with remoxipride pharmacology, as well as the brain uptake of the dopamine and serotonin precursors. This is the first time that pharmacometabolomics and PKPD modeling were integrated. The resulting PKPD cluster model described diverse pharmacometabolomics responses and provided a further understanding of remoxipride pharmacodynamics. Future research should focus on the simultaneous pharmacometabolomics analysis in brain and plasma to increase the interpretability of these responses. PMID: 28882765 [PubMed - as supplied by publisher]

Estimation of time-varying growth, uptake and excretion rates from dynamic metabolomics data. Bioinformatics. 2017 Jul 15;33(14):i301-i310 Authors: Cinquemani E, Laroute V, Cocaign-Bousquet M, de Jong H, Ropers D Abstract Motivation: Technological advances in metabolomics have made it possible to monitor the concentration of extracellular metabolites over time. From these data, it is possible to compute the rates of uptake and excretion of the metabolites by a growing cell population, providing precious information on the functioning of intracellular metabolism. The computation of the rate of these exchange reactions, however, is difficult to achieve in practice for a number of reasons, notably noisy measurements, correlations between the concentration profiles of the different extracellular metabolites, and discontinuties in the profiles due to sudden changes in metabolic regime. Results: We present a method for precisely estimating time-varying uptake and excretion rates from time-series measurements of extracellular metabolite concentrations, specifically addressing all of the above issues. The estimation problem is formulated in a regularized Bayesian framework and solved by a combination of extended Kalman filtering and smoothing. The method is shown to improve upon methods based on spline smoothing of the data. Moreover, when applied to two actual datasets, the method recovers known features of overflow metabolism in Escherichia coli and Lactococcus lactis , and provides evidence for acetate uptake by L. lactis after glucose exhaustion. The results raise interesting perspectives for further work on rate estimation from measurements of intracellular metabolites. Availability and implementation: The Matlab code for the estimation method is available for download at https://team.inria.fr/ibis/rate-estimation-software/ , together with the datasets. Contact: eugenio.cinquemani@inria.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID: 28881984 [PubMed - in process]

MaBoSS 2.0: an environment for stochastic Boolean modeling. Bioinformatics. 2017 Jul 15;33(14):2226-2228 Authors: Stoll G, Caron B, Viara E, Dugourd A, Zinovyev A, Naldi A, Kroemer G, Barillot E, Calzone L Abstract Motivation: Modeling of signaling pathways is an important step towards the understanding and the treatment of diseases such as cancers, HIV or auto-immune diseases. MaBoSS is a software that allows to simulate populations of cells and to model stochastically the intracellular mechanisms that are deregulated in diseases. MaBoSS provides an output of a Boolean model in the form of time-dependent probabilities, for all biological entities (genes, proteins, phenotypes, etc.) of the model. Results: We present a new version of MaBoSS (2.0), including an updated version of the core software and an environment. With this environment, the needs for modeling signaling pathways are facilitated, including model construction, visualization, simulations of mutations, drug treatments and sensitivity analyses. It offers a framework for automated production of theoretical predictions. Availability and Implementation: MaBoSS software can be found at https://maboss.curie.fr , including tutorials on existing models and examples of models. Contact: gautier.stoll@upmc.fr or laurence.calzone@curie.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID: 28881959 [PubMed - in process]

Related Articles Isolation and characterization of exosomes derived from fertile sheep hydatid cysts. Vet Parasitol. 2017 Mar 15;236:22-33 Authors: Siles-Lucas M, Sánchez-Ovejero C, González-Sánchez M, González E, Falcón-Pérez JM, Boufana B, Fratini F, Casulli A, Manzano-Román R Abstract Cystic echinococcosis (CE) is a chronic and complex zoonotic disease. Information on the mechanisms involved in parasite establishment, growth and persistence remain limited. These may be modulated by a crosstalk between extracellular vesicles (EVs). EVs including exosomes and microvesicles are able to carry developmental signaling proteins which coordinate growth and establishment of several parasites. Here, an exosome enriched EV fraction was isolated from hydatid fluid (HF) of fertile sheep cysts. A proteomic analysis of this fraction identified a number of parasite-derived vesicle-membrane associated proteins as well as cytosolic proteins. Additionally, the exosomal enriched fraction contained proteins of host origin. Specific proteins -antigen B2 and TSPAN14- in the exosomal fraction were further assayed by immunoblot and transmission electron microscopy. To the best of our knowledge, this is the first report on the presence of parasite exosomes in fertile hydatid cyst fluid. Further characterization of the exosome cargo will allow the discovery of new markers for the detection of CE in humans and animals, and the treatment of CE patients, and provide new insights regarding the role of these EVs in the establishment and persistence of hydatid cysts. PMID: 28288760 [PubMed - indexed for MEDLINE]

Related Articles Simultaneous quantitation of hydrazine and acetylhydrazine in human plasma by high performance liquid chromatography-tandem mass spectrometry after derivatization with p-tolualdehyde. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Aug 30;1063:189-195 Authors: Song L, Gao D, Li S, Wang Y, Liu H, Jiang Y Abstract A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for simultaneous quantitative analysis of hydrazine and acetylhydrazine in human plasma based on the strategy of p-tolualdehyde derivatization. The derivatization reactions were easily realized by ultrasonic manipulation for 40min. Good separation of the derivatization products was achieved using a C18 column by gradient elution. The optimized mass transition ion-pairs (m/z) monitored for the two hydrazine derivatives were m/z 237.1≫>119.9 and m/z 176.9≫>117.8, respectively. The limit of detection (LOD) and limit of quantification (LOQ) for hydrazine were 0.002 and 0.005ngmL(-1) separately. And they were 0.03 and 0.05ngmL(-1) for acetylhydrazine, respectively. The linear range was 0.005-50ngmL(-1) for hydrazine and 0.05-500ngmL(-1) for acetylhydrazine with R(2) greater than 0.999. The recovery range was determined to be 95.38-108.12% with the relative standard deviation (RSD) in the range of 1.24-14.89%. The method was successfully applied to detect 30 clinical plasma samples of pulmonary tuberculosis patients treated with isoniazid. The concentrations were from 0.04-1.99ngmL(-1) for hydrazine and 0.06-142.43ngmL(-1) for acetylhydrazine. The results indicated that our developed method had the potential for the detection of hydrazine toxicology in complex biological samples. Furthermore, the method has an important significance to clinical treatment with drugs. PMID: 28881295 [PubMed - as supplied by publisher]

Related Articles Assessing biological effects of fluoxetine in developing zebrafish embryos using gas chromatography-mass spectrometry based metabolomics. Chemosphere. 2017 Aug 31;188:157-167 Authors: Mishra P, Gong Z, Kelly BC Abstract Continuous low-dose exposure of pharmaceutically active compounds (PhACs) in aquatic ecosystems is a concern worldwide. In this study, we utilized a gas chromatography mass spectrometry (GC-MS) based metabolomics approach to assess endogenous metabolite changes in developing zebrafish embryos exposed to different concentrations of the widely used antidepressant, fluoxetine. Embryos were exposed from 2 h post fertilization (hpf) until 96 hpf. Using the Fiehn GC-MS library, a total of 31 metabolites were positively identified in embryos. Statistical analyses revealed significant dysregulation of 11 metabolites in fluoxetine exposed embryos. Metabolite classes that were significantly altered included, amino acids, monosaccharides, glycerophosphates, fatty acids, carboxylic acid derivatives and sugars. Concentrations of amino acids, maltose, d-malic acid, 3-phosphoglycerate and d-glucose were significantly reduced in exposed embryos. Conversely, concentrations of citric acid were in some cases significantly elevated in exposed embryos. Metabolic pathway analysis revealed perturbation of five main pathways, including (i) alanine, aspartate and glutamate metabolism, (ii) phenylalanine, tyrosine and tryptophan biosynthesis, (iii) phenylalanine metabolism. (iv) tyrosine metabolism and (v) starch and sucrose metabolism. The results indicate fluoxetine exposure causes perturbation of energy and amino acid metabolism, which may adversely impact embryogenesis due to depletion of energy reserves during this period. Also, the observed alterations in aspartic acid, phenylalanine and tyrosine in fluoxetine exposed embryos suggests potential disruption of normal neurobehavioral and liver function. The results further demonstrate that GC-MS based metabolomics is an effective approach for assessing toxicodynamics and threshold effect levels of environmental pollutants in aquatic organisms. PMID: 28881243 [PubMed - as supplied by publisher]

Related Articles Metabolomics applied to islet nutrient sensing mechanisms. Diabetes Obes Metab. 2017 Sep;19 Suppl 1:90-94 Authors: Jensen MV, Gooding JR, Ferdaoussi M, Dai XQ, Peterson BS, MacDonald PE, Newgard CB Abstract After multiple decades of investigation, the precise mechanisms involved in fuel-stimulated insulin secretion are still being revealed. One avenue for gaining deeper knowledge is to apply emergent tools of "metabolomics," involving mass spectrometry and nuclear magnetic resonance-based profiling of islet cells in their fuel-stimulated compared with basal states. The current article summarizes recent insights gained from application of metabolomics tools to the specific process of glucose-stimulated insulin secretion, revealing 2 new mechanisms that may provide targets for improving insulin secretion in diabetes. PMID: 28880482 [PubMed - in process]

Related Articles Profiling novel metabolic biomarkers for Parkinson's disease using in-depth metabolomic analysis. Mov Disord. 2017 Sep 07;: Authors: Han W, Sapkota S, Camicioli R, Dixon RA, Li L Abstract OBJECTIVE: To profile the amine/phenol submetabolome to determine potential metabolite biomarkers associated with Parkinson's disease (PD) and PD with incipient dementia. METHODS: At baseline of a 3-wave (18-month intervals) longitudinal study, serum samples were collected from 42 healthy controls and 43 PD patients. By wave 3 (year 3), 16 PD patients were diagnosed with dementia and were classified as PD with incipient dementia at baseline. Metabolomic profiling using dansylation isotope labeling liquid chromatography mass spectrometry was conducted to compare controls with the full PD, PD with no dementia, and PD with incipient dementia groups. RESULTS: Metabolomic analyses detected 719 common metabolites in 80% of the samples. Some were significantly altered in pairwise comparison of different groups (fold change of >1.2 or <0.83 with q < 0.05). We discriminated PD and controls by using a 5-metabolite panel, vanillic acid, 3-hydroxykynurenine, isoleucyl-alanine, 5-acetylamino-6-amino-3-methyluracil, and theophylline. The receiver operating characteristic curve produced an area-under-the-curve value of 0.955 with 87.5% sensitivity and 93.0% specificity. In comparing PD with no dementia with PD with incipient dementia, we used an 8-metabolite panel, His-Asn-Asp-Ser, 3,4-dihydroxyphenylacetone, desaminotyrosine, hydroxy-isoleucine, alanyl-alanine, putrescine [-2H], purine [+O] and its riboside. This produced an area-under-the-curve value of 0.862 with 80.0% sensitivity and 77.0% specificity. CONCLUSIONS: The significantly altered metabolites can be used to differentiate (1) PD patients from healthy controls with high accuracy and (2) the stable PD with no dementia group from those with incipient dementia. Following further validation in larger cohorts, these metabolites could be used for both discrimination and establishing prognosis in PD. © 2017 International Parkinson and Movement Disorder Society. PMID: 28880465 [PubMed - as supplied by publisher]

Related Articles New Protocol Based on UHPLC-MS/MS for Quantitation of Metabolites in Xylose-Fermenting Yeasts. J Am Soc Mass Spectrom. 2017 Sep 06;: Authors: Campos CG, Veras HCT, de Aquino Ribeiro JA, Costa PPKG, Araújo KP, Rodrigues CM, de Almeida JRM, Abdelnur PV Abstract Xylose fermentation is a bottleneck in second-generation ethanol production. As such, a comprehensive understanding of xylose metabolism in naturally xylose-fermenting yeasts is essential for prospection and construction of recombinant yeast strains. The objective of the current study was to establish a reliable metabolomics protocol for quantification of key metabolites of xylose catabolism pathways in yeast, and to apply this protocol to Spathaspora arborariae. Ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was used to quantify metabolites, and afterwards, sample preparation was optimized to examine yeast intracellular metabolites. S. arborariae was cultivated using xylose as a carbon source under aerobic and oxygen-limited conditions. Ion pair chromatography (IPC) and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were shown to efficiently quantify 14 and 5 metabolites, respectively, in a more rapid chromatographic protocol than previously described. Thirteen and eleven metabolites were quantified in S. arborariae under aerobic and oxygen-limited conditions, respectively. This targeted metabolomics protocol is shown here to quantify a total of 19 metabolites, including sugars, phosphates, coenzymes, monosaccharides, and alcohols, from xylose catabolism pathways (glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle) in yeast. Furthermore, to our knowledge, this is the first time that intracellular metabolites have been quantified in S. arborariae after xylose consumption. The results indicated that fine control of oxygen levels during fermentation is necessary to optimize ethanol production by S. arborariae. The protocol presented here may be applied to other yeast species and could support yeast genetic engineering to improve second generation ethanol production. Graphical Abstract ᅟ. PMID: 28879550 [PubMed - as supplied by publisher]

Related Articles Spontaneous miscarriage in first trimester pregnancy is associated with altered urinary metabolite profile. BBA Clin. 2017 Dec;8:48-55 Authors: Ku CW, Tan ZW, Lim MK, Tam ZY, Lin CH, Ng SP, Allen JC, Lek SM, Tan TC, Tan NS Abstract Threatened miscarriage is the most common gynecological emergency, occurring in about 20% of pregnant women. Approximately one in four of these patients go on to have spontaneous miscarriage and the etiology of miscarriage still remains elusive. In a bid to identify possible biomarkers and novel treatment targets, many studies have been undertaken to elucidate the pathways that lead to a miscarriage. Luteal phase deficiency has been shown to contribute to miscarriages, and the measurement of serum progesterone as a prognostic marker and the prescription of progesterone supplementation has been proposed as possible diagnostic and treatment methods. However, luteal phase deficiency only accounts for 35% of miscarriages. In order to understand the other causes of spontaneous miscarriage and possible novel urine biomarkers for miscarriage, we looked at the changes in urinary metabolites in women with threatened miscarriage. To this end, we performed a case-control study of eighty patients who presented with threatened miscarriage between 6 and 10 weeks gestation. Urine metabolomics analyses of forty patients with spontaneous miscarriages and forty patients with ongoing pregnancies at 16 weeks gestation point to an impaired placental mitochondrial β-oxidation of fatty acids as the possible cause of spontaneous miscarriage. This study also highlighted the potential of urine metabolites as a non-invasive screening tool for the risk stratification of women presenting with threatened miscarriage. PMID: 28879096 [PubMed]

Related Articles Serum metabolites in non-alcoholic fatty-liver disease development or reversion; a targeted metabolomic approach within the PREDIMED trial. Nutr Metab (Lond). 2017;14:58 Authors: Papandreou C, Bullò M, Tinahones FJ, Martínez-González MÁ, Corella D, Fragkiadakis GA, López-Miranda J, Estruch R, Fitó M, Salas-Salvadó J Abstract BACKGROUND: Limited prospective studies have examined changes in non-alcoholic fatty-liver disease (NAFLD) related serum-metabolites and none the effects of NAFLD-reversion. We aimed to evaluate whether perturbations in metabolites indicate predisposition to NAFLD development and to assess the effects of NAFLD reversion on metabolite profiles. METHODS: A targeted liquid-chromatography tandem mass-spectrometry metabolic profiling (n = 453 metabolites) approach was applied, using serum from 45 subjects of the PREDIMED study, at baseline and after a median 3.8-year follow-up. NAFLD was determined using the hepatic steatosis index; with three groups classified and studied: Group 1, not characterized as NAFLD cases during the follow-up (n = 15); Group 2, characterized as NAFLD during the follow-up (n = 15); Group 3, characterized as NAFLD-reversion during the follow-up (n = 15). RESULTS: At baseline, significantly lower storage and transport lipids (triacylglycerols and cholesteryl esters), several monoetherglycerophosphocholines, acylglycerophosphocholines, ceramides and ceramide to sphingomyelin ratio (P < 0.05), were found; whereas a higher L-cystine to L-glutamate ratio (P < 0.05) was observed, in group 2 as compared to group 1.P-ether acylglycerophosphocholines, ceramides and sphingolipids were significantly different betweengroup 3 and group 1 (P < 0.05). Higher 16:1n-7 to 16:0, and 18:0 to16:0 ratio (P < 0.05), while lower 18:1n-9 to 18:0, 16:0 to 18:2n-6, and 18:3n-6 to 18:2n-6 ratio (P < 0.05) were observed in the final, compared to baseline values, in groups 2 and 3. CONCLUSION: The rearrangement of lipid biosynthesis and serum transport may indicate predisposition to NAFLD development. Despite an expected reduction of hepatic lipotoxicity and improved hepatic function in the participants of the study characterized as NAFLD-reversing, the side effects of NAFLD in serum metabolic profiles remained present. TRIAL REGISTRATION: The trial is registered at ISRCTN35739639. Registration date: 5th October 2005. PMID: 28878811 [PubMed]

Related Articles Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells. Sci Rep. 2017 Sep 06;7(1):10632 Authors: Chornyy S, Parkhomenko Y, Chorna N Abstract Accumulating evidences suggest that p53 is a key coordinator of cellular events triggered by oxidative stress often associated with the impairment in thiamine metabolism and its functions. However, there are limited data regarding the pursuant feedback between p53 transactivation and thiamine homeostasis. Impairment in thiamine metabolism can be induced experimentally via interference with the thiamine uptake and/or inhibition of the thiamin pyrophosphate-dependent enzymes using thiamine antagonists - amprolium (AM), oxythiamine (OT) or pyrithiamine (PT). We found that exposure of neuronally differentiated SH-SY5Y cells to AM, OT and PT triggered upregulation of p53 gene expression, post-translational modification of p53 via phosphorylation and activation of p53 DNA-binding activity. Phosphorylation of p53 at Ser20 was equally efficient in upregulation of thiamine transporter 1 (THTR1) by all antagonists. However, induction of the expressions of the pyruvate dehydrogenase E1 component subunit beta (PDHB) and oxoglutarate dehydrogenase (OGDH) required dual phosphorylation of p53 at Ser9 and Ser20, seen in cells treated with PT and OT. Moreover, pretreatment of the cells with a decoy oligonucleotide carrying wild-type p53-response element markedly attenuated OT-induced THTR1, PDHB and OGDH gene expression suggesting an important role of p53 in transactivation of these genes. Finally, analysis of gene and metabolic networks showed that OT triggers cell apoptosis through the p53-dependent intrinsic pathway. PMID: 28878400 [PubMed - in process]

Related Articles Non-Polar Natural Products from Bromelia laciniosa, Neoglaziovia variegata and Encholirium spectabile (Bromeliaceae). Molecules. 2017 Sep 06;22(9): Authors: Juvik OJ, Holmelid B, Francis GW, Lie Andersen H, de Oliveira AP, Gonçalves de Oliveira Júnior R, Guedes da Silva Almeida JR, Fossen T Abstract Extensive regional droughts are already a major problem on all inhabited continents and severe regional droughts are expected to become an increasing and extended problem in the future. Consequently, extended use of available drought resistant food plants should be encouraged. Bromelia laciniosa , Neoglaziovia variegata and Encholirium spectabile are excellent candidates in that respect because they are established drought resistant edible plants from the semi-arid Caatinga region. From a food safety perspective, increased utilization of these plants would necessitate detailed knowledge about their chemical constituents. However, their chemical compositions have previously not been determined. For the first time, the non-polar constituents of B. laciniosa , N. variegata and E. spectabile have been identified. This is the first thorough report on natural products from N. variegata , E. spectabile , and B. laciniosa . Altogether, 20 non-polar natural products were characterized. The identifications were based on hyphenated gas chromatography-high resolution mass spectrometry (GC-HRMS) and supported by 1D and 2D Nuclear Magnetic Resonance (NMR) plant metabolomics. PMID: 28878176 [PubMed - in process]

Related Articles Metabolomics Analysis of Urine Samples from Children after Acetaminophen Overdose. Metabolites. 2017 Sep 06;7(3): Authors: Schnackenberg LK, Sun J, Bhattacharyya S, Gill P, James LP, Beger RD Abstract Acetaminophen (APAP), a commonly used over-the-counter analgesic, accounts for approximately fifty percent of the cases of acute liver failure (ALF) in the United States due to overdose, with over half of those unintentional. Current clinical approaches for assessing APAP overdose rely on identifying the precise time of overdose and quantitating acetaminophen alanine aminotransferase (ALT) levels in peripheral blood. Novel specific and sensitive biomarkers may provide additional information regarding patient status post overdose. Previous non-clinical metabolomics studies identified potential urinary biomarkers of APAP-induced hepatotoxicity and metabolites involved pathways of tricarboxylic acid cycle, ketone metabolism, and tryptophan metabolism. In this study, biomarkers identified in the previous non-clinical study were evaluated in urine samples collected from healthy subjects ( N = 6, median age 14.08 years) and overdose patients ( N = 13, median age 13.91 years) as part of an IRB-approved multicenter study of APAP toxicity in children. The clinical results identified metabolites from pathways previously noted, and pathway analysis indicated analogous pathways were significantly altered in both the rats and humans after APAP overdose. The results suggest a metabolomics approach may enable the discovery of specific, translational biomarkers of drug-induced hepatotoxicity that may aid in the assessment of patients. PMID: 28878168 [PubMed]

Related Articles NAD metabolism fuels human and mouse intestinal inflammation. Gut. 2017 Sep 06;: Authors: Gerner RR, Klepsch V, Macheiner S, Arnhard K, Adolph TE, Grander C, Wieser V, Pfister A, Moser P, Hermann-Kleiter N, Baier G, Oberacher H, Tilg H, Moschen AR Abstract OBJECTIVE: Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism. DESIGN: We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD. RESULTS: FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1(-⁄-) mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10. CONCLUSION: Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation. PMID: 28877980 [PubMed - as supplied by publisher]

Related Articles Randomized controlled trial on the impact of early-life intervention with bifidobacteria on the healthy infant fecal microbiota and metabolome. Am J Clin Nutr. 2017 Sep 06;: Authors: Bazanella M, Maier TV, Clavel T, Lagkouvardos I, Lucio M, Maldonado-Gòmez MX, Autran C, Walter J, Bode L, Schmitt-Kopplin P, Haller D Abstract Background: Early-life colonization of the intestinal tract is a dynamic process influenced by numerous factors. The impact of probiotic-supplemented infant formula on the composition and function of the infant gut microbiota is not well defined.Objective: We sought to determine the effects of a bifidobacteria-containing formula on the healthy human intestinal microbiome during the first year of life.Design: A double-blind, randomized, placebo-controlled study of newborn infants assigned to a standard whey-based formula containing a total of 10(8) colony-forming units (CFU)/g of Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, B. longum subspecies infantis (intervention), or to a control formula without bifidobacteria (placebo). Breastfed controls were included. Diversity and composition of fecal microbiota were determined by 16S ribosomal RNA gene amplicon sequencing, and metabolite profiles were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry over a period of 2 y.Results: Infants (n = 106) were randomly assigned to either the interventional (n = 48) or placebo (n = 49) group; 9 infants were exclusively breastfed throughout the entire intervention period of 12 mo. Infants exposed to bifidobacteria-supplemented formula showed decreased occurrence of Bacteroides and Blautia spp. associated with changes in lipids and unknown metabolites at month 1. Microbiota and metabolite profiles of intervention and placebo groups converged during the study period, and long-term colonization (24 mo) of the supplemented Bifidobacterium strains was not detected. Significant differences in microbiota and metabolites were detected between infants fed breast milk and those fed formula (P < 0.005) and between infants birthed vaginally and those birthed by cesarean delivery (P < 0.005). No significant differences were observed between infant feeding groups regarding growth, antibiotic uptake, or other health variables (P > 0.05).Conclusion: The supplementation of bifidobacteria to infant diet can modulate the occurrence of specific bacteria and metabolites during early life with no detectable long-term effects. This trial was registered at germanctr.de as DRKS00003660. PMID: 28877893 [PubMed - as supplied by publisher]