PubMed

Related Articles A Metabolomic and Lipidomic Serum Signature from Nonhuman Primates Administered with a Promising Radiation Countermeasure, Gamma-Tocotrienol. Int J Mol Sci. 2017 Dec 28;19(1): Authors: Cheema AK, Mehta KY, Fatanmi OO, Wise SY, Hinzman CP, Wolff J, Singh VK Abstract The development of radiation countermeasures for acute radiation syndrome (ARS) has been underway for the past six decades, leading to the identification of multiple classes of radiation countermeasures. However, to date, only two growth factors (Neupogen and Neulasta) have been approved by the United States Food and Drug Administration (US FDA) for the mitigation of hematopoietic acute radiation syndrome (H-ARS). No radioprotector for ARS has been approved by the FDA yet. Gamma-tocotrienol (GT3) has been demonstrated to have radioprotective efficacy in murine as well as nonhuman primate (NHP) models. Currently, GT3 is under advanced development as a radioprotector that can be administered prior to radiation exposure. We are studying this agent for its safety profile and efficacy using the NHP model. In this study, we analyzed global metabolomic and lipidomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in serum samples of NHPs administered GT3. Our study, using 12 NHPs, demonstrates that alterations in metabolites manifest only 24 h after GT3 administration. Furthermore, metabolic changes are associated with transient increase in the bioavailability of antioxidants, including lactic acid and cholic acid and anti-inflammatory metabolites 3 deoxyvitamin D3, and docosahexaenoic acid. Taken together, our results show that the administration of GT3 to NHPs causes metabolic shifts that would provide an overall advantage to combat radiation injury. This initial assessment also highlights the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3. PMID: 29283379 [PubMed - in process]

Related Articles Metabolism of a sea lamprey pesticide by fish liver enzymes part A: identification and synthesis of TFM metabolites. Anal Bioanal Chem. 2017 Dec 28;: Authors: Bussy U, Chung-Davidson YW, Buchinger T, Li K, Smith SA, Jones AD, Li W Abstract The sea lamprey (Petromyzon marinus) is a destructive invasive species in the Great Lakes that contributed to the collapse of native fish populations in the mid-1900s. 3-Trifluoromethyl-4-nitrophenol (TFM) is a selective pesticide that has been applied to sea lamprey infested tributaries of the Great Lakes to kill larvae since the 1960s and has reduced the populations by as much as 90%. However, the metabolism of TFM by sea lamprey and non-target species is not fully illuminated. Elucidation of TFM metabolism is critical for understanding its mode of action and possible environmental impact. Here, we describe the screening, identification, synthesis and structural characterization of TFM metabolites in livers from sea lamprey and three non-target species that differ in their ability to survive TFM exposure. We identified glucuronidation, sulfation, N-acetylation, glutathione conjugation, and aromatic nitro group reduction as potential detoxification mechanisms. Seven metabolites were synthesized for use as markers of TFM metabolism in fish. Quantitative 1H NMR was used to assay synthesized metabolite stock solutions that were then used as standard material to develop a quantitative LC-MS/MS method for TFM metabolites. PMID: 29282500 [PubMed - as supplied by publisher]

Related Articles Development of Multimarker Diagnostic Models from Metabolomics Analysis for Gestational Diabetes Mellitus. Mol Cell Proteomics. 2017 Dec 27;: Authors: Hou W, Meng X, Zhao A, Zhao W, Pan J, Tang J, Huang Y, Li H, Jia W, Liu F, Jia W Abstract Although metabolomics are desirable to understand the pathophysiology of gestational diabetes mellitus (GDM), comprehensive metabolomic studies of GDM are rare. We aimed to offer a holistic view of metabolites alteration in GDM patients and investigate the possible multimarker models for GDM diagnosis. Biochemical parameters and perinatal data of 131 GDM cases and 138 controls were collected. Fasting serum samples at 75 g oral glucose tolerance test were used for metabolites by ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry, ultra performance liquid chromatography-triple triple-quadrupole-mass spectrometry and gas chromatography- time-of- flight mass spectrometry platforms. Significant changes were observed in free fatty acids, bile acids, branched chain amino acids, organic acids, lipids and organooxygen compounds between two groups. In receiver operating characteristic (ROC) analysis, different combinations of candidate biomarkers and metabolites in multimarker models achieved satisfactory discriminative abilities for GDM, with the values of area under the curve (AUC) ranging from 0.721 to 0.751. Model consisting of body mass index (BMI), retinol binding protein 4 (RBP4), n-acetylaspartic acid and C16:1 (cis-7) manifested the best discrimination [AUC 0.751 (95% CI: 0.693-0.809), P<0.001], followed by model consisting of BMI, Cystatin C, acetylaspartic acid and 6,7-diketoLCA [AUC 0.749 (95% CI: 0.691-0.808), P<0.001]. Metabolites alteration reflected disorders of glucose metabolism, lipid metabolism, amino acid metabolism, bile acid metabolism as well as intestinal flora metabolism in GDM state. Multivariate models combining clinical markers and metabolites have the potential to differentiate GDM subjects from healthy controls. PMID: 29282297 [PubMed - as supplied by publisher]

Related Articles Metabolomic analyses to evaluate the effect of drought stress on selected African Eggplant accessions. J Sci Food Agric. 2018 Jan;98(1):205-216 Authors: Mibei EK, Owino WO, Ambuko J, Giovannoni JJ, Onyango AN Abstract BACKGROUND: Drought stress is one of the main abiotic stresses that affect crops. It leads to biochemical changes that can have adverse effects on plant growth, development and productivity. African eggplants are important vegetable and fruit crops reported to adapt and thrive well under drought stress. The diversified metabolites arising due to stress have not been well defined. A gas chromatographic-mass spectrometric metabolomic approach was applied to characterize the effect of drought stress on metabolites at different stages of growth. Nineteen accessions were selected for analysis and drought was imposed by withholding water until soil moisture reached 60% field capacity. Fresh leaf tissues were sampled before stress, 2 and 4 weeks after stress and metabolite profiling done. RESULTS: Significant changes in metabolite content were observed, and potentially important metabolites with respect to stress responses were characterized. Proline, glutamate, sucrose, fructose and tricarboxylic acid cycle metabolites were shown to be positively correlated with stress. Principal component analysis showed a clear discrimination between the different accessions, growth stages and stress/control conditions. CONCLUSION: The results illustrate that drought stress has a significant impact on the concentrations of some metabolites, such as amino acids, sugars and organic acids, which may contribute to drought stress effects and tolerance. © 2017 Society of Chemical Industry. PMID: 28573744 [PubMed - indexed for MEDLINE]

Urothelial MaxiK-activity regulates mucosal and detrusor metabolism. PLoS One. 2017;12(12):e0189387 Authors: Wang Y, Deng GG, Davies KP Abstract There is increasing evidence for a role of MaxiK potassium channel-activity in regulating the metabolism and intracellular signaling of non-contractile bladder mucosal tissues. At present however no studies have determined the impact of urothelial MaxiK-activity on overall bladder metabolism. To address this we have investigated the effect of bladder lumen instillation of the MaxiK inhibitor, iberiotoxin (IBTX), on mucosal and detrusor metabolism using metabolomics. Since IBTX does not cross plasma membranes, when instilled into the bladder lumen it would only effect urothelially expressed MaxiK-activity. Surprisingly IBTX treatment caused more effect on the metabolome of the detrusor than mucosa (the levels of 17% of detected detrusor metabolites were changed in comparison to 6% of metabolites in mucosal tissue following IBTX treatment). In mucosal tissues, the major effects can be linked to mitochondrial-associated metabolism whereas in detrusor there were additional changes in energy generating pathways (such as glycolysis and the TCA cycle). In the detrusor, changes in metabolism are potentially a result of IBTX effecting MaxiK-linked signaling pathways between the mucosa and detrusor, secondary to changes in physiological activity or a combination of both. Overall we demonstrate that urothelial MaxiK-activity plays a significant role in determining mitochondrially-associated metabolism in mucosal tissues, which effects the metabolism of detrusor tissue. Our work adds further evidence that the urothelium plays a major role in determining overall bladder physiology. Since decreased MaxiK-activity is associated with several bladder pathophysiology's, the changes in mucosal metabolism reported here may represent novel downstream targets for therapeutic interventions. PMID: 29281667 [PubMed - in process]

Transcriptomic and Metabolomic Reprogramming from Roots to Haustoria in the Parasitic Plant, Thesium chinense. Plant Cell Physiol. 2017 Dec 20;: Authors: Ichihashi Y, Kusano M, Kobayashi M, Suetsugu K, Yoshida S, Wakatake T, Kumaishi K, Shibata A, Saito K, Shirasu K Abstract Most of plants show remarkable developmental plasticity in the generation of diverse types of new organs upon external stimuli, allowing them to adapt to their environment. Haustorial formation in parasitic plants is an example of such developmental reprogramming, but its molecular mechanism is largely unknown. In this study, we performed field-omics using transcriptomics and metabolomics to profile the molecular switch occurring in haustorial formation of the root parasitic plant, Thesium chinense, collected from its natural habitat. RNA-sequencing with de novo assembly revealed that the transcripts of very-long-chain fatty acid (VLCFA) biosynthesis genes, auxin biosynthesis/signaling-related genes, and lateral root developmental genes are highly abundant in the haustoria. Gene co-expression network analysis identified a network module linking VLCFA and auxin-responsive lateral root development pathway. GC-TOF-MS analysis consistently revealed a unique metabolome profile with many types of fatty acids in the T. chinense root system, including the accumulation of a 25-carbon long chain saturated fatty acid in the haustoria. Our field-omics data provide evidence supporting the hypothesis that the molecular developmental machinery used for lateral root formation in non-parasitic plants has been co-opted into the developmental reprogramming of haustorial formation in the linage of parasitic plants. PMID: 29281058 [PubMed - as supplied by publisher]

Metabolomics and Precision Medicine in Trauma: The State of the Field. Shock. 2017 Dec 26;: Authors: Jayaraman SP, Anand RJ, DeAntonio JH, Mangino M, Aboutanos MB, Kasirajan V, Ivatury R, Valadka AB, Glushakova O, Hayes RL, Bachmann LM, Brophy GM, Contaifer D, Warncke UO, Brophy DF, Wijesinghe DS Abstract Trauma is a major problem in the United States. Mortality from trauma is the number one cause of death under the age of 45 in the US and is the third leading cause of death for all age groups. There are nearly 200,000 deaths per year due to trauma in the US at a cost of over $671 billion in combined health care costs and lost productivity. Unsurprisingly, trauma accounts for about 30% of all life-years lost in the US. Due to immense development of trauma systems, a large majority of trauma patients survive the injury but then go on to die from complications arising from the injury. These complications are marked by early and significant metabolic changes accompanied by inflammatory responses that lead to progressive organ failure, and ultimately, death. Early resuscitative and surgical interventions followed by close monitoring to identify and rescue treatment failures are key to successful outcomes. Currently, the adequacy of resuscitation is measured using vital signs, noninvasive methods such as bedside echocardiography or stroke volume variation, and other laboratory endpoints of resuscitation, such as lactate and base deficit. However, these methods may be too crude to understand cellular and subcellular changes that may be occurring in trauma patients. Better diagnostic and therapeutic markers are needed to assess the adequacy of interventions and monitor responses at a cellular and subcellular level and inform clinical decision making before complications are clinically apparent. The developing field of metabolomics holds great promise in the identification and application of biochemical markers towards the clinical decision making process. PMID: 29280924 [PubMed - as supplied by publisher]

A baseline metabolomic signature is associated with immunological CD4+ T-cell recovery after 36 months of ART in HIV-infected patients. AIDS. 2017 Dec 26;: Authors: Rodríguez-Gallego E, Gómez J, Pacheco YM, Peraire J, Viladés C, Beltrán-Debón R, Mallol R, López-Dupla M, Veloso S, Alba V, Blanco J, Cañellas N, Rull A, Leal M, Correig X, Domingo P, Vidal F Abstract OBJECTIVES: Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after ART in order to envisage the underlying mechanistic pathways that influence the treatment response. DESIGN: This was a multi-centre, prospective cohort study in ART-naïve and a pre-ART low nadir (<200 cells/μl) HIV-infected patients (n = 64). METHODS: We obtained clinical data and metabolomic profiles for each individual, in which low molecular weight metabolites, lipids and lipoproteins (including particle concentrations and sizes) were measured by nuclear magnetic resonance spectroscopy. Immunological recovery was defined as reaching CD4 T-cell count ≥250 cells/μL after 36 months of virologically successful ART. We used univariate comparisons, Random Forest test and ROC curves to identify and evaluate the predictive factors of immunological recovery after treatment. RESULTS: HIV-infected patients with a baseline metabolic pattern characterized by high levels of large HDL particles, HDL cholesterol and larger sizes of LDL particles had a better immunological recovery after treatment. Conversely, patients with high ratios of non HDL lipoprotein particles did not experience this full recovery. Medium VLDL particles and glucose increased the classification power of the multivariate model despite not showing any significant differences between the two groups. CONCLUSIONS: In HIV-infected patients, a baseline healthier metabolomic profile is related to a better response to ART where the lipoprotein profile, mainly large HDL particles, may play a key role. PMID: 29280761 [PubMed - as supplied by publisher]

Related Articles Metabolism of a sea lamprey pesticide by fish liver enzymes part B: method development and application in quantification of TFM metabolites formed in vivo. Anal Bioanal Chem. 2017 Dec 26;: Authors: Bussy U, Chung-Davidson YW, Buchinger T, Li K, Smith SA, Daniel Jones A, Li W Abstract The sea lamprey (Petromyzon marinus) is a destructive invasive species in the Great Lakes. Since the 1960s, tons of the lampricide 3-trifluoromethyl-4-nitrophenol (TFM) has been applied to selected tributaries each year to eliminate or reduce sea lamprey larval populations. Therefore, the environmental impact of TFM needs to be evaluated. However, the metabolism of TFM and its mechanism of selective toxicity in sea lamprey is not yet fully understood. Based upon our previous report on the identification, synthesis, and characterization of TFM metabolites observed in liver incubates from sea lamprey and non-target fishes, we now provide a robust assay for quantifying TFM and its metabolites in fish liver tissue. This method is important for assessing bioaccumulation of TFM in the ecosystems. The compounds purified in our previous report were used to develop and validate a quantitative ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay for TFM and TFM metabolites formed in vivo. Several sample preparation techniques were compared, and a protein precipitation method was selected. The unavailability of stable isotopic internal standards was overcome by using a matrix matching method. After a thorough validation, this method was applied to determine the concentrations of TFM and its metabolites in fish liver tissues from animals exposed to TFM, and in the comparison between dead animals and survivors. Seven of eight expected metabolites were observed, some for the first time in vivo. Our results indicate that in vivo nitroreduction, glucuronidation, sulfation, and glutathione conjugation are involved in TFM metabolism in sea lamprey. PMID: 29279987 [PubMed - as supplied by publisher]

Related Articles The Future of Low-Density Lipoprotein Cholesterol in an Era of Nonfasting Lipid Testing and Potent Low-Density Lipoprotein Lowering. Circulation. 2018 Jan 02;137(1):20-23 Authors: Farukhi Z, Mora S PMID: 29279336 [PubMed - in process]

Related Articles Rapid evaporative ionization mass spectrometry and chemometrics for high-throughput screening of growth promoters in meat producing animals. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017 Dec 26;: Authors: Guitton Y, Dervilly-Pinel G, Jandova R, Stead S, Takats Z, Le Bizec B Abstract In a proof of concept perspective, Rapid Evaporative Ionization Mass Spectrometry (REIMS) was explored for the direct analysis of meat samples from β-agonist treated livestock. In this context, the combination of REIMS with untargeted metabolomics was investigated to identify carcasses from treated animals on the basis of a modification of indirect metabolites profile. The REIMS analysis generated specific lipid profiles which enabled the differentiation of meat samples collected from pigs treated with ractopamine via their feeding regime. Furthermore, the strategy was found successful when tested on different muscle types (loin, shoulder and thigh), which further expands its applicability. Classification performances were greater than 95% accurate which fully answers requirements of a screening strategy. This research indicates that REIMS implemented in an untargeted-metabolomics workflow can be considered as a high-throughput and accurate strategy for real-time meat classification in relation to ractopamine (and wider β-agonists) treatment in pig production. This approach may subsequently be implemented as a rapid screening test, at the slaughterhouse or at boarder inspection points, to detect such practice. PMID: 29279042 [PubMed - as supplied by publisher]

Related Articles The classification of almonds (Prunus dulcis) by country and variety using UHPLC-HRMS-based untargeted metabolomics. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017 Dec 26;: Authors: Gil Solsona R, Boix C, Ibáñez M, Sancho JV Abstract The aim of this study was to use an untargeted UHPLC-HRMS-based metabolomics approach allowing discrimination between almonds based on their origin and variety. Samples were homogenized, extracted with ACN:H2O (80:20) containing 0.1% HCOOH and injected in a UHPLC-QTOF instrument in both positive and negative ionization modes. Principal component analysis (PCA) was performed to ensure the absence of outliers. Partial least squares - discriminant analysis (PLS-DA) was employed to create and validate the models for country (with 5 different compounds) and variety (with 20 features), showing more than 95% accuracy. Additional samples were injected and the model was evaluated with blind samples, with more than 95% of samples being correctly classified using both models. MS/MS experiments were carried out to tentatively elucidate the highlighted marker compounds (pyranosides, peptides or amino acids amongst others). This study has shown the potential of HRMS to perform and validate classification models, also providing information concerning the identification of the unexpected biomarkers which showed the highest discriminant power. PMID: 29279031 [PubMed - as supplied by publisher]

Related Articles Evidencing 98 secondary metabolites of Penicillium verrucosum using substrate isotopic labeling and high-resolution mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Dec 15;1071:29-43 Authors: Hautbergue T, Puel O, Tadrist S, Meneghetti L, Péan M, Delaforge M, Debrauwer L, Oswald IP, Jamin EL Abstract Industrial applications of fungal compounds, coupled with the emergence of fungal threats to natural ecosystems and public health, have increased interest in filamentous fungi. Among all pathogenic fungi, Penicillium verrucosum is one of the most common mold-infecting stored cereals in temperate regions. However, it is estimated that 80% of fungal secondary metabolites remain unknown. To detect new P. verrucosum compounds, an untargeted metabolomic approach was applied to fungus grown on wheat grains labeled with stable isotopes: (i) natural grains (99% 12C); (ii) grains enriched with 97% of 13C; and (iii) grains enriched with 53% of 13C and 97% of 15N. Analyses performed by high-performance liquid chromatography coupled with high-resolution mass spectrometry (HPLC-HRMS) enabled the specific detection of fungal metabolites, and the unambiguous characterization of their chemical formulas. In this way, 98 secondary metabolites were detected and their chemical formulas were determined. Of these, only 18 identifications could be made based on databases, the literature and mass spectrometry fragmentation experiments, with the result that 80 were totally unknown. Molecular networks were generated to analyze these results, leading to the characterization by MSn experiments of a new fungisporin produced by P. verrucosum. More generally, this article provides precise mass spectrometric data about all these compounds for further studies of the Penicillium metabolome. PMID: 28351740 [PubMed - indexed for MEDLINE]

Related Articles From untargeted LC-QTOF analysis to characterisation of opines in abalone adductor muscle: Theory meets practice. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Dec 15;1071:44-48 Authors: Venter L, Jansen van Rensburg PJ, Loots DT, Vosloo A, Lindeque JZ Abstract Abalone have a unique ability to use pyruvate, various amino acids and dehydrogenases, to produce opines as means to prevent the accumulation of NADH during anaerobic conditions. In this study, the theoretical masses, formulae and fragment patterns of butylated opines were used to predict which of these compounds could be found in the abalone adductor muscle using untargeted liquid chromatography quadrupole time-of flight-mass spectrometry. These findings were validated using synthesised opine standards. In essence alanopine, lysopine, strombine and tauropine produced in abalone adductor muscle could be characterised using the highest identification confidence levels. PMID: 28262445 [PubMed - indexed for MEDLINE]

Related Articles Staging research of human lung cancer tissues by high-resolution magic angle spinning proton nuclear magnetic resonance spectroscopy (HRMAS 1 H NMR) and multivariate data analysis. Asia Pac J Clin Oncol. 2017 Oct;13(5):e232-e238 Authors: Chen W, Lu S, Wang G, Chen F, Bai C Abstract AIM: High-resolution magic-angle spinning proton nuclear magnetic resonance (HRMAS 1 H NMR) spectroscopy technique was employed to analyze the metabonomic characterizations of lung cancer tissues in hope to identify potential diagnostic biomarkers for malignancy detection and staging research of lung tissues. METHODS: HRMAS 1 H NMR spectroscopy technique can rapidly provide important information for accurate diagnosis and staging of cancer tissues owing to its noninvasive nature and limited requirement for the samples, and thus has been acknowledged as an excellent tool to investigate tissue metabolism and provide a more realistic insight into the metabonomics of tissues when combined with multivariate data analysis (MVDA) such as component analysis and orthogonal partial least squares-discriminant analysis in particular. RESULTS: HRMAS 1 H NMR spectra displayed the metabonomic differences of 32 lung cancer tissues at the different stages from 32 patients. The significant changes (P < 0.05) of some important metabolites such as lipids, aspartate and choline-containing compounds in cancer tissues at the different stages had been identified. Furthermore, the combination of HRMAS 1 H NMR spectroscopy and MVDA might potentially and precisely provided for a high sensitivity, specificity, prediction accuracy in the positive identification of the staging for the cancer tissues in contrast with the pathological data in clinic. CONCLUSION: This study highlighted the potential of metabonomics in clinical settings so that the techniques might be further exploited for the diagnosis and staging prediction of lung cancer in future. PMID: 27670847 [PubMed - indexed for MEDLINE]

Correlation between gut microbiota and personality in adults: a cross-sectional study. Brain Behav Immun. 2017 Dec 23;: Authors: Kim HN, Yun Y, Ryu S, Chang Y, Kwon MJ, Cho J, Shin H, Kim HL Abstract Personality affects fundamental behavior patterns and has been related with health outcomes and mental disorders. Recent evidence has emerged supporting a relationship between the microbiota and behavior, referred to as brain-gut relationships. Here, we first report correlations between personality traits and gut microbiota. This research was performed using the Revised NEO Personality Inventory and the sequencing data of the 16S rRNA gene in 672 adults. The diversity and the composition of the human gut microbiota exhibited significant difference when stratified by personality traits. We found that personality traits were significantly correlated with diversity of gut microbiota, while their differences were extremely subtle. High neuroticism and low conscientiousness groups were correlated with high abundance of Gammaproteobacteria and Proteobacteria, respectively when covariates, including age, sex, BMI and nutrient intake, were controlled. Additionally, high conscientiousness group also showed increased abundance of some universal butyrate-producing bacteria including Lachnospiraceae. This study was of observational and cross-sectional design and our findings must be further validated through metagenomic or metatranscriptomic methodologies, or metabolomics-based analyses. Our findings will contribute to elucidating potential links between the gut microbiota and personality, and provide useful insights toward developing and testing personality- and microbiota-based interventions for promoting health. PMID: 29278751 [PubMed - as supplied by publisher]

Thermodynamic analysis of computed pathways integrated into the metabolic networks of E. coli and Synechocystis reveals contrasting expansion potential. Metab Eng. 2017 Dec 23;: Authors: Asplund-Samuelsson J, Janasch M, Hudson EP Abstract Introducing biosynthetic pathways into an organism is both reliant on and challenged by endogenous biochemistry. Here we compared the expansion potential of the metabolic network in the photoautotroph Synechocystis with that of the heterotroph E. coli using the novel workflow POPPY (Prospecting Optimal Pathways with PYthon). First, E. coli and Synechocystis metabolomic and fluxomic data were combined with metabolic models to identify thermodynamic constraints on metabolite concentrations (NET analysis). Then, thousands of automatically constructed pathways were placed within each network and subjected to a network-embedded variant of the max-min driving force analysis (NEM). We found that the networks had different capabilities for imparting thermodynamic driving forces toward certain compounds. Key metabolites were constrained differently in Synechocystis due to opposing flux directions in glycolysis and carbon fixation, the forked tri-carboxylic acid cycle, and photorespiration. Furthermore, the lysine biosynthesis pathway in Synechocystis was identified as thermodynamically constrained, impacting both endogenous and heterologous reactions through low 2-oxoglutarate levels. Our study also identified important yet poorly covered areas in existing metabolomics data and provides a reference for future thermodynamics-based engineering in Synechocystis and beyond. The POPPY methodology represents a step in making optimal pathway-host matches, which is likely to become important as the practical range of host organisms is diversified. PMID: 29278749 [PubMed - as supplied by publisher]

Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis. Clin Chim Acta. 2017 Dec 23;: Authors: Srivastava NK, Yadav R, Mukherjee S, Sinha N Abstract BACKGROUND: Muscular dystrophy is an inherited muscle disease, characterized by progressive muscle wasting and weakness of variable distribution and severity. METHODS: In vitro, high-resolution proton nuclear magnetic resonance (NMR) spectroscopy based analysis was performed on perchloric acid (PCA) extract of muscle specimens of patients suffering from various types of muscular dystrophies to identify alteration in hydrophilic low-molecular weight substances (aqueous metabolites) as compared to muscle of control subjects as well as in between the types of muscular dystrophy. Muscle tissue specimens were obtained from Duchenne muscular dystrophy (DMD) [n=11], Becker muscular dystrophy (BMD) [n=12], facioscapulohumeral dystrophy (FSHD) [n=9] and limb girdle muscular dystrophy (LGMD)-2B [n=22]. Control muscle specimens [n=40] were also taken. RESULTS: Concentration of branched chain amino acids (BCA), glutamine/glutamate (Gln/Glu), acetate (Ace) and fumarate (Fum) was decreased and His was increased in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control subjects. Alanine (Ala) was significantly reduced in BMD, FSHD and LGMD-2B patients as compared to control subjects. Tyrosine (Tyr) was present only in the muscle tissue of control subjects. Propionate (Prop) was present in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients and was absent in muscle tissue of control subjects. Concentration of BCA and Prop is significantly reduced in patients with DMD as compared to BMD, but Glucose is significantly higher in patients with DMD as compared to BMD. Quantity of Glucose, His and Gln/glu are significantly higher in patients with DMD as compared to FSHD, but Prop is significantly reduced in patients with DMD as compared to FSHD. Concentration of Ala and His is significantly higher in patients with DMD as compared to LGMD-2B, but BCA, Glucose and Prop are significantly reduced in patients with DMD as compared to LGMD-2B. Concentration of His is significantly higher in patients with BMD as compared to FSHD. Concentration of His is significantly reduced and Glucose is higher in patients with LGMD-2B as compared to BMD. Glucose concentration is significantly reduced in patients with FSHD as compared to LGMD-2B. ROC curves supported the noticeable discrimination in between the patients with DMD and FSHD for the quantity of Gln/Glu, and patients with LGMD-2B and DMD for the quantity of Ala. Collectively, these findings showed the perturbation of muscle metabolism in muscular dystrophy. CONCLUSIONS: The data of presented study may be used as supporting information for existing methods of the diagnosis for patients with muscular dystrophy. PMID: 29278724 [PubMed - as supplied by publisher]

Stage-specific metabolic features of differentiating neurons: Implications for toxicant sensitivity. Toxicol Appl Pharmacol. 2017 Dec 23;: Authors: Delp J, Gutbier S, Cerff M, Zasada C, Niedenführ S, Zhao L, Smirnova L, Hartung T, Borlinghaus H, Schreiber F, Bergemann J, Gätgens J, Beyss M, Azzouzi S, Waldmann T, Kempa S, Nöh K, Leist M Abstract Developmental neurotoxicity (DNT) may be induced when chemicals disturb a key neurodevelopmental process, and many tests focus on this type of toxicity. Alternatively, DNT may occur when chemicals are cytotoxic only during a specific neurodevelopmental stage. The toxicant sensitivity is affected by the expression of toxicant targets and by resilience factors. Although cellular metabolism plays an important role, little is known how it changes during human neurogenesis, and how potential alterations affect toxicant sensitivity of mature vs. immature neurons. We used immature (d0) and mature (d6) LUHMES cells (dopaminergic human neurons) to provide initial answers to these questions. Transcriptome profiling and characterization of energy metabolism suggested a switch from predominantly glycolytic energy generation to a more pronounced contribution of the tricarboxylic acid cycle (TCA) during neuronal maturation. Therefore, we used pulsed stable isotope-resolved metabolomics (pSIRM) to determine intracellular metabolite pool sizes (concentrations), and isotopically non-stationary 13C-metabolic flux analysis (INST 13C-MFA) to calculate metabolic fluxes. We found that d0 cells mainly use glutamine to fuel the TCA. Furthermore, they rely on extracellular pyruvate to allow continuous growth. This metabolic situation does not allow for mitochondrial or glycolytic spare capacity, i.e. the ability to adapt energy generation to altered needs. Accordingly, neuronal precursor cells displayed a higher sensitivity to several mitochondrial toxicants than mature neurons differentiated from them. In summary, this study shows that precursor cells lose their glutamine dependency during differentiation while they gain flexibility of energy generation and thereby increase their resistance to low concentrations of mitochondrial toxicants. PMID: 29278688 [PubMed - as supplied by publisher]

Synthesis of [15 N]-Cholamine Bromide Hydrobromide. J Labelled Comp Radiopharm. 2017 Dec 26;: Authors: Szeto J, Lemoine R, Nguyen R, Olson LL, Tanga MJ Abstract [15 N]-Cholamine is an isotope tag for metabolomics research, because it possesses two important properties: an NMR active isotope and a permanent charge for MS sensitivity. Here we present a scalable synthesis of [15 N]-cholamine. PMID: 29278650 [PubMed - as supplied by publisher]