PubMed

Related Articles A metabolomic, geographic, and seasonal analysis of the contribution of pollen-derived adenosine to allergic sensitization. Metabolomics. 2016 Dec;12(12): Authors: Mueller GA, Thompson PM, DeRose EF, O'Connell TM, London RE Abstract BACKGROUND: Studies on ragweed and birch pollen extracts suggested that the adenosine content is an important factor in allergic sensitization. However, exposure levels from other pollens and considerations of geographic and seasonal factors have not been evaluated. OBJECTIVE: This study compared the metabolite profile of pollen species important for allergic disease, specifically measured the adenosine content, and evaluated exposure to pollen-derived adenosine. METHODS: An NMR metabolomics approach was used to measure metabolite concentrations in twenty-six pollen extracts. Pollen count data was analyzed from five cities to model exposure. RESULTS: A principal component analysis of the various metabolites identified by NMR showed that pollen extracts could be differentiated primarily by sugar content: glucose, fructose, sucrose, and myo-inositol. In extracts of 10 mg of pollen/ml, the adenosine was highest for grasses (45 μM) followed by trees (23 μM) and weeds (19 μM). Pollen count data showed that tree pollen was typically 5-10 times the amount of other pollens. At the daily peaks of tree, grass, and weed season the pollen-derived adenosine exposure per day is likely to only be 1.1, 0.11, and 0.12 μg, respectively. Seasonal models of pollen exposure and respiration suggest that it would be a rare event limited to tree pollen season for concentrations of pollen-derived adenosine to approach physiological levels. CONCLUSIONS: Sugar content and other metabolites may be useful in classifying pollens. Unless other factors create localized exposures that are very different from these models, pollen-derived adenosine is unlikely to be a major factor in allergic sensitization. PMID: 28798556 [PubMed]

Related Articles Working Up a Good Sweat - The Challenges of Standardising Sweat Collection for Metabolomics Analysis. Clin Biochem Rev. 2017 Feb;38(1):13-34 Authors: Hussain JN, Mantri N, Cohen MM Abstract INTRODUCTION: Human sweat is a complex biofluid of interest to diverse scientific fields. Metabolomics analysis of sweat promises to improve screening, diagnosis and self-monitoring of numerous conditions through new applications and greater personalisation of medical interventions. Before these applications can be fully developed, existing methods for the collection, handling, processing and storage of human sweat need to be revised. This review presents a cross-disciplinary overview of the origins, composition, physical characteristics and functional roles of human sweat, and explores the factors involved in standardising sweat collection for metabolomics analysis. METHODS: A literature review of human sweat analysis over the past 10 years (2006-2016) was performed to identify studies with metabolomics or similarly applicable 'omics' analysis. These studies were reviewed with attention to sweat induction and sampling techniques, timing of sweat collection, sweat storage conditions, laboratory derivation, processing and analytical platforms. RESULTS: Comparative analysis of 20 studies revealed numerous factors that can significantly impact the validity, reliability and reproducibility of sweat analysis including: anatomical site of sweat sampling, skin integrity and preparation; temperature and humidity at the sweat collection sites; timing and nature of sweat collection; metabolic quenching; transport and storage; qualitative and quantitative measurements of the skin microbiota at sweat collection sites; and individual variables such as diet, emotional state, metabolic conditions, pharmaceutical, recreational drug and supplement use. CONCLUSION: Further development of standard operating protocols for human sweat collection can open the way for sweat metabolomics to significantly add to our understanding of human physiology in health and disease. PMID: 28798503 [PubMed]

Related Articles Adipose tissue, metabolic and inflammatory responses to stroke are altered in obese mice. Dis Model Mech. 2017 Aug 10;: Authors: Haley MJ, Mullard G, Hollywood KA, Cooper GJ, Dunn WB, Lawrence CB Abstract Obesity is an independent risk factor for stroke, though several clinical studies have reported that obesity improves stroke outcome. Obesity is hypothesised to aid recovery by protecting against post-stroke catabolism. We therefore assessed whether obese mice had an altered metabolic and inflammatory response to stroke. Obese ob/ob mice underwent 20 min middle cerebral artery occlusion and 24 h reperfusion. Lipid metabolism and expression of inflammatory cytokines were assessed in the plasma, liver and adipose tissue. The obese-specific metabolic response to stroke was assessed in plasma using non-targeted UPLC-MS metabolomics coupled with univariate and multivariate analysis. Obesity had no effect on the extent of weight loss 24 h after stroke but affected the metabolic and inflammatory responses to stroke, predominantly affecting lipid metabolism. Specifically, obese mice had increases in plasma free fatty acids and expression of adipose lipolytic enzymes. Metabolomics identified several classes of metabolites affected by stroke in obese mice, including fatty acids and membrane lipids (glycerophospholipids, lysophospholipids and sphingolipids). Obesity also featured increases in inflammatory cytokines in the plasma and adipose tissue. Overall these results demonstrate that obesity affected the acute metabolic and inflammatory response to stroke and suggest a potential role for adipose tissue in this effect. These findings could have implications for longer-term recovery and also further highlight the importance of considering comorbidities in preclinical stroke research, especially when identifying biomarkers for stroke. However, further work is required to assess whether these changes translate into long-term effects on recovery. PMID: 28798136 [PubMed - as supplied by publisher]

Related Articles Venlafaxine exerts antidepressant effects possibly by activating MAPK-ERK1/2 and P13K-AKT pathways in the hippocampus. Behav Brain Res. 2017 Aug 07;: Authors: Shen P, Hu Q, Dong M, Bai S, Liang Z, Chen Z, Li P, Hu Z, Zhong X, Zhu D, Wang H, Xie P Abstract Serotonin noradrenaline reuptake inhibitors are effective antidepressant drugs, which include venlafaxine and duloxetine. Venlafaxine is commonly used in a clinical context, but the molecular biological mechanisms behind its effects have not been fully determined. Here, we explored the potential biological effects of venlafaxine on mouse hippocampus. Mice were randomly divided into two groups and injected daily with 0.9% NaCl solution or venlafaxine. A GC-MS-based metabolomic approach was used to identify possible metabolic differences between these groups, and the key proteins involved in the relevant pathways were validated by western blotting. In our experiments, 27 hippocampal metabolites that distinguished the venlafaxine group from the control group were identified. These differential metabolites were subjected to Ingenuity Pathway Analysis, which revealed that they were strongly related to two metabolic pathways (MAPK-ERK1/2 and P13K-AKT signaling pathways). Six key proteins, BDNF, p-c-Raf, p-MAPK, p-MEK, p-AKT, and CREB, were verified by western blotting and the results were consistent with the differential metabolites identified by GC-MS. This study sheds light on the biological mechanisms underlying the effects of venlafaxine. PMID: 28797602 [PubMed - as supplied by publisher]

Related Articles Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J. 2017 Aug 01;36(15):2233-2250 Authors: Chen PH, Smith TJ, Wu J, Siesser PF, Bisnett BJ, Khan F, Hogue M, Soderblom E, Tang F, Marks JR, Major MB, Swarts BM, Boyce M, Chi JT Abstract O-GlcNAcylation is an essential, nutrient-sensitive post-translational modification, but its biochemical and phenotypic effects remain incompletely understood. To address this question, we investigated the global transcriptional response to perturbations in O-GlcNAcylation. Unexpectedly, many transcriptional effects of O-GlcNAc transferase (OGT) inhibition were due to the activation of NRF2, the master regulator of redox stress tolerance. Moreover, we found that a signature of low OGT activity strongly correlates with NRF2 activation in multiple tumor expression datasets. Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regulator of NRF2, as a direct substrate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiquitination and degradation of NRF2. Interestingly, O-GlcNAc levels and NRF2 activation co-vary in response to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstream stress resistance. Our results reveal a novel regulatory connection between nutrient-sensitive glycosylation and NRF2 signaling and provide a blueprint for future approaches to discover functionally important O-GlcNAcylation events on other KLHL family proteins in various experimental and disease contexts. PMID: 28663241 [PubMed - indexed for MEDLINE]

Related Articles Metabolic profiling of apples from different production systems before and after controlled atmosphere (CA) storage studied by (1)H high resolution-magic angle spinning (HR-MAS) NMR. Food Chem. 2017 Oct 15;233:391-400 Authors: Vermathen M, Marzorati M, Diserens G, Baumgartner D, Good C, Gasser F, Vermathen P Abstract Determination of metabolic alterations in apples induced by such processes as different crop protection strategies or storage, are of interest to assess correlations with fruit quality or fruit disorders. Preliminary results proposed the metabolic discrimination of apples from organic (BIO), integrated (IP) and low-input (LI) production. To determine contributions of temporal metabolic developments and to define the type of metabolic changes during storage, (1)H high resolution-magic angle spinning (HR-MAS) NMR spectroscopy of apple pulp was performed before and after two time points of controlled atmosphere storage. Statistical analysis revealed similar metabolic changes over time for IP-, LI- and BIO-samples, mainly decreasing lipid and sucrose, and increasing fructose, glucose and acetaldehyde levels, which are potential contributors to fruit aroma. Across the production systems, BIO apples had consistently higher levels of fructose and monomeric phenolic compounds but lower levels of condensed polyphenols than LI and IP apples, while the remaining metabolites assimilated. PMID: 28530590 [PubMed - indexed for MEDLINE]

Related Articles A systems biology approach reveals major metabolic changes in the thermoacidophilic archaeon Sulfolobus solfataricus in response to the carbon source L-fucose versus D-glucose. Mol Microbiol. 2016 Dec;102(5):882-908 Authors: Wolf J, Stark H, Fafenrot K, Albersmeier A, Pham TK, Müller KB, Meyer BH, Hoffmann L, Shen L, Albaum SP, Kouril T, Schmidt-Hohagen K, Neumann-Schaal M, Bräsen C, Kalinowski J, Wright PC, Albers SV, Schomburg D, Siebers B Abstract Archaea are characterised by a complex metabolism with many unique enzymes that differ from their bacterial and eukaryotic counterparts. The thermoacidophilic archaeon Sulfolobus solfataricus is known for its metabolic versatility and is able to utilize a great variety of different carbon sources. However, the underlying degradation pathways and their regulation are often unknown. In this work, the growth on different carbon sources was analysed, using an integrated systems biology approach. The comparison of growth on L-fucose and D-glucose allows first insights into the genome-wide changes in response to the two carbon sources and revealed a new pathway for L-fucose degradation in S. solfataricus. During growth on L-fucose major changes in the central carbon metabolic network, as well as an increased activity of the glyoxylate bypass and the 3-hydroxypropionate/4-hydroxybutyrate cycle were observed. Within the newly discovered pathway for L-fucose degradation the following key reactions were identified: (i) L-fucose oxidation to L-fuconate via a dehydrogenase, (ii) dehydration to 2-keto-3-deoxy-L-fuconate via dehydratase, (iii) 2-keto-3-deoxy-L-fuconate cleavage to pyruvate and L-lactaldehyde via aldolase and (iv) L-lactaldehyde conversion to L-lactate via aldehyde dehydrogenase. This pathway as well as L-fucose transport shows interesting overlaps to the D-arabinose pathway, representing another example for pathway promiscuity in Sulfolobus species. PMID: 27611014 [PubMed - indexed for MEDLINE]

Related Articles Inflammation Thread Runs across Medical Laboratory Specialities. Mediators Inflamm. 2016;2016:4121837 Authors: Nydegger U, Lung T, Risch L, Risch M, Medina Escobar P, Bodmer T Abstract We work on the assumption that four major specialities or sectors of medical laboratory assays, comprising clinical chemistry, haematology, immunology, and microbiology, embraced by genome sequencing techniques, are routinely in use. Medical laboratory markers for inflammation serve as model: they are allotted to most fields of medical lab assays including genomics. Incessant coding of assays aligns each of them in the long lists of big data. As exemplified with the complement gene family, containing C2, C3, C8A, C8B, CFH, CFI, and ITGB2, heritability patterns/risk factors associated with diseases with genetic glitch of complement components are unfolding. The C4 component serum levels depend on sufficient vitamin D whilst low vitamin D is inversely related to IgG1, IgA, and C3 linking vitamin sufficiency to innate immunity. Whole genome sequencing of microbial organisms may distinguish virulent from nonvirulent and antibiotic resistant from nonresistant varieties of the same species and thus can be listed in personal big data banks including microbiological pathology; the big data warehouse continues to grow. PMID: 27493451 [PubMed - indexed for MEDLINE]

Related Articles Seminal plasma metabolomics approach for the diagnosis of unexplained male infertility. PLoS One. 2017;12(8):e0181115 Authors: Qiao S, Wu W, Chen M, Tang Q, Xia Y, Jia W, Wang X Abstract We used a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach to obtain the metabolic profiling of unexplained male infertility (UMI), and identified seminal plasma biomarkers associated with UMI by a two-stage population study. A robust OPLS-DA model based on these identified metabolites was able to distinguish 82% of the UMI patients from health controls with a specificity of 92%. In this model, 44 metabolites were found differentially expressed in UMI subjects compared with health controls. By pathway enrichment analysis, we identified several major changed metabolic pathways related to UMI. Our findings provide new perspective for the diagnosis of UMI. PMID: 28797078 [PubMed - in process]

Related Articles Systems and synthetic biology perspective of the versatile plant-pathogenic and polysaccharide-producing bacterium Xanthomonas campestris. Microbiology. 2017 Aug 10;: Authors: Schatschneider S, Schneider J, Blom J, Létisse F, Niehaus K, Goesmann A, Vorhölter FJ Abstract Bacteria of the genus Xanthomonas are a major group of plant pathogens. They are hazardous to important crops and closely related to human pathogens. Being collectively a major focus of molecular phytopathology, an increasing number of diverse and intricate mechanisms are emerging by which they communicate, interfere with host signalling and keep competition at bay. Interestingly, they are also biotechnologically relevant polysaccharide producers. Systems biotechnology techniques have revealed their central metabolism and a growing number of remarkable features. Traditional analyses of Xanthomonas metabolism missed the Embden-Meyerhof-Parnas pathway (glycolysis) as being a route by which energy and molecular building blocks are derived from glucose. As a consequence of the emerging full picture of their metabolism process, xanthomonads were discovered to have three alternative catabolic pathways and they use an unusual and reversible phosphofructokinase as a key enzyme. In this review, we summarize the synthetic and systems biology methods and the bioinformatics tools applied to reconstruct their metabolic network and reveal the dynamic fluxes within their complex carbohydrate metabolism. This is based on insights from omics disciplines; in particular, genomics, transcriptomics, proteomics and metabolomics. Analysis of high-throughput omics data facilitates the reconstruction of organism-specific large- and genome-scale metabolic networks. Reconstructed metabolic networks are fundamental to the formulation of metabolic models that facilitate the simulation of actual metabolic activities under specific environmental conditions. PMID: 28795660 [PubMed - as supplied by publisher]

Related Articles Accurate Identification of Unknown and Known Metabolic Mixture Components by Combining 3D NMR with FT-ICR MS/MS. J Proteome Res. 2017 Aug 10;: Authors: Wang C, He L, Li D, Bruschweiler-Li L, Marshall AG, Bruschweiler R Abstract Metabolite identification in metabolomics samples is a key step that critically impacts downstream analysis. We recently introduced the SUMMIT NMR/MS hybrid approach for the identification of the molecular structure of unknown metabolites, based on the combination of NMR, mass spectrometry (MS), and combinatorial cheminformatics. Here, we demonstrate the feasibility of the approach for an untargeted analysis of both a model mixture and E. coli cell lysate, based on 2D/3D NMR experiments in combination with FT-ICR MS and MS/MS data. For 19 of the 25 model metabolites SUMMIT yielded complete structures that matched those in the mixture independent of database information. Of those, 7 top-ranked structures matched those in the mixture, and 4 of those were further validated by positive ion MS/MS. For 5 metabolites, not part of the 19 metabolites, correct molecular structural motifs could be identified. For E. coli, SUMMIT MS/NMR identified 20 previously known metabolites with 3 or more 1H spins independent of database information. Moreover, for 15 unknown metabolites, molecular structural fragments were determined consistent with their spin systems and chemical shifts. By providing structural information for entire metabolites or molecular fragments, SUMMIT MS/NMR greatly assists the targeted or untargeted analysis of complex mixtures of unknown compounds. PMID: 28795575 [PubMed - as supplied by publisher]

Related Articles Plasma Metabolomics Reveals Steroidal Alkaloids as Novel Biomarkers of Tomato Intake in Mice. Mol Nutr Food Res. 2017 Aug 09;: Authors: Cichon MJ, Riedl KM, Wan L, Thomas-Ahner JM, Francis DM, Clinton SK, Schwartz SJ Abstract SCOPE: Diets rich in tomato products are associated with a reduced risk of various chronic disease processes. The carotenoid lycopene is most intensely studied as the bioactive mediating health effects, yet tomatoes contain an array of phytochemicals. We conducted an untargeted metabolomics study on blood plasma to identify novel markers of tomato consumption absorbed from the diet and released into the bloodstream in mice. METHODS AND RESULTS: Male mice were fed a control AIN-93G diet or the same diet supplemented with 0.25% lycopene beadlets, or 10% freeze-dried red tomato, tangerine tomato, or low-carotenoid tomato for 4 weeks. Untargeted UHPLC-QTOF-MS data acquisition and differential analysis of plasma metabolites revealed several structurally related deglycosylated tomato steroidal alkaloids, including tomatidine and hydroxylated/desaturated derivatives, in plasma after the consumption of all 3 tomato varieties. Additionally, plasma metabolite profiles reflected glycoalkaloid forms found in the tomato diets. CONCLUSION: Dietary tomato glycoalkaloids are cleaved during digestion to aglycones and further metabolized post-absorption. Steroidal alkaloids in plasma may serve as novel and specific biomarkers of tomato consumption and represent a class of phytochemical metabolites that could potentially have in vivo bioactivity impacting health and disease processes. This article is protected by copyright. All rights reserved. PMID: 28795489 [PubMed - as supplied by publisher]

Related Articles Mass spectrometry data of metabolomics analysis of Nepenthes pitchers. Data Brief. 2017 Oct;14:295-297 Authors: Rosli MAF, Azizan KA, Baharum SN, Goh HH Abstract Hybridisation plays a significant role in the evolution and diversification of plants. Hybridisation among Nepenthes species is extensive, either naturally or man-made. To investigate the effects of hybridisation on the chemical compositions, we carried out metabolomics study on pitcher tissue of Nepenthes ampullaria, Nepenthes rafflesiana and their hybrid, Nepenthes × hookeriana. Pitcher samples were harvested and extracted in methanol:chloroform:water via sonication-assisted extraction before analysed using LC-TOF-MS. MS data were analysed using XCMS online version 2.2.5. This is the first MS data report towards the profiling, identification and comprehensive comparison of metabolites present in Nepenthes species. PMID: 28795107 [PubMed]

Related Articles Metabolomic Evaluation of the Consequences of Plasma Cystathionine Elevation in Adults with Stable Angina Pectoris. J Nutr. 2017 Aug 09;: Authors: DeRatt BN, Ralat MA, Lysne V, Tayyari F, Dhar I, Edison AS, Garrett TJ, Midttun Ø, Ueland PM, Nygård OK, Gregory JF Abstract Background: An elevated circulating cystathionine concentration, which arises in part from insufficiencies of vitamin B-6, B-12, or folate, has been shown to be associated with cardiovascular disease (CVD) risk. Hydrogen sulfide (H2S) is a gasotransmitter involved in vasodilation, neuromodulation, and inflammation. Most endogenously produced H2S is formed by pyridoxal phosphate (PLP)-dependent enzymes by noncanonical reactions of the transsulfuration pathway that yield H2S concurrently form lanthionine and homolanthionine. Thus, plasma lanthionine and homolanthionine concentrations can provide relative information about H2S production in vivo.Objective: To determine the metabolic consequences of an elevated plasma cystathionine concentration in adults with stable angina pectoris (SAP), we conducted both targeted and untargeted metabolomic analyses.Methods: We conducted NMR and LC-mass spectrometry (MS) metabolomic analyses on a subset of 80 plasma samples from the Western Norway Coronary Angiography Cohort and selected, based on plasma cystathionine concentrations, a group with high cystathionine concentrations [1.32 ± 0.60 μmol/L (mean ± SD); n = 40] and a group with low cystathionine concentrations [0.137 ± 0.011 μmol/L (mean ± SD); n = 40]. Targeted and untargeted metabolomic analyses were performed and assessed with the use of Student's t tests corrected for multiple testing. Overall differences between the cystathionine groups were assessed by untargeted NMR and LC-MS metabolomic methods and evaluated by partial least squares discriminant analysis (PLS-DA) with significant discriminating metabolites identified with 99% confidence.Results: Subjects with high cystathionine concentrations had 75% higher plasma lanthionine concentrations (0.12 ± 0.044 μmol/L) than subjects with low cystathionine concentrations [0.032 ± 0.013 μmol/L (P < 0.001)]. Although plasma homolanthionine concentrations were notably higher than lanthionine concentrations, they were not different between the groups (P = 0.47). PLS-DA results showed that a high plasma cystathionine concentration in SAP was associated with higher glucose, branched-chain amino acids, and phenylalanine concentrations, lower kidney function, and lower glutathione and plasma PLP concentrations due to greater catabolism. The high-cystathionine group had a greater proportion of subjects in the postprandial state.Conclusion: These data suggest that metabolic perturbations consistent with higher CVD risk exist in SAP patients with elevated plasma cystathionine concentrations. PMID: 28794210 [PubMed - as supplied by publisher]

Related Articles Estimation of Chicken Intake by Adults Using Metabolomics-Derived Markers. J Nutr. 2017 Aug 09;: Authors: Yin X, Gibbons H, Rundle M, Frost G, McNulty BA, Nugent AP, Walton J, Flynn A, Gibney MJ, Brennan L Abstract Background: Improved assessment of meat intake with the use of metabolomics-derived markers can provide objective data and could be helpful in clarifying proposed associations between meat intake and health.Objective: The objective of this study was to identify novel markers of chicken intake using a metabolomics approach and use markers to determine intake in an independent cohort.Methods: Ten participants [age: 62 y; body mass index (in kg/m(2)): 28.25] in the NutriTech food intake study consumed increasing amounts of chicken, from 88 to 290 g/d, in a 3-wk span. Urine and blood samples were analyzed by nuclear magnetic resonance and mass spectrometry, respectively. A multivariate data analysis was performed to identify markers associated with chicken intake. A calibration curve was built based on dose-response association using NutriTech data. A Bland-Altman analysis evaluated the agreement between reported and calculated chicken intake in a National Adult Nutrition Survey cohort.Results: Multivariate data analysis of postprandial and fasting urine samples collected in participants in the NutriTech study revealed good discrimination between high (290 g/d) and low (88 g/d) chicken intakes. Urinary metabolite profiles showed differences in metabolite levels between low and high chicken intakes. Examining metabolite profiles revealed that guanidoacetate increased from 1.47 to 3.66 mmol/L following increasing chicken intakes from 88 to 290 g/d (P < 0.01). Using a calibration curve developed from the NutriTech study, chicken intake was calculated through the use of data from the National Adult Nutrition Survey, in which consumers of chicken had a higher guanidoacetate excretion (0.70 mmol/L) than did nonconsumers (0.47 mmol/L; P < 0.01). A Bland-Altman analysis revealed good agreement between reported and calculated intakes, with a bias of -30.2 g/d. Plasma metabolite analysis demonstrated that 3-methylhistidine was a more suitable indicator of chicken intake than 1-methylhistidine.Conclusions: Guanidoacetate was successfully identified and confirmed as a marker of chicken intake, and its measurement in fasting urine samples could be used to determine chicken intake in a free-living population. This trial was registered at clinicaltrials.gov as NCT01684917. PMID: 28794208 [PubMed - as supplied by publisher]

Related Articles The Human Serum Metabolome of Vitamin B-12 Deficiency and Repletion, and Associations with Neurological Function in Elderly Adults. J Nutr. 2017 Aug 09;: Authors: Brito A, Grapov D, Fahrmann J, Harvey D, Green R, Miller JW, Fedosov SN, Shahab-Ferdows S, Hampel D, Pedersen TL, Fiehn O, Newman JW, Uauy R, Allen LH Abstract Background: The specific metabolomic perturbations that occur in vitamin B-12 deficiency, and their associations with neurological function, are not well characterized.Objective: We sought to characterize the human serum metabolome in subclinical vitamin B-12 deficiency and repletion.Methods: A before-and-after treatment study provided 1 injection of 10 mg vitamin B-12 (with 100 mg pyridoxine and 100 mg thiamin) to 27 community-dwelling elderly Chileans (∼74 y old) with vitamin B-12 deficiency, as evaluated with serum vitamin B-12, total plasma homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin. The combined indicator of vitamin B-12 status (cB-12) was computed. Targeted metabolites [166 acylcarnitines, amino acids, sugars, glycerophospholipids, and sphingolipids (liquid chromatography-tandem mass spectrometry)], and untargeted metabolites [247 chemical entities (gas chromatography time-of-flight mass spectrometry)] were measured at baseline and 4 mo after treatment. A peripheral nerve score was developed. Differences before and after treatment were examined. For targeted metabolomics, the data from 18 individuals with adequate vitamin B-12 status (selected from the same population) were added to the before-and-after treatment data set. Network visualizations and metabolic pathways are illustrated.Results: The injection increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001), and reduced tHcy and serum MMA (P < 0.001). Metabolomic changes from before to after treatment included increases (P < 0.001) in acylcarnitines, plasmalogens, and other phospholipids, whereas proline and other intermediaries of one-carbon metabolism-that is, methionine and cysteine-were reduced (P < 0.001). Direct significant correlations (P < 0.05 after the false discovery rate procedure) were identified between acylcarnitines, plasmalogens, phospholipids, lyso-phospholipids, and sphingomyelins compared with vitamin B-12 status and nerve function. Multiple connections were identified with primary metabolites (e.g., an inverse relation between vitamin B-12 markers and tryptophan, tyrosine, and pyruvic, succinic, and citric acids, and a direct correlation between the nerve score and arginine).Conclusions: The human serum metabolome in vitamin B-12 deficiency and the changes that occur after supplementation are characterized. Metabolomics revealed connections between vitamin B-12 status and serum metabolic markers of mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function, including some previously implicated in Alzheimer and Parkinson diseases. This trial was registered at www.controlled-trials.com as ISRCTN02694183. PMID: 28794205 [PubMed - as supplied by publisher]

Related Articles Uptake and transformations of engineered nanomaterials: Critical responses observed in terrestrial plants and the model plant Arabidopsis thaliana. Sci Total Environ. 2017 Aug 05;607-608:1497-1516 Authors: Montes A, Bisson MA, Gardella JA, Aga DS Abstract With the applications of engineered nanomaterials (ENMs) continually expanding and production quickly growing, residues of ENMs will end up in the environment at levels that may be harmful to non-target organisms. Many of the tunable properties that have made them desirable, such as type, size, charge, or coating, also contribute to the current difficulties in understanding the fate of ENMs in the environment. This review article focuses on studies that investigate plant-ENM interactions, including techniques used to study these interactions and documented plant responses due to the phytotoxic effects of ENMs. The many variables which can be altered for an experiment, such as type, size, and concentration of ENMs, make it difficult to formulate generalizations about the uptake mechanism involved, or to make an inference on the subcellular localization and distribution of the internalized ENMs in plant tissue. In order to avoid these challenges, studies can utilize a model organism such as Arabidopsis thaliana, and a combination of analytical techniques that can reveal complementary information in order to assess how the different experimental conditions influence the uptake and phytotoxicity of ENMs. This review presents recent studies regarding plant-ENM interactions employing Arabidopsis to demonstrate how the use of this model plant can advance our understanding of plant-ENM interactions and guide additional studies using other plant species. Overarching results suggest that more sensitive tests and consistency in experimental designs are needed to fully assess and understand the phytotoxic effects of ENMs in the environment. PMID: 28793406 [PubMed - as supplied by publisher]

Related Articles Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. J Exp Med. 2017 Jan;214(1):107-123 Authors: He B, Hoang TK, Wang T, Ferris M, Taylor CM, Tian X, Luo M, Tran DQ, Zhou J, Tatevian N, Luo F, Molina JG, Blackburn MR, Gomez TH, Roos S, Rhoads JM, Liu Y Abstract Regulatory T (T reg) cell deficiency causes lethal, CD4(+) T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency-mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3(+) T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota-inosine-A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction. PMID: 27994068 [PubMed - indexed for MEDLINE]

Related Articles Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells. Antioxid Redox Signal. 2017 Mar 10;26(8):351-363 Authors: Palmieri EM, Menga A, Lebrun A, Hooper DC, Butterfield DA, Mazzone M, Castegna A Abstract AIMS: Microglial cells are brain-resident macrophages engaged in surveillance and maintained in a constant state of relative inactivity. However, their involvement in autoimmune diseases indicates that in pathological conditions microglia gain an inflammatory phenotype. The mechanisms underlying this change in the microglial phenotype are still unclear. Since metabolism is an important modulator of immune cell function, we focused our attention on glutamine synthetase (GS), a modulator of the response to lipopolysaccharide (LPS) activation in other cell types, which is expressed by microglia. RESULTS: GS inhibition enhances release of inflammatory mediators of LPS-activated microglia in vitro, leading to perturbation of the redox balance and decreased viability of cocultured neurons. GS inhibition also decreases insulin-mediated glucose uptake in microglia. In vivo, microglia-specific GS ablation enhances expression of inflammatory markers upon LPS treatment. In the spinal cords from experimental autoimmune encephalomyelitis (EAE), GS expression levels and glutamine/glutamate ratios are reduced. INNOVATION: Recently, metabolism has been highlighted as mediator of immune cell function through the discovery of mechanisms that (behind these metabolic changes) modulate the inflammatory response. The present study shows for the first time a metabolic mechanism mediating microglial response to a proinflammatory stimulus, pointing to GS activity as a master modulator of immune cell function and thus unraveling a potential therapeutic target. CONCLUSIONS: Our study highlights a new role of GS in modulating immune response in microglia, providing insights into the pathogenic mechanisms associated with inflammation and new strategies of therapeutic intervention. Antioxid. Redox Signal. 26, 351-363. PMID: 27758118 [PubMed - indexed for MEDLINE]

Related Articles NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med. 2016 Sep;22(9):1002-12 Authors: Moon JS, Nakahira K, Chung KP, DeNicola GM, Koo MJ, Pabón MA, Rooney KT, Yoon JH, Ryter SW, Stout-Delgado H, Choi AM Abstract Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation. PMID: 27455510 [PubMed - indexed for MEDLINE]