PubMed

Serum Metabolomics of Burkitt Lymphoma Mouse Models. PLoS One. 2017;12(1):e0170896 Authors: Yang F, Du J, Zhang H, Ruan G, Xiang J, Wang L, Sun H, Guan A, Shen G, Liu Y, Guo X, Li Q, Tang Y Abstract Burkitt lymphoma (BL) is a rare and highly aggressive type of non-Hodgkin lymphoma. The mortality rate of BL patients is very high due to the rapid growth rate and frequent systemic spread of the disease. A better understanding of the pathogenesis, more sensitive diagnostic tools and effective treatment methods for BL are essential. Metabolomics, an important aspect of systems biology, allows the comprehensive analysis of global, dynamic and endogenous biological metabolites based on their nuclear magnetic resonance (NMR) and mass spectrometry (MS). It has already been used to investigate the pathogenesis and discover new biomarkers for disease diagnosis and prognosis. In this study, we analyzed differences of serum metabolites in BL mice and normal mice by NMR-based metabolomics. We found that metabolites associated with energy metabolism, amino acid metabolism, fatty acid metabolism and choline phospholipid metabolism were altered in BL mice. The diagnostic potential of the metabolite differences was investigated in this study. Glutamate, glycerol and choline had a high diagnostic accuracy; in contrast, isoleucine, leucine, pyruvate, lysine, α-ketoglutarate, betaine, glycine, creatine, serine, lactate, tyrosine, phenylalanine, histidine and formate enabled the accurate differentiation of BL mice from normal mice. The discovery of abnormal metabolism and relevant differential metabolites may provide useful clues for developing novel, noninvasive approaches for the diagnosis and prognosis of BL based on these potential biomarkers. PMID: 28129369 [PubMed - in process]

Parenteral and enteral nutrition in surgical critical-care: plasma metabolomics demonstrates divergent effects on nitrogen, fatty-acid, ribonucleotide and oxidative metabolism. J Trauma Acute Care Surg. 2017 Jan 26;: Authors: Parent BA, Seaton M, Djukovic D, Gu H, Wheelock B, Raftery D, O'Keefe GE Abstract BACKGROUND: Artificial nutrition support is central to the care of critically ill patients and is primarily provided enterally (EN). There are circumstances when parenteral nutrition (PN) is considered necessary. We are uncertain how each of these approaches confer clinical benefits beyond simply providing calories. We sought to better understand how each of these techniques influence metabolism in critically-ill patients using a broad-based metabolomics approach. Metabolic responses to EN and PN may differ in ways that could help us understand how to optimize use of these therapies. METHODS: We prospectively enrolled subjects over 7 months in 2015 at an urban, level-one trauma center. Subjects were included prior to starting either EN or PN during their inpatient admission. Plasma samples were obtained between 1-12 hours before initiation of artificial nutrition, and 3 and 7 days later. All samples were analyzed with liquid chromatography/mass-spectrometry-based metabolomics. Differences in metabolite concentrations were assessed via principal component analyses and multiple linear regression. RESULTS: We enrolled 30 subjects. Among the critically-ill subjects, 10 received EN and 10 received PN. In subjects receiving EN, amino acid and urea cycle metabolites (citrulline, p=0.04; ornithine, p=0.05) increased, as did ribonucleic acid metabolites (uridine, p=0.04; cysteine, 0=0.05; oxypurinol, p=0.04). Oxidative stress decreased over time. (increased betaine, p=0.05; decreased 4-pyridoxic acid, p=0.04). In subjects receiving PN amino acid concentrations increased over time (taurine, p=0.04; phenylalanine, p=0.05); omega 6 and omega 3 fatty acid concentrations decreased over time (p=0.05 and 0.03, respectively). CONCLUSION: EN was associated with amino-acid repletion, urea cycle upregulation, restoration of antioxidants, and increasing RNA synthesis. Parenteral nutrition was associated with increased amino acid concentrations, but did not influence protein metabolism or antioxidant repletion. This suggests that parenteral amino acids are utilized less effectively than those given enterally. The biomarkers reported in this study may be useful in guiding nutrition therapy for critically-ill patients. LEVEL OF EVIDENCE: III, Study Type: Diagnostic Tests or Criteria. PMID: 28129265 [PubMed - as supplied by publisher]

Discovery of C-Glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 by a Combined NMR-Based Metabolomics and Bioinformatics Workflow. J Nat Prod. 2017 Jan 27;: Authors: Wu C, Du C, Ichinose K, Choi YH, van Wezel GP Abstract Mining of microbial genomes has revealed that actinomycetes harbor far more biosynthetic potential for bioactive natural products than anticipated. Activation of (cryptic) biosynthetic gene clusters and identification of the corresponding metabolites has become a focal point for drug discovery. Here, we applied NMR-based metabolomics combined with bioinformatics to identify novel C-glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 and to elucidate the biosynthetic pathway. Following activation of the cryptic qin gene cluster for a type II polyketide synthase (PKS) by constitutive expression of its pathway-specific activator, bioinformatics coupled to NMR profiling facilitated the chromatographic isolation and structural elucidation of qinimycins A-C (1-3). The intriguing structural features of the qinimycins, including 8-C-glycosylation, 5,14-epoxidation, and 13-hydroxylation, distinguished these molecules from the model pyranonaphthoquinones actinorhodin, medermycin, and granaticin. Another novelty lies in the unusual fusion of a deoxyaminosugar to the pyranonaphthoquinone backbone during biosynthesis of the antibiotics BE-54238 A and B (4, 5). Qinimycins showed weak antimicrobial activity against Gram-positive bacteria. Our work shows the utility of combining bioinformatics, targeted activation of cryptic gene clusters, and NMR-based metabolic profiling as an effective pipeline for the discovery of microbial natural products with distinctive skeletons. PMID: 28128554 [PubMed - as supplied by publisher]

Schisandrol B protects against cholestatic liver injury through pregnane X receptor. Br J Pharmacol. 2017 Jan 27;: Authors: Zeng H, Jiang Y, Chen P, Fan X, Li D, Liu A, Ma X, Xie W, Liu P, Gonzalez FJ, Huang M, Bi H Abstract BACKGROUND AND PURPOSE: Currently, ursodeoxycholic acid is the only FDA-approved drug for limited cholestatic liver diseases, and thus the development of new therapeutic approaches is of great importance. This study aimed to evaluate the anti-cholestasis effect of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera. EXPERIMENTAL APPROACH: Hepatoprotective effect of SolB against lithocholic acid (LCA)-induced intrahepatic extrahepatic cholestasis was evaluated in mice. Metabolomic analysis and gene analysis were performed to reveal the involvement of PXR (pregnane X receptor). Further molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the vital role of PXR pathway on SolB's anti-cholestasis effect. KEY RESULTS: SolB was found to significantly protect against LCA-induced intrahepatic and BDL-induced extrahepatic cholestasis. Furthermore, therapeutic treatment of SolB significantly decreased the mortality of cholestatic mice. Metabolomics and gene analysis revealed that SolB accelerates the metabolism of bile acid, promotes bile acid efflux into the intestine, and induces hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Further mechanistic study show that SolB can activate human PXR and up-regulate PXR target genes in human cell lines. Additionally, SolB could not significantly protect Pxr-null mice from liver injury induced by intrahepatic cholestasis thus providing genetic evidence that the effect of SolB is PXR-dependent. CONCLUSION AND IMPLICATIONS: These findings provide direct evidence for the hepatoprotection of SolB against cholestasis by activating PXR. Therefore, SolB may be an effective approach for the prevention and treatment of cholestatic liver diseases. PMID: 28128437 [PubMed - as supplied by publisher]

Related Articles Comparative Metabolome Profile between Tobacco and Soybean Grown under Water-Stressed Conditions. Biomed Res Int. 2017;2017:3065251 Authors: Rabara RC, Tripathi P, Rushton PJ Abstract Understanding how plants respond to water deficit is important in order to develop crops tolerant to drought. In this study, we compare two large metabolomics datasets where we employed a nontargeted metabolomics approach to elucidate metabolic pathways perturbed by progressive dehydration in tobacco and soybean plants. The two datasets were created using the same strategy to create water deficit conditions and an identical metabolomics pipeline. Comparisons between the two datasets therefore reveal common responses between the two species, responses specific to one of the species, responses that occur in both root and leaf tissues, and responses that are specific to one tissue. Stomatal closure is the immediate response of the plant and this did not coincide with accumulation of abscisic acid. A total of 116 and 140 metabolites were observed in tobacco leaves and roots, respectively, while 241 and 207 were observed in soybean leaves and roots, respectively. Accumulation of metabolites is significantly correlated with the extent of dehydration in both species. Among the metabolites that show increases that are restricted to just one plant, 4-hydroxy-2-oxoglutaric acid (KHG) in tobacco roots and coumestrol in soybean roots show the highest tissue-specific accumulation. The comparisons of these two large nontargeted metabolomics datasets provide novel information and suggest that KHG will be a useful marker for drought stress for some members of Solanaceae and coumestrol for some legume species. PMID: 28127554 [PubMed - in process]

Related Articles Reply to Roerink et al.: Metabolomics of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2017 Jan 26;: Authors: Naviaux RK, Gordon E PMID: 28126717 [PubMed - as supplied by publisher]

Related Articles The application of skin metabolomics in the context of transdermal drug delivery. Pharmacol Rep. 2016 Oct 13;69(2):252-259 Authors: Li J, Xu W, Liang Y, Wang H Abstract Metabolomics is a powerful emerging tool for the identification of biomarkers and the exploration of metabolic pathways in a high-throughput manner. As an administration site for percutaneous absorption, the skin has a variety of metabolic enzymes, except other than hepar. However, technologies to fully detect dermal metabolites remain lacking. Skin metabolomics studies have mainly focused on the regulation of dermal metabolites by drugs or on the metabolism of drugs themselves. Skin metabolomics techniques include collection and preparation of skin samples, data collection, data processing and analysis. Furthermore, studying dermal metabolic effects via metabolomics can provide novel explanations for the pathogenesis of some dermatoses and unique insights for designing targeted prodrugs, promoting drug absorption and controlling drug concentration. This paper reviews current progress in the field of skin metabolomics, with a specific focus on dermal drug delivery systems and dermatosis. PMID: 28126641 [PubMed - as supplied by publisher]

Related Articles Co-option of the sphingolipid metabolism for the production of nitroalkene defensive chemicals in termite soldiers. Insect Biochem Mol Biol. 2017 Jan 23;: Authors: Jirošová A, Jančařík A, Menezes RC, Bazalová O, Dolejšová K, Vogel H, Jedlička P, Buček A, Brabcová J, Majer P, Hanus R, Svatoš A Abstract The aliphatic nitroalkene (E)-nitropentadec-1-ene (NPD), reported in early seventies in soldiers of the termite genus Prorhinotermes, was the first documented nitro compound produced by insects. Yet, its biosynthetic origin has long remained unknown. Here, we investigated in detail the biosynthesis of NPD in P. simplex soldiers. First, we track the dynamics in major metabolic pathways during soldier ontogeny, with emphasis on likely NPD precursors and intermediates. Second, we propose a hypothesis of NPD formation and verify its individual steps using in vivo incubations of putative precursors and intermediates. Third, we use a de novo assembled RNA-Seq profiles of workers and soldiers to identify putative enzymes underlying NPD formation. And fourth, we describe the caste- and age-specific expression dynamics of candidate initial genes of the proposed biosynthetic pathway. Our observations provide a strong support to the following biosynthetic scenario of NPD formation, representing an analogy of the sphingolipid pathway starting with the condensation of tetradecanoic acid with l-serine and leading to the formation of a C16 sphinganine. The C16 sphinganine is then oxidized at the terminal carbon to give rise to 2-amino-3-hydroxyhexadecanoic acid, further oxidized to 2-amino-3-oxohexadecanoic acid. Subsequent decarboxylation yields 1-aminopentadecan-2-one, which then proceeds through six-electron oxidation of the amino moiety to give rise to a 1-nitropentadecan-2-one. Keto group reduction and hydroxyl moiety elimination leads to NPD. The proposed biosynthetic sequence has been constructed from age-related quantitative dynamics of individual intermediates and confirmed by the detection of labeled products downstream of the administered labeled intermediates. Comparative RNA-Seq analyses followed by qRT-PCR validation identified orthologs of serine palmitoyltransferase and 3-ketodihydrosphingosine reductase genes as highly expressed in the NPD production site, i.e. the frontal gland of soldiers. A dramatic onset of expression of the two genes in the first days of soldier's life coincides with the start of NPD biosynthesis, giving further support to the proposed biosynthetic hypothesis. PMID: 28126587 [PubMed - as supplied by publisher]

Related Articles Editorial overview: Recent innovations in the metabolomics revolution. Curr Opin Biotechnol. 2017 Jan 23;: Authors: Kamphorst JJ, Lewis IA PMID: 28126441 [PubMed - as supplied by publisher]

Related Articles Synergistic Action of Genistein and Calcitriol in Immature Osteosarcoma MG-63 Cells by SGPL1 Up-Regulation. PLoS One. 2017;12(1):e0169742 Authors: Engel N, Adamus A, Schauer N, Kühn J, Nebe B, Seitz G, Kraft K Abstract BACKGROUND: Phytoestrogens such as genistein, the most prominent isoflavone from soy, show concentration-dependent anti-estrogenic or estrogenic effects. High genistein concentrations (>10 μM) also promote proliferation of bone cancer cells in vitro. On the other hand, the most active component of the vitamin D family, calcitriol, has been shown to be tumor protective in vitro and in vivo. The purpose of this study was to examine a putative synergism of genistein and calcitriol in two osteosarcoma cell lines MG-63 (early osteoblast), Saos-2 (mature osteoblast) and primary osteoblasts. METHODS: Thus, an initial screening based on cell cycle phase alterations, estrogen (ER) and vitamin D receptor (VDR) expression, live cell metabolic monitoring, and metabolomics were performed. RESULTS: Exposure to the combination of 100 μM genistein and 10 nM calcitriol reduced the number of proliferative cells to control levels, increased ERß and VDR expression, and reduced extracellular acidification (40%) as well as respiratory activity (70%), primarily in MG-63 cells. In order to identify the underlying cellular mechanisms in the MG-63 cell line, metabolic profiling via GC/MS technology was conducted. Combined treatment significantly influenced lipids and amino acids preferably, whereas metabolites of the energy metabolism were not altered. The comparative analysis of the log2-ratios revealed that after combined treatment only the metabolite ethanolamine was highly up-regulated. This is the result: a strong overexpression (350%) of the enzyme sphingosine-1-phosphate lyase (SGPL1), which irreversibly degrades sphingosine-1-phosphate (S1P), thereby, generating ethanolamine. S1P production and secretion is associated with an increased capability of migration and invasion of cancer cells. CONCLUSION: From these results can be concluded that the tumor promoting effect of high concentrations of genistein in immature osteosarcoma cells is reduced by the co-administration of calcitriol, primarily by the breakdown of S1P. It should be tested whether this anti-metastatic pathway can be stimulated by combined treatment also in metastatic xenograft mice models. PMID: 28125641 [PubMed - in process]

Related Articles Serum Metabolomic Profiling Identifies Characterization of Non-Obstructive Azoospermic Men. Int J Mol Sci. 2017 Jan 25;18(2): Authors: Zhang Z, Zhang Y, Liu C, Zhao M, Yang Y, Wu H, Zhang H, Lin H, Zheng L, Jiang H Abstract Male infertility is considered a common health problem, and non-obstructive azoospermia with unclear pathogenesis is one of the most challenging tasks for clinicians. The objective of this study was to investigate the differential serum metabolic pattern in non-obstructive azoospermic men and to determine potential biomarkers related to spermatogenic dysfunction. Serum samples from patients with non-obstructive azoospermia (n = 22) and healthy controls (n = 31) were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Serum metabolomic profiling could differentiate non-obstructive azoospermic patients from healthy control subjects. A total of 24 metabolites were screened and identified as potential markers, many of which are involved in energy production, oxidative stress and cell apoptosis in spermatogenesis. Moreover, the results showed that various metabolic pathways, including d-glutamine and d-glutamate metabolism, taurine and hypotaurine metabolism, pyruvate metabolism, the citrate cycle and alanine, aspartate and glutamate metabolism, were disrupted in patients with non-obstructive azoospermia. Our results indicated that the serum metabolic disorders may contribute to the etiology of non-obstructive azoospermia. This study suggested that serum metabolomics could identify unique metabolic patterns of non-obstructive azoospermia and provide novel insights into the pathogenesis underlying male infertility. PMID: 28125052 [PubMed - in process]

Related Articles Employing Two-stage Derivatisation and GC-MS to Assay for Cathine and Related Stimulant Alkaloids across the Celastraceae. Phytochem Anal. 2017 Jan 26;: Authors: Tembrock LR, Broeckling CD, Heuberger AL, Simmons MP, Stermitz FR, Uvarov JM Abstract INTRODUCTION: Catha edulis (qat, khat, mirra) is a woody plant species that is grown and consumed in East Africa and Yemen for its stimulant alkaloids cathinone, cathine and norephedrine. Two Celastraceae species, in addition to qat, have been noted for their stimulant properties in ethnobotanical literature. Recent phylogenetic reconstructions place four genera in a clade sister to Catha edulis, and these genera are primary candidates to search for cathine and related alkaloids. OBJECTIVE: Determine if cathine or related alkaloids are present in species of Celastraceae other than Catha edulis. METHODS: Leaf samples from 43 Celastraceae species were extracted in water followed by basification of the aqueous extract and partitioning with methyl-t-butyl ether to provide an alkaloid-enriched fraction. The extract was derivatised in a two-stage process and analysed using GC-MS for the presence of cathine. Related alkaloids and other metabolites in this alkaloid-enriched fraction were tentatively identified. RESULTS: Cathinone, cathine and norephedrine were not detected in any of the 43 Celastraceae species assayed other than Catha edulis. However, the phenylalanine- or tyrosine-derived alkaloid phenylethylamine was identified in five species. Nine species were found to be enriched for numerous sterol- and terpene-like compounds. CONCLUSION: These results indicate that cathine is unique to Catha edulis, and not the compound responsible for the stimulant properties reported in related Celastraceae species. Copyright © 2017 John Wiley & Sons, Ltd. PMID: 28124803 [PubMed - as supplied by publisher]

Related Articles Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism. Mol Metab. 2017 Jan;6(1):38-47 Authors: Stechemesser L, Eder SK, Wagner A, Patsch W, Feldman A, Strasser M, Auer S, Niederseer D, Huber-Schönauer U, Paulweber B, Zandanell S, Ruhaltinger S, Weghuber D, Haschke-Becher E, Grabmer C, Rohde E, Datz C, Felder TK, Aigner E Abstract OBJECTIVE: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways. METHODS: In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56). An additional phlebotomy study included 29 patients with biopsy-proven iron overload before and after iron removal. A detailed clinical and biochemical characterization was obtained and metabolomic profiling was performed via a targeted metabolomics approach. RESULTS: Subjects with MetS and elevated ferritin had higher fasting glucose (p < 0.001), HbA1c (p = 0.035) and 1 h glucose in oral glucose tolerance test (p = 0.002) compared to MetS subjects without iron overload, whereas other clinical and biochemical features of the MetS were not different. The metabolomic study revealed significant differences between MetS with high and low ferritin in the serum concentrations of sarcosine, citrulline and particularly long-chain phosphatidylcholines. Methionine, glutamate, and long-chain phosphatidylcholines were significantly different before and after phlebotomy (p < 0.05 for all metabolites). CONCLUSIONS: Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism. PMID: 28123936 [PubMed - in process]

Related Articles A metabolomic study of biomarkers of meat and fish intake. Am J Clin Nutr. 2017 Jan 25;: Authors: Cheung W, Keski-Rahkonen P, Assi N, Ferrari P, Freisling H, Rinaldi S, Slimani N, Zamora-Ros R, Rundle M, Frost G, Gibbons H, Carr E, Brennan L, Cross AJ, Pala V, Panico S, Sacerdote C, Palli D, Tumino R, Kühn T, Kaaks R, Boeing H, Floegel A, Mancini F, Boutron-Ruault MC, Baglietto L, Trichopoulou A, Naska A, Orfanos P, Scalbert A Abstract BACKGROUND: Meat and fish intakes have been associated with various chronic diseases. The use of specific biomarkers may help to assess meat and fish intake and improve subject classification according to the amount and type of meat or fish consumed. OBJECTIVE: A metabolomic approach was applied to search for biomarkers of meat and fish intake in a dietary intervention study and in free-living subjects from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. DESIGN: In the dietary intervention study, 4 groups of 10 subjects consumed increasing quantities of chicken, red meat, processed meat, and fish over 3 successive weeks. Twenty-four-hour urine samples were collected during each period and analyzed by high-resolution liquid chromatography-mass spectrometry. Signals characteristic of meat or fish intake were replicated in 50 EPIC subjects for whom a 24-h urine sample and 24-h dietary recall were available and who were selected for their exclusive intake or no intake of any of the 4 same foods. RESULTS: A total of 249 mass spectrometric features showed a positive dose-dependent response to meat or fish intake in the intervention study. Eighteen of these features best predicted intake of the 4 food groups in the EPIC urine samples on the basis of partial receiver operator curve analyses with permutation testing (areas under the curve ranging between 0.61 and 1.0). Of these signals, 8 metabolites were identified. Anserine was found to be specific for chicken intake, whereas trimethylamine-N-oxide showed good specificity for fish. Carnosine and 3 acylcarnitines (acetylcarnitine, propionylcarnitine, and 2-methylbutyrylcarnitine) appeared to be more generic indicators of meat and meat and fish intake, respectively. CONCLUSION: The meat and fish biomarkers identified in this work may be used to study associations between meat and fish intake and disease risk in epidemiologic studies. This trial was registered at clinicaltrials.gov as NCT01684917. PMID: 28122782 [PubMed - as supplied by publisher]

Metformin: a metabolic modulator. Oncotarget. 2017 Jan 22;: Authors: Pietrocola F, Kroemer G Abstract Recent findings have shed new light on the mechanisms of action through which biguanides exert their anti-aging and cytostatic effects in Caenorhabditis elegans and human cell lines. The drop in energy charge resulting from the metformin mediated inhibition of mitochondrial activity affects the function of the nuclear pore complex, blocks mTOR signaling and enhances the expression of ACAD10. Whether the inhibition of this pathway is truly responsible for the anti-diabetic and cancer effects of the drug in mammals remains to be established. PMID: 28122334 [PubMed - as supplied by publisher]

Metabolic robustness in young roots underpins a predictive model of maize hybrid performance in the field. Plant J. 2017 Jan 25;: Authors: de Abreu E Lima F, Westhues M, Cuadros-Inostroza Á, Willmitzer L, Melchinger AE, Nikoloski Z Abstract Heterosis has been extensively exploited for yield gain in maize (Zea mays L.). Here we conducted a comparative metabolomics-based analysis of young roots from in vitro germinating seedlings and from leaves of field-grown plants in a panel of inbred lines from the Dent and Flint heterotic patterns as well as selected F1 hybrids. We found that metabolite levels in hybrids were more robust than in inbred lines. Using state-of-the-art modeling techniques, the most robust metabolites from roots and leaves explained up to 37% and 44% of the variance in the biomass from plants grown in two distinct field trials. In addition, a correlation-based analysis highlighted the trade-off between defense-related metabolites and hybrid performance. Therefore, our findings demonstrated the potential of metabolic profiles from young maize roots grown under tightly controlled conditions to predict hybrid performance in multiple field trials, thus bridging the greenhouse-field gap. This article is protected by copyright. All rights reserved. PMID: 28122143 [PubMed - as supplied by publisher]

Colonic Absorption of Low-Molecular-Weight Metabolites Influenced by the Intestinal Microbiome: A Pilot Study. PLoS One. 2017;12(1):e0169207 Authors: Matsumoto M, Ooga T, Kibe R, Aiba Y, Koga Y, Benno Y Abstract Low-molecular-weight metabolites produced by the intestinal microbiome play a direct role in health and disease. However, little is known about the ability of the colon to absorb these metabolites. It is also unclear whether these metabolites are bioavailable. Here, metabolomics techniques (capillary electrophoresis with time-of-flight mass spectrometry, CE-TOFMS), germ-free (GF) mice, and colonized (Ex-GF) mice were used to identify the colonic luminal metabolites transported to colonic tissue and/or blood. We focused on the differences in each metabolite between GF and Ex-GF mice to determine the identities of metabolites that are transported to the colon and/or blood. CE-TOFMS identified 170, 246, 166, and 193 metabolites in the colonic feces, colonic tissue, portal plasma, and cardiac plasma, respectively. We classified the metabolites according to the following influencing factors: (i) the membrane transport system of the colonocytes, (ii) metabolism during transcellular transport, and (iii) hepatic metabolism based on the similarity in the ratio of each metabolite between GF and Ex-GF mice and found 62 and 22 metabolites that appeared to be absorbed from the colonic lumen to colonocytes and blood, respectively. For example, 11 basic amino acids were transported to the systemic circulation from the colonic lumen. Furthermore, many low-molecular-weight metabolites influenced by the intestinal microbiome are bioavailable. The present study is the first to report the transportation of metabolites from the colonic lumen to colonocytes and somatic blood in vivo, and the present findings are critical for clarifying host-intestinal bacterial interactions. PMID: 28121990 [PubMed - in process]

Urinary metabolomics for noninvasive detection of antibody-mediated rejection in children after kidney transplantation. Transplantation. 2017 Jan 25;: Authors: Blydt-Hansen TD, Sharma A, Gibson IW, Wishart DS, Mandal R, Ho J, Nickerson P, Rush D Abstract BACKGROUND: Biomarkers are needed that identify patients with antibody-mediated rejection (ABMR). The goal of this study was to evaluate the utility of urinary metabolomics for early noninvasive detection of ABMR in pediatric kidney transplant recipients. METHODS: Urine samples (n=396) from a prospective, observational cohort of 59 renal transplant patients with surveillance or indication biopsies were assayed for 133 unique metabolites by quantitative mass spectrometry. Samples were classified according to Banff criteria for ABMR and partial least squares discriminant analysis was used to identify associated changes in metabolite patterns by creating a composite index based on all 133 metabolites. RESULTS: Urine samples of patients with (n=40) and without ABMR (n=278) were analyzed and a classifier for ABMR was identified (AUC=0.84; 95% CI 0.77-0.91; p=0.006). Application of the classifier to "indeterminate" samples (samples that partially fulfilled Banff criteria for ABMR; n=65) yielded an ABMR score of 0.19±0.15, intermediate between scores for ABMR and no ABMR (0.28±0.14 and 0.10±0.13 respectively, p≤0.001). The ABMR score was associated with the presence of DSA, biopsy indication, Banff ct, t, ah and cg scores, and retained accuracy when applied to subclinical cases (creatinine <25% increase from baseline) or had minimal or no transplant glomerulopathy (Banff cg0-1). Exploratory classifiers that segregated samples based on concurrent T cell-mediated rejection (TCMR) identified overlapping metabolite signatures between ABMR and TCMR, suggesting similar pathophysiology of tissue injury. CONCLUSIONS: These preliminary findings identify a urine metabolic classifier for ABMR. Independent validation is needed to verify its utility for accurate, non-invasive ABMR detection. PMID: 28121909 [PubMed - as supplied by publisher]

Assessment of Metabolic changes in Mycobacterium smegmatis wild type and alr mutant strains: evidence for a new pathway of D-alanine biosynthesis. J Proteome Res. 2017 Jan 25;: Authors: Marshall DD, Halouska S, Zinniel DK, Fenton RJ, Kenealy K, Chahal HK, Rathnaiah G, Barletta RG, Powers R Abstract In mycobacteria, D-alanine is an essential precursor for peptidoglycan biosynthesis. The only confirmed enzymatic pathway to form D-alanine is through the racemization of L-alanine by alanine racemase (Alr, EC 5.1.1.1). Nevertheless, the essentiality of Alr in Mycobacterium tuberculosis and Mycobacterium smegmatis for cell survivability in the absence of D-alanine has been a point of controversy with contradictory results reported in the literature. To address this issue, we examined the effects of alr inactivation on the cellular metabolism of M. smegmatis. The M. smegmatis alr insertion mutant TAM23, upon passage in media without D-alanine, exhibited essentially identical growth to wild type mc(2)155 in the absence of D-alanine. NMR metabolomics revealed drastically distinct phenotypes between mc(2)155 and TAM23. A metabolic switch was observed for TAM23 as a function of supplemented D-alanine. In the absence of D-alanine, the metabolic response directed carbon through an unidentified transaminase to provide the essential D-alanine required for survival. The process is reversed when D-alanine is available, in which the D-alanine is directed to peptidoglycan biosynthesis. Our results provide further support for the hypothesis that Alr is not an essential function of M. smegmatis, and that specific Alr inhibitors will have no bactericidal action. PMID: 28121156 [PubMed - as supplied by publisher]

Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom. Sci Rep. 2017 Jan 25;7:41177 Authors: Gachet MS, Schubert A, Calarco S, Boccard J, Gertsch J Abstract The remarkable absence of arachidonic acid (AA) in seed plants prompted us to systematically study the presence of C20 polyunsaturated fatty acids, stearic acid, oleic acid, jasmonic acid (JA), N-acylethanolamines (NAEs) and endocannabinoids (ECs) in 71 plant species representative of major phylogenetic clades. Given the difficulty of extrapolating information about lipid metabolites from genetic data we employed targeted metabolomics using LC-MS/MS and GC-MS to study these signaling lipids in plant evolution. Intriguingly, the distribution of AA among the clades showed an inverse correlation with JA which was less present in algae, bryophytes and monilophytes. Conversely, ECs co-occurred with AA in algae and in the lower plants (bryophytes and monilophytes), thus prior to the evolution of cannabinoid receptors in Animalia. We identified two novel EC-like molecules derived from the eicosatetraenoic acid juniperonic acid, an omega-3 structural isomer of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol in gymnosperms, lycophytes and few monilophytes. Principal component analysis of the targeted metabolic profiles suggested that distinct NAEs may occur in different monophyletic taxa. This is the first report on the molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicating biosynthetic plasticity and potential physiological roles of EC-like lipids in plants. PMID: 28120902 [PubMed - in process]