PubMed

Related Articles A combination of NMR and liquid chromatography to characterize the protective effects of Rhus tripartita extracts on ethanol-induced toxicity and inflammation on intestinal cells. J Pharm Biomed Anal. 2017 Dec 19;150:347-354 Authors: Ben Barka Z, Grintzalis K, Polet M, Heude C, Sommer U, Ben Miled H, Ben Rhouma K, Mohsen S, Tebourbi O, Schneider YJ Abstract Consumption of ethanol may have severe effects on human organs and tissues and lead to acute and chronic inflammation of internal organs. The present study aims at investigating the potential protective effects of three different extracts prepared from the leaves, root, and stem of the sumac, Rhus tripartita, against ethanol-induced toxicity and inflammation using intestinal cells as a cell culture system, in vitro model of the intestinal mucosa. The results showed an induction of cytotoxicity by ethanol, which was partially reversed by co-administration of the plant extracts. As part of investigating the cellular response and the mechanism of toxicity, the role of reduced thiols and glutathione-S-transferases were assessed. In addition, intestinal cells were artificially imposed to an inflammation state and the anti-inflammatory effect of the extracts was estimated by determination of interleukin-8. Finally, a detailed characterization of the contents of the three plant extracts by high resolution Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry revealed significant differences in their chemical compositions. PMID: 29287261 [PubMed - as supplied by publisher]

Related Articles Improving the discovery of secondary metabolite natural products using ion mobility-mass spectrometry. Curr Opin Chem Biol. 2017 Dec 26;42:160-166 Authors: Schrimpe-Rutledge AC, Sherrod SD, McLean JA Abstract Secondary metabolite discovery requires an unbiased, comprehensive workflow to detect unknown unknowns for which little to no molecular knowledge exists. Untargeted mass spectrometry-based metabolomics is a powerful platform, particularly when coupled with ion mobility for high-throughput gas-phase separations to increase peak capacity and obtain gas-phase structural information. Ion mobility data are described by the amount of time an ion spends in the drift cell, which is directly related to an ion's collision cross section (CCS). The CCS parameter describes the size, shape, and charge of a molecule and can be used to characterize unknown metabolomic species. Here, we describe current and emerging applications of ion mobility-mass spectrometry for prioritization, discovery and structure elucidation, and spatial/temporal characterization. PMID: 29287234 [PubMed - as supplied by publisher]

Related Articles Microprobe Capillary Electrophoresis Mass Spectrometry for Single-cell Metabolomics in Live Frog (Xenopus laevis) Embryos. J Vis Exp. 2017 Dec 22;(130): Authors: Onjiko RM, Portero EP, Moody SA, Nemes P Abstract The quantification of small molecules in single cells raises new potentials for better understanding the basic processes that underlie embryonic development. To enable single-cell investigations directly in live embryos, new analytical approaches are needed, particularly those that are sensitive, selective, quantitative, robust, and scalable to different cell sizes. Here, we present a protocol that enables the in situ analysis of metabolism in single cells in freely developing embryos of the South African clawed frog (Xenopus laevis), a powerful model in cell and developmental biology. This approach uses a capillary microprobe to aspirate a defined portion from single identified cells in the embryo, leaving neighboring cells intact for subsequent analysis. The collected cell content is analyzed by a microscale capillary electrophoresis electrospray ionization (CE-ESI) interface coupled to a high-resolution tandem mass spectrometer. This approach is scalable to various cell sizes and compatible with the complex three-dimensional structure of the developing embryo. As an example, we demonstrate that microprobe single-cell CE-ESI-MS enables the elucidation of metabolic cell heterogeneity that unfolds as a progenitor cell gives rise to descendants during development of the embryo. Besides cell and developmental biology, the single-cell analysis protocols described here are amenable to other cell sizes, cell types, or animal models. PMID: 29286491 [PubMed - in process]

Related Articles Metabolomic Analysis of 92 Pulmonary Embolism Patients from a Nested Case-control Study Identifies Metabolites Associated with Adverse Clinical Outcomes. J Thromb Haemost. 2017 Dec 29;: Authors: Zeleznik OA, Poole EM, Lindstrom S, Kraft P, Van Hylckama Vlieg A, Lasky-Su JA, Harrington LB, Hagan K, Kim J, Parry BA, Giordano N, Kabrhel C Abstract BACKGROUND: Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. OBJECTIVES: To improve our understanding of the physiology differentiating low-risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. PATIENTS/METHODS: We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 hours of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. RESULTS: When we compared 46 low-risk to 46 intermediate/high-risk PE, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: TCA Cycle, Fatty Acid Metabolism (Acyl Carnitine), and Purine Metabolism, (Hypo)Xanthine/Inosine Containing. Additionally, Energy, Nucleotide, and Amino Acid pathways were down-regulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk to 18 high-risk PE patients, 41 metabolites differed at a nominal p-value level. These metabolites were enriched in Fatty Acid Metabolism (Acyl Cholines), and Hemoglobin and Porphyrin Metabolism. CONCLUSION: Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE. This article is protected by copyright. All rights reserved. PMID: 29285876 [PubMed - as supplied by publisher]

Related Articles MALDI-Imaging detects endogenous Digoxin in glioblastoma cells infected by Zika virus - would it be the oncolytic key? J Mass Spectrom. 2017 Dec 28;: Authors: de O Lima E, Guerreiro TM, Melo CFOR, de Oliveira DN, Machado D, Lancelloti M, Catharino RR Abstract Recently, microcephaly cases have increased in Americas and have been matter of concern due to Zika virus (ZIKV) recent outbreak. Previous studies have shown that ZIKV-infected progenitor neuronal cells present morphological abnormalities and increased rates of cell death, which may be indicators of microcephaly causes. As recent studies indicate Zika virus' tropism for brain cells, how would a glioblastoma (GBM) lineage behave under ZIKV infection, considering GBM the most common and malignant brain tumor in adults, presenting extreme chemoresistance and high morbidity and mortality rates? The current trend of using genetically engineered oncolytic pathogens as a safe way to eliminate tumors is under development, with trials already in course. Therefore, the present study evaluated the possible oncolytic effects and metabolomic alterations of Zika virus infection at human malignant M059J glioblastoma cells. Microscopic evaluation was performed using optical microscopy, which showed cytopathic effects induced by ZIKV at GBM cells. For the metabolomics study, both control and infected cell cultures were submitted to MALDI-MSI analysis. Mass spectrometry data were submitted to PLS-DA statistical analysis, and distinct biomarkers were elected for each infected groups. This study brings light to unexpectedly induced metabolic changes, as endogenous Digoxin as important biomarker for ZIKV-GBM group, associated with cytopathic effects induced by viral infection. These results evidences that genetically engineered ZIKV might be a potential new strategy for neural cancer management through the induction of endogenous digoxin synthesis in glioblastoma cells. PMID: 29285820 [PubMed - as supplied by publisher]

Related Articles Endogenous metabolites-mediated communication between OAT1/OAT3 and OATP1B1 may explain the association between SLCO1B1 SNPs and methotrexate toxicity. Clin Pharmacol Ther. 2017 Dec 29;: Authors: Martinez D, Muhrez K, Woillard JB, Berthelot A, Gyan E, Choquet S, Andrès CR, Marquet P, Barin-Le Guellec C Abstract Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients with hematological malignancies. Using a targeted urinary metabolomics approach, we identified 38 and 34 metabolites which were differentially excreted between wild-type and carriers of the c.388A>G or c.521T>C variant alleles, respectively, half of them being associated with methotrexate toxicity. These metabolites mainly consisted of fatty acid derivatives and microbiota catabolites, including glycine conjugates and other uremic toxins, all known OATs substrates. These results suggest that dysfunction of a transporter affects the excretion profile of endogenous or exogenous substrates, possibly through metabolite-mediated interactions involving other transport systems, even in distant organs. This opens the way for better comprehension of complex pharmacokinetics and transporter-mediated drug-drug or nutrient-drug interactions. This article is protected by copyright. All rights reserved. PMID: 29285751 [PubMed - as supplied by publisher]

Related Articles Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione. Oncotarget. 2017 Dec 01;8(62):105882-105904 Authors: Kürschner G, Zhang Q, Clima R, Xiao Y, Busch JF, Kilic E, Jung K, Berndt N, Bulik S, Holzhütter HG, Gasparre G, Attimonelli M, Babu M, Meierhofer D Abstract Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD+, NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor. PMID: 29285300 [PubMed]

Related Articles NMR-based metabolomic techniques identify potential urinary biomarkers for early colorectal cancer detection. Oncotarget. 2017 Dec 01;8(62):105819-105831 Authors: Wang Z, Lin Y, Liang J, Huang Y, Ma C, Liu X, Yang J Abstract Better early detection methods are needed to improve the outcomes of patients with colorectal cancer (CRC). Proton nuclear magnetic resonance spectroscopy (1H-NMR), a potential non-invasive early tumor detection method, was used to profile urine metabolites from 55 CRC patients and 40 healthy controls (HCs). Pattern recognition through orthogonal partial least squares-discriminant analysis (OPLS-DA) was applied to 1H-NMR processed data. Model specificity was confirmed by comparison with esophageal cancers (EC, n=18). Unique metabolomic profiles distinguished all CRC stages from HC urine samples. A total of 16 potential biomarker metabolites were identified in stage I/II CRC, indicating amino acid metabolism, glycolysis, tricarboxylic acid (TCA) cycle, urea cycle, choline metabolism, and gut microflora metabolism pathway disruptions. Metabolite profiles from early stage CRC and EC patients were also clearly distinguishable, suggesting that upper and lower gastrointestinal cancers have different metabolomic profiles. Our study assessed important metabolomic variations in CRC patient urine samples, provided information complementary to that collected from other biofluid-based metabolomics analyses, and elucidated potential underlying metabolic mechanisms driving CRC. Our results support the utility of NMR-based urinary metabolomics fingerprinting in early diagnosis of CRC. PMID: 29285295 [PubMed]

Related Articles Proteomics and metabolomics for analysis of the dynamics of microbiota. Expert Rev Proteomics. 2017 Dec 28;:1-4 Authors: Van Belkum A, Broadwell D, Lovern D, Petersen L, Weinstock G, Dunne WM PMID: 29284309 [PubMed - as supplied by publisher]

Related Articles Mitochondrial aldehyde dehydrogenase 2 deficiency aggravates energy metabolism disturbance and diastolic dysfunction in diabetic mice. J Mol Med (Berl). 2016 Nov;94(11):1229-1240 Authors: Wang C, Fan F, Cao Q, Shen C, Zhu H, Wang P, Zhao X, Sun X, Dong Z, Ma X, Liu X, Han S, Wu C, Zou Y, Hu K, Ge J, Sun A Abstract Diabetes causes energy metabolism disturbance and may lead to cardiac dysfunction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects cardiac function from myocardial damage. Therefore, understanding of its roles in diabetic heart is critical for developing new therapeutics targeting ALDH2 and mitochondrial function for diabetic hearts. This study investigated the impact of ALDH2 deficiency on diastolic function and energy metabolism in diabetic mice. Diabetes was induced in ALDH2 knockout and wild-type mice by streptozotocin. Cardiac function was determined by echocardiography. Glucose uptake, energy status, and metabolic profiles were used to evaluate cardiac energy metabolism. The association between ALDH2 polymorphism and diabetes was also analyzed in patients. Echocardiography revealed preserved systolic function and impaired diastolic function in diabetic ALDH2-deficient mice. Energy reserves (phosphocreatine/adenosine triphosphate ratio) were reduced in the diabetic mutants and were associated with diastolic dysfunction. Western blot analysis showed that diabetes induces accumulated lipid peroxidation products and escalated AMP-activated protein kinase-LKB1 pathway. Further, ALDH2 deficiency exacerbated the diabetes-induced deficient myocardial glucose uptake and other perturbations of metabolic profiles. Finally, ALDH2 mutations were associated with worse diastolic dysfunction in diabetic patients. Together, our results demonstrate that ALDH2 deficiency and resulting energy metabolism disturbance is a part of pathology of diastolic dysfunction of diabetic hearts, and suggest that patients with ALDH2 mutations are vulnerable to diabetic damage. KEY MESSAGE: ALDH2 deficiency exacerbates diastolic dysfunction in early diabetic hearts. ALDH2 deficiency triggers decompensation of metabolic reserves and energy metabolism disturbances in early diabetic hearts. ALDH2 deficiency potentiates oxidative stress and AMPK phosphorylation induced by diabetes via post-translational regulation of LKB1. Diabetic patients with ALDH2 mutations are predisposed to worse diastolic dysfunction. PMID: 27488451 [PubMed - indexed for MEDLINE]

Related Articles Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress. J Mol Med (Berl). 2016 Nov;94(11):1241-1253 Authors: Eguchi A, Lazic M, Armando AM, Phillips SA, Katebian R, Maraka S, Quehenberger O, Sears DD, Feldstein AE Abstract We recently reported that stressed adipocytes release extracellular vesicles (EVs) that act as "find-me" signals to promote macrophage migration and activation. In this study, we performed a comprehensive characterization of stressed adipocyte-derived EVs, assessing their antigenic composition, lipidomics, and RNA profiles. Perilipin A was identified as one of the adipose-specific proteins and studied as a potential novel biomarker to detect adipocyte-derived EVs in circulation. Circulating EVs were significantly increased in mice with diet-induced obesity (DIO) and in obese humans with metabolic syndrome compared to lean controls. This increase was associated with decreased glucose tolerance in the DIO mice and metabolic dysfunction, elevated insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in the obese humans. EVs from both DIO mice and obese humans were enriched in perilipin A, a central gatekeeper of the adipocyte lipid storehouse and a marker of adipocyte differentiation. In obese humans, circulating levels of EVs enriched in perilipin A were dynamic, decreasing 35 % (p < 0.05) after a 3-month reduced calorie diet intervention. This translational study provides an extensive characterization of adipocyte-derived EVs. The findings identify perilipin A as a novel biomarker of circulating EVs of adipocyte origin and support the development of circulating perilipin A-positive EVs as indicators of adipose tissue health. KEY MESSAGE: • Extensive characterization of 3T3L1 EVs identified perilipin A in their composition. • Circulating EVs are elevated in obese mice and associated with glucose intolerance. • Circulating EVs are elevated in obese human and correlated with metabolic factors. • Perilipin A and EV levels are increased in the circulation of obese mice and human. • Circulating EV and perilipin A levels decrease with low calorie intervention. PMID: 27394413 [PubMed - indexed for MEDLINE]

Related Articles The role of Wnt/β-catenin signaling pathway in melanoma epithelial-to-mesenchymal-like switching: evidences from patients-derived cell lines. Oncotarget. 2016 Jul 12;7(28):43295-43314 Authors: Kovacs D, Migliano E, Muscardin L, Silipo V, Catricalà C, Picardo M, Bellei B Abstract Deregulations or mutations of WNT/β-catenin signaling have been associated to both tumour formation and progression. However, contradictory results concerning the role of β-catenin in human melanoma address an open question on its oncogenic nature and prognostic value in this tumour. Changes in WNT signaling pathways have been linked to phenotype switching of melanoma cells between a highly proliferative/non-invasive and a slow proliferative/metastatic condition. We used a novel panel of cell lines isolated from melanoma specimens, at initial passages, to investigate phenotype differences related to the levels and activity of WNT/β-catenin signaling pathway. This in vitro cell system revealed a marked heterogeneity that comprises, in some cases, two distinct tumour-derived subpopulations of cells presenting a different activation level and cellular distribution of β-catenin. In cells derived from the same tumor, we demonstrated that the prevalence of LEF1 (high β-catenin expressing cells) or TCF4 (low β-catenin expressing cells) as β-catenin partner for DNA binding, is associated to the expression of two distinct profiles of WNT-responsive genes. Interestingly, melanoma cells expressing relative low level of β-catenin and an invasive markers signature were associated to the TNF-α-induced pro-inflammatory pathway and to the chemotherapy resistance, suggesting that the co-existence of melanoma subpopulations with distinct biological properties could influence the impact of chemo- and immunotherapy. PMID: 27175588 [PubMed - indexed for MEDLINE]

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]