PubMed

Related Articles Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D3 administration. Metabolism. 2017 May;70:31-41 Authors: Alvarez JA, Chong EY, Walker DI, Chandler JD, Michalski ES, Grossmann RE, Uppal K, Li S, Frediani JK, Tirouvanziam R, Tran VT, Tangpricha V, Jones DP, Ziegler TR Abstract BACKGROUND: Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown. OBJECTIVE: We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation. DESIGN: Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation. RESULTS: Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways-predominantly representing amino acid pathways-differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment. CONCLUSIONS: Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting. PMID: 28403943 [PubMed - in process]

Related Articles Determining the presence of asthma-related molecules and salivary contamination in exhaled breath condensate. Respir Res. 2017 Apr 12;18(1):57 Authors: Cruickshank-Quinn C, Armstrong M, Powell R, Gomez J, Elie M, Reisdorph N Abstract BACKGROUND: Researchers investigating lung diseases, such as asthma, have questioned whether certain compounds previously reported in exhaled breath condensate (EBC) originate from saliva contamination. Moreover, despite its increasing use in 'omics profiling studies, the constituents of EBC remain largely uncharacterized. The present study aims to define the usefulness of EBC in investigating lung disease by comparing EBC, saliva, and saliva-contaminated EBC using targeted and untargeted mass spectrometry and the potential of metabolite loss from adsorption to EBC sample collection tubes. METHODS: Liquid chromatography mass spectrometry (LC-MS) was used to analyze samples from 133 individuals from three different cohorts. Levels of amino acids and eicosanoids, two classes of molecules previously reported in EBC and saliva, were measured using targeted LC-MS. Cohort 1 was used to examine contamination of EBC by saliva. Samples from Cohort 1 consisted of clean EBC, saliva-contaminated EBC, and clean saliva from 13 healthy volunteers; samples were analyzed using untargeted LC-MS. Cohort 2 was used to compare eicosanoid levels from matched EBC and saliva collected from 107 asthmatic subjects. Samples were analyzed using both targeted and untargeted LC-MS. Cohort 3 samples consisted of clean-EBC collected from 13 subjects, including smokers and non-smokers, and were used to independently confirm findings; samples were analyzed using targeted LC-MS, untargeted LC-MS, and proteomics. In addition to human samples, an in-house developed nebulizing system was used to determine the potential for EBC samples to be contaminated by saliva. RESULTS: Out of the 400 metabolites detected in both EBC and saliva, 77 were specific to EBC; however, EBC samples were concentrated 20-fold to achieve this level of sensitivity. Amino acid concentrations ranged from 196 pg/mL - 4 μg/mL (clean EBC), 1.98 ng/mL - 6 μg/mL (saliva-contaminated EBC), and 13.84 ng/mL - 1256 mg/mL (saliva). Eicosanoid concentration ranges were an order of magnitude lower; 10 pg/mL - 76.5 ng/mL (clean EBC), 10 pg/mL - 898 ng/mL (saliva-contaminated EBC), and 2.54 ng/mL - 272.9 mg/mL (saliva). Although the sample size of the replication cohort (Cohort 3) did not allow for statistical comparisons, two proteins and 19 eicosanoids were detected in smoker vs. non-smoker clean-EBC. CONCLUSIONS: We conclude that metabolites are present and detectable in EBC using LC-MS; however, a large starting volume of sample is required. PMID: 28403875 [PubMed - in process]

Related Articles The Use of High-Resolution Metabolomics in Occupational Exposure and Health Research. Ann Work Expo Health. 2017 May 01;61(4):395-397 Authors: Vermeulen R PMID: 28403429 [PubMed - in process]

Related Articles Brain metabolomic profiling of eastern honey bee (Apis cerana) infested with the mite Varroa destructor. PLoS One. 2017;12(4):e0175573 Authors: Wu JL, Zhou CX, Wu PJ, Xu J, Guo YQ, Xue F, Getachew A, Xu SF Abstract The mite Varroa destructor is currently the greatest threat to apiculture as it is causing a global decrease in honey bee colonies. However, it rarely causes serious damage to its native hosts, the eastern honey bees Apis cerana. To better understand the mechanism of resistance of A. cerana against the V. destructor mite, we profiled the metabolic changes that occur in the honey bee brain during V. destructor infestation. Brain samples were collected from infested and control honey bees and then measured using an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based global metabolomics method, in which 7918 and 7462 ions in ESI+ and ESI- mode, respectively, were successfully identified. Multivariate statistical analyses were applied, and 64 dysregulated metabolites, including fatty acids, amino acids, carboxylic acid, and phospholipids, amongst others, were identified. Pathway analysis further revealed that linoleic acid metabolism; propanoate metabolism; and glycine, serine, and threonine metabolism were acutely perturbed. The data obtained in this study offer insight into the defense mechanisms of A. cerana against V. destructor mites and provide a better method for understanding the synergistic effects of parasitism on honey bee colonies. PMID: 28403242 [PubMed - in process]

Related Articles FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice. Cell Rep. 2017 Apr 11;19(2):255-266 Authors: Hirano A, Braas D, Fu YH, Ptáček LJ Abstract The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals. PMID: 28402850 [PubMed - in process]

Related Articles Influences of Normalization Method on Biomarker Discovery in Gas Chromatography-Mass Spectrometry Based Untargeted Metabolomics: What Should be Considered? Anal Chem. 2017 Apr 12;: Authors: Chen J, Zhang P, Lv M, Guo H, Huang Y, Zhang Z, Xu F Abstract Data reduction techniques in Gas Chromatography-Mass Spectrometry based untargeted metabolomics has made the following workflow of data analysis more lucid. However, the normalization process still perplexes researchers and its effects are always ignored. In order to reveal the influences of normalization method, five representative normalization methods (Mass Spectrometry Total Useful Signal, Median, Probabilistic Quotient Normalization, Remove Unwanted Variation-random and Systematic Ratio Normalization) were compared in three real datasets with different types. First, data reduction techniques were used to refine the original data. Then QC samples and relative log abundance plots were utilized to evaluate the unwanted variations and the efficiencies of normalization process. Furthermore, the potential biomarkers which were screened out by Mann-Whitney U test, receiver operating characteristic curve analysis, Random Forest and feature selection algorithm Boruta in different normalized datasets were compared. The results indicated the determination of normalization method was difficult since the commonly accepted rules were easy to fulfill, but different normalization methods had un-foreseen influences on both the kind and number of potential biomarkers. So finally, an integrated strategy for normalization method selection was recommended. PMID: 28402628 [PubMed - as supplied by publisher]

Related Articles Lipidomics of equine sperm and seminal plasma: Identification of amphiphilic (O-acyl)-ω-hydroxy-fatty acids. Theriogenology. 2016 Sep 15;86(5):1212-21 Authors: Wood PL, Scoggin K, Ball BA, Troedsson MH, Squires EL Abstract Using a nontargeted lipidomics analysis of equine sperm and seminal plasma, we were able to characterize a diverse array of individual lipids including ethanolamine and choline ether lipids and seminolipids essential to membrane raft function. We also detected, for the first time in sperm, the presence of (O-acyl)-ω-hydroxy-fatty acids (OAHFA) with up to 52 carbon chain lengths, which were localized to the head and not the tail of sperm. The only previous identification of OAHFAs has been in meibomian glands and their sebaceous secretions. The identities of these lipid amphiphiles were validated both by high-resolution mass spectrometry and by tandem mass spectrometry (<1 ppm mass error), which identified the fatty acid (FA) and hydroxy-FA components of individual OAHFAs. The amphiphilic and surfactant properties of these unique lipids could provide an interface between the complex lipid layers of the acrosome and the aqueous environment of the suspending seminal plasma. The potential roles of OAHFAs in orientation of critical proteins in the acrosomal membrane also remain to be explored with these new findings. Another unique finding of our lipidomics study was that phosphatidylethanolamines with mono- or di-unsaturated FA substitutions are present in seminal plasma but not in sperm suggesting a potential role of these glycerophospholipids in sperm capacitation and protecting sperm cells in the female reproductive tract. In summary, we have identified for the first time, the presence of OAHFAs in sperm and several phosphatidylethanolamines in seminal plasma, suggesting that these complex lipids may play critical roles in sperm function. PMID: 27180330 [PubMed - indexed for MEDLINE]

Related Articles mzML2ISA & nmrML2ISA: generating enriched ISA-Tab metadata files from metabolomics XML data. Bioinformatics. 2017 Apr 07;: Authors: Larralde M, Lawson TN, Weber RJ, Moreno P, Haug K, Rocca-Serra P, Viant MR, Steinbeck C, Salek RM Abstract Summary: Submission to the MetaboLights repository for metabolomics data currently places the burden of reporting instrument and acquisition parameters in ISA-Tab format on users, who have to do it manually, a process that is time consuming and prone to user input error. Since the large majority of these parameters are embedded in instrument raw data files, an opportunity exists to capture this metadata more accurately. Here we report a set of Python packages that can automatically generate ISA-Tab metadata file stubs from raw XML metabolomics data files. The parsing packages are separated into mzML2ISA (encompassing mzML and imzML formats) and nmrML2ISA (nmrML format only). Overall, the use of mzML2ISA & nmrML2ISA reduces the time needed to capture metadata substantially (capturing 90% of metadata on assay and sample levels), is much less prone to user input errors, improves compliance with minimum information reporting guidelines and facilitates more finely grained data exploration and querying of datasets. Availability and Implementation: mzML2ISA & nmrML2ISA are available under version 3 of the GNU General Public Licence at https://github.com/ISA-tools . Documentation is available from http://2isa.readthedocs.io/en/latest/ . Contact: reza.salek@ebi.ac.uk or isatools@googlegroups.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID: 28402395 [PubMed - as supplied by publisher]

Related Articles MetCirc: Navigating mass spectral similarity in high-resolution MS/MS metabolomics data. Bioinformatics. 2017 Apr 11;: Authors: Naake T, Gaquerel E Abstract Summary: Among the main challenges in metabolomics are the rapid dereplication of previously characterized metabolites across a range of biological samples and the structural prediction of unknowns from MS/MS data. Here, we developed MetCirc to comprehensively align and calculate pairwise similarity scores among MS/MS spectral data and visualize these across a range of biological samples. MetCirc comprises functionalities to interactively organize these data according to compound familial groupings and to accelerate the discovery of shared metabolites and hypothesis formulation for unknowns. As such, MetCirc provides a significant advance to address biological questions in areas where chemodiversity plays a role. Availability and Implementation: MetCirc, implemented in the open-source R language, together with its vignette are available in the Bioconductor project and at https://github.com/PlantDefenseMetabolism/MetCirc. Contact: thomasnaake@googlemail.com or emmanuel.gaquerel@cos.uni -heidelberg.de. Supplementary information: MS/MS data available with the R package are part of a larger published data-set and available at the open metabolomics database Metabolights, www.ebi.ac.uk (accession no. MTBLS335). An R script to reproduce the circular layout of the figure in the manuscript isavailable at Bioinformatics online. PMID: 28402393 [PubMed - as supplied by publisher]

Related Articles Culturomics: A New Kid on the Block of OMICS to Enable Personalized Medicine. OMICS. 2017 Apr 12;: Authors: Kambouris ME, Pavlidis C, Skoufas E, Arabatzis M, Kantzanou M, Velegraki A, Patrinos GP Abstract This innovation analysis highlights the underestimated and versatile potential of the new field of culturomics and examines its relation to other OMICS system sciences such as infectiomics, metabolomics, phenomics, and pharmacomicrobiomics. The advent of molecular biology, followed by the emergence of various disciplines of the genomics, and most importantly metagenomics, brought about the sharp decline of conventional microbiology methods. Emergence of culturomics has a natural synergy with therapeutic and clinical genomic approaches so as to realize personalized medicine. Notably, the concept of culturomics expands on that of phenomics and allows a reintroduction of the culture-based phenotypic characterization into the 21st century research repertoire, bolstered by robust technology for automated and massive execution, but its potential is largely unappreciated at present; the few available references show unenthusiastic pursuit and in narrow applications. This has not to be so: depending on the specific brand of culturomics, the scope of applications may extend to medicine, agriculture, environmental sciences, pharmacomicrobiomics, and biotechnology innovation. Moreover, culturomics may produce Big Data. This calls for a new generation of data scientists and innovative ways of harnessing and valorizing Big Data beyond classical genomics. Much more detailed and objective classification and identification of microbiota may soon be at hand through culturomics, thus enabling precision diagnosis toward truly personalized medicine. Culturomics may both widen the scope of microbiology and improve its contributions to diagnostics and personalized medicine, characterizing microbes and determining their associations with health and disease dynamics. PMID: 28402209 [PubMed - as supplied by publisher]

Related Articles Metabolomics reveals new metabolic perturbations in children with type 1 diabetes. Pediatr Diabetes. 2017 Apr 12;: Authors: Galderisi A, Pirillo P, Moret V, Stocchero M, Gucciardi A, Perilongo G, Moretti C, Monciotti C, Giordano G, Baraldi E Abstract OBJECTIVE: Using an untargeted metabolomics approach we investigated the metabolome of children with type 1 diabetes (T1D) in comparison with healthy peers and explored the contribution of HbA1c and clinical features to the observed difference. RESEARCH DESIGN AND METHODS: We enrolled children with T1D aged 6-15 years, attending the pediatric diabetes clinic of University of Padova (Italy). Healthy controls were enrolled on voluntary basis and matched for age, sex, pubertal status, body mass index (BMI). We performed a liquid chromatography and mass spectrometry analysis (LC-MS) on fasting urinary samples of the 2 groups. RESULTS: A total of 56 patients with T1D aged (11.4 ± 2.2) years, and 30 healthy controls (10.7 ± 2.8) years were enrolled. We identified 59 urinary metabolites having a higher level in children with T1D, mainly represented by gluco- and mineralcorticoids, phenylalanine and tryptophan catabolites (kynurenine), small peptides, glycerophospholipids, fatty acids, and gut bacterial products. We did not find any association between HbA1c, pubertal status, disease duration, and metabolome profile within the case group. CONCLUSIONS: T1D profoundly disrupts the metabolome of pediatric patients. The excess of cortisol and aldosterone may contribute to the development of macrovascular complications in adulthood, while the increase of tryptophan derivates may have a role in neuronal damage associated to hyperglycemia. Determinants of such findings, other than HbA1c, should be explored. PMID: 28401628 [PubMed - as supplied by publisher]

Related Articles The LIN28/let-7 Pathway in Cancer. Front Genet. 2017;8:31 Authors: Balzeau J, Menezes MR, Cao S, Hagan JP Abstract Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer. PMID: 28400788 [PubMed - in process]

Related Articles Optimization of Huang-Lian-Jie-Du-Decoction for Ischemic Stroke Treatment and Mechanistic Study by Metabolomic Profiling and Network Analysis. Front Pharmacol. 2017;8:165 Authors: Zhang Q, Wang J, Liao S, Li P, Xu D, Lv Y, Yang M, Kong L Abstract Optimal drug proportions and mechanism deciphering of multicomponent drugs are critical for developing novel therapies to cope with complex diseases, such as stroke. In the present study, orthogonal experimental design was applied to explore the optimal proportion of the four component herbs in Huang-Lian-Jie-Du-Decoction (HLJDD) on the treatment of ischemic stroke. The treatment efficacies and mechanisms were assessed using global and amino acids (AAs) targeted metabolomics, as well as correlation network analysis. The global NMR metabolomics results revealed that AAs metabolism was significantly perturbed in middle cerebral artery occlusion rats. The levels of 23 endogenous AAs were then subjected to HPLC-QTOF-MS/MS analysis. These results complemented with neurobehavioral evaluations, cerebral infarct assessments, biochemical evaluations, histological inspections and immunohistochemistry observations strongly demonstrated that HLJDD with optimal proportion of 6 (Rhizoma coptidis): 4 (Radix scutellariae): 1 (Cortex phellodendr): 3 (Fructus Gardeniae) had the best efficacy on ischemic stroke, which could be ascribed to its modulation on AA metabolism. This integrated metabolomics approach showed the potential and applicable in deciphering the complex mechanisms of traditional Chinese medicine formulae on the treatment of complicated diseases, which provided new means to assess the treatment effects of herb combinations and to further development of drugs or therapies based on these formulae. PMID: 28400733 [PubMed - in process]

Related Articles Serum Metabolomics Analysis Reveals a Distinct Metabolic Profile of Patients with Primary Biliary Cholangitis. Sci Rep. 2017 Apr 11;7(1):784 Authors: Hao J, Yang T, Zhou Y, Gao GY, Xing F, Peng Y, Tao YY, Liu CH Abstract Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease associated with profound metabolic changes. The purpose of this study was to identify a distinctive metabolic signature from the training set with 29 PBC patients, 30 hepatitis B virus (HBV)-caused cirrhosis (HBC) and 41 healthy controls, and to validate the applicability and stability of the distinctive model from the validation set with 21 PBC patients, 7 autoimmune hepatitis (AIH) and 9 HBC. The sera were investigated using high resolution nuclear magnetic resonance (NMR) and the datasets were analyzed pairwise using pattern recognition methods. 45 distinguishable metabolites were identified and 15 metabolic pathways were reprogrammed. The altered metabolic pathways were associated with glucose, fatty acid and amino acid metabolites. Logistic regression and ROC analysis were used to establish a diagnostic model with the equated (p) = -12.22-3.46*log(4-hydroxyproline) + 6.62*log(3-hydroxyisovalerate) - 2.44*log(citraconate) - 3.80*log(pyruvate). The area under the curve (AUC) of the optimized model was 0.937 (95% confidence interval (CI): 0.868-0.976) in the training set and 0.890 (95% CI: 0.743-0.969) in the validation set. These results not only revealed the potential pathogenesis of PBC, but also provided a feasible diagnostic tool for PBC populations through detection of serum metabolites. PMID: 28400566 [PubMed - in process]

Related Articles Metabolomics-driven approach to solving a CoA imbalance for improved 1-butanol production in Escherichia coli. Metab Eng. 2017 Apr 08;: Authors: Ohtake T, Pontrelli S, Laviña WA, Liao JC, Putri SP, Fukusaki E Abstract High titer 1-butanol production in Escherichia coli has previously been achieved by overexpression of a modified clostridial 1-butanol production pathway and subsequent deletion of native fermentation pathways. This strategy couples growth with production as 1-butanol pathway offers the only available terminal electron acceptors required for growth in anaerobic conditions. With further inclusion of other well-established metabolic engineering principles, a titer of 15g/L has been obtained. In achieving this titer, many currently existing strategies have been exhausted, and 1-butanol toxicity level has been surpassed. Therefore, continued engineering of the host strain for increased production requires implementation of alternative strategies that seek to identify non-obvious targets for improvement. In this study, a metabolomics-driven approach was used to reveal a CoA imbalance resulting from a pta deletion that caused undesirable accumulation of pyruvate, butanoate, and other CoA-derived compounds. Using metabolomics, the reduction of butanoyl-CoA to butanal catalyzed by alcohol dehydrogenase AdhE2 was determined as a rate-limiting step. Fine-tuning of this activity and subsequent release of free CoA restored the CoA balance that resulted in a titer of 18.3g/L upon improvement of total free CoA levels using cysteine supplementation. By enhancing AdhE2 activity, carbon flux was directed towards 1-butanol production and undesirable accumulation of pyruvate and butanoate was diminished. This study represents the initial report describing the improvement of 1-butanol production in E. coli by resolving CoA imbalance, which was based on metabolome analysis and rational metabolic engineering strategies. PMID: 28400330 [PubMed - as supplied by publisher]

Related Articles Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria. Mol Genet Metab. 2017 Apr 06;: Authors: Ney DM, Murali SG, Stroup BM, Nair N, Sawin EA, Rohr F, Levy HL Abstract BACKGROUND: Deficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF). METHODS: Subjects with PKU consumed a low-Phe diet combined with AA-MF or GMP-MF for 3weeks each in a randomized, controlled, crossover study. Metabolomic analysis was conducted by Metabolon, Inc. on plasma (n=18) and urine (n=9) samples. Catecholamines and 6-sulfatoxymelatonin were measured in 24-h urine samples. RESULTS: Intake of Tyr and Trp was ~50% higher with AA-MF, and AA-MF were consumed in larger quantities, less frequently during the day compared with GMP-MF. Performance on neuropsychological tests and concentrations of neurotransmitters derived from Tyr and Trp were not significantly different with AA-MF or GMP-MF. Plasma serotonin levels of gut origin were higher in subjects with variant compared with classical PKU, and with GMP-MF compared with AA-MF in subjects with variant PKU. Metabolomics analysis identified higher levels of microbiome-derived compounds synthesized from Tyr, such as phenol sulfate, and higher levels of compounds synthesized from Trp in the kynurenine pathway, such as quinolinic acid, with ingestion of AA-MF compared with GMP-MF. CONCLUSIONS: The Tyr from AA-MF is less bioavailable due, in part, to greater degradation by intestinal microbes compared with the Tyr from prebiotic GMP-MF. Research is needed to understand how metabolism of Trp via the kynurenine pathway and changes in the intestinal microbiota affect health for individuals with PKU. This trial is registered at www.clinicaltrials.gov as NCT01428258. PMID: 28400091 [PubMed - as supplied by publisher]

Related Articles Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther. 2017 Apr 11;19(1):76 Authors: Takahashi S, Saegusa J, Sendo S, Okano T, Akashi K, Irino Y, Morinobu A Abstract BACKGROUND: The recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice. METHODS: The expression of glycolysis- or glutaminolysis-related enzymes was evaluated by real-time polymerase chain reaction (PCR) and Western blotting, and the intracellular metabolites were evaluated by metabolomic analyses. The effects of glucose or glutamine on RA-FLS cell growth were investigated using glucose- or glutamine-free medium. Glutaminase (GLS)1 small interfering RNA (siRNA) and the GLS1 inhibitor compound 968 were used to inhibit GLS1 in RA-FLS, and compound 968 was used to study the effect of GLS1 inhibition in zymosan A-injected SKG mice. RESULTS: GLS1 expression was increased in RA-FLS, and metabolomic analyses revealed that glutamine metabolism was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA transfection or GLS1 inhibitor treatment. Treating RA-FLS with either interleukin-17 or platelet-derived growth factor resulted in increased GLS1 levels. Compound 968 ameliorated the autoimmune arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice. CONCLUSIONS: Our results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA. PMID: 28399896 [PubMed - in process]

Related Articles Polyamine Metabolites Profiling for Characterization of Lung and Liver Cancer Using an LC-Tandem MS Method with Multiple Statistical Data Mining Strategies: Discovering Potential Cancer Biomarkers in Human Plasma and Urine. Molecules. 2016 Aug 10;21(8): Authors: Xu H, Liu R, He B, Bi CW, Bi K, Li Q Abstract Polyamines, one of the most important kind of biomarkers in cancer research, were investigated in order to characterize different cancer types. An integrative approach which combined ultra-high performance liquid chromatography-tandem mass spectrometry detection and multiple statistical data processing strategies including outlier elimination, binary logistic regression analysis and cluster analysis had been developed to discover the characteristic biomarkers of lung and liver cancer. The concentrations of 14 polyamine metabolites in biosamples from lung (n = 50) and liver cancer patients (n = 50) were detected by a validated UHPLC-MS/MS method. Then the concentrations were converted into independent variables to characterize patients of lung and liver cancer by binary logic regression analysis. Significant independent variables were regarded as the potential biomarkers. Cluster analysis was engaged for further verifying. As a result, two values was discovered to identify lung and liver cancer, which were the product of the plasma concentration of putrescine and spermidine; and the ratio of the urine concentration of S-adenosyl-l-methionine and N-acetylspermidine. Results indicated that the established advanced method could be successfully applied to characterize lung and liver cancer, and may also enable a new way of discovering cancer biomarkers and characterizing other types of cancer. PMID: 27517900 [PubMed - indexed for MEDLINE]

Related Articles The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine. Antioxid Redox Signal. 2017 Apr 11;: Authors: Cortese-Krott MM, Koning A, Kuhnle GG, Nagy P, Bianco C, Pasch A, Wink DA, Fukuto J, Jackson AA, van Goor H, Olson KR, Feelisch M Abstract SIGNIFICANCE: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not administration of antioxidants is ineffective, suggesting our current understanding of the underlying regulatory processes is incomplete. Recent Advances. Similar to reactive oxygen and nitrogen species (ROS, RNS), reactive sulfur species (RSS) are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept coined the reactive species interactome (RSI). The RSI is a primeval multi-level redox-regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stresses to enhance fitness and resilience at the local and whole-organism level. CRITICAL ISSUES: To better characterise the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems and effects on cellular, organ and whole-organism bioenergetics using systems-level/network analyses. FUTURE DIRECTIONS: Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other stresses will provide new prevention/intervention opportunities for personalized medicine. PMID: 28398072 [PubMed - as supplied by publisher]

Related Articles Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. Sci Rep. 2017 Apr 11;7:46337 Authors: de Mello VD, Paananen J, Lindström J, Lankinen MA, Shi L, Kuusisto J, Pihlajamäki J, Auriola S, Lehtonen M, Rolandsson O, Bergdahl IA, Nordin E, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Landberg R, Eriksson JG, Tuomilehto J, Hanhineva K, Uusitupa M Abstract Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of β-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity. PMID: 28397877 [PubMed - in process]