PubMed

Related Articles Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer. Oncogene. 2015 Jun 4;34(23):3053-62 Authors: Aranda F, Bloy N, Pesquet J, Petit B, Chaba K, Sauvat A, Kepp O, Khadra N, Enot D, Pfirschke C, Pittet M, Zitvogel L, Kroemer G, Senovilla L Abstract cis-Diamminedichloroplatinum(II) (CDDP), which is mostly referred to as cisplatin, is a widely used antineoplastic. The efficacy of cisplatin can be improved by combining it with the vitamin B6 precursor pyridoxine. Here, we evaluated the putative synergistic interaction of CDDP with pyridoxine in the treatment of an orthotopic mouse model of non-small-cell lung cancer (NSCLC). CDDP and pyridoxine exhibited hyperadditive therapeutic effects. However, this synergy was only observed in the context of an intact immune system and disappeared when the otherwise successful drug combination was applied to the same NSCLC cancer implanted in the lungs of athymic mice (which lack T lymphocytes). Immunocompetent mice that had been cured from NSCLC by the combined regimen of CDDP plus pyridoxine became resistant against subcutaneous rechallenge with the same (but not with an unrelated) cancer cell line. In vitro, CDDP and pyridoxine did not only cause synergistic killing of NSCLC cells but also elicited signs of immunogenic cell death including an endoplasmic reticulum stress response and exposure of calreticulin at the surface of the NSCLC cells. NSCLC cells treated with CDDP plus pyridoxine in vitro elicited a protective anticancer immune response upon their injection into immunocompetent mice. Altogether, these results suggest that the combined regimen of cisplatin plus pyridoxine mediates immune-dependent antineoplastic effects against NSCLC. PMID: 25065595 [PubMed - indexed for MEDLINE]

Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome. Cell Metab. 2015 Aug 4;22(2):320-331 Authors: Shoaie S, Ghaffari P, Kovatcheva-Datchary P, Mardinoglu A, Sen P, Pujos-Guillot E, de Wouters T, Juste C, Rizkalla S, Chilloux J, Hoyles L, Nicholson JK, MICRO-Obes Consortium, Dore J, Dumas ME, Clement K, Bäckhed F, Nielsen J Abstract The human gut microbiome is known to be associated with various human disorders, but a major challenge is to go beyond association studies and elucidate causalities. Mathematical modeling of the human gut microbiome at a genome scale is a useful tool to decipher microbe-microbe, diet-microbe and microbe-host interactions. Here, we describe the CASINO (Community And Systems-level INteractive Optimization) toolbox, a comprehensive computational platform for analysis of microbial communities through metabolic modeling. We first validated the toolbox by simulating and testing the performance of single bacteria and whole communities in vitro. Focusing on metabolic interactions between the diet, gut microbiota, and host metabolism, we demonstrated the predictive power of the toolbox in a diet-intervention study of 45 obese and overweight individuals and validated our predictions by fecal and blood metabolomics data. Thus, modeling could quantitatively describe altered fecal and serum amino acid levels in response to diet intervention. PMID: 26244934 [PubMed - as supplied by publisher]

A proteomic perspective of the interplay of Staphylococcus aureus and human alveolar epithelial cells during infection. J Proteomics. 2015 Aug 2; Authors: Surmann K, Simon M, Hildebrandt P, Pförtner H, Michalik S, Stentzel S, Steil L, Dhople VM, Bernhardt J, Schlüter R, Depke M, Gierok P, Lalk M, Bröker BM, Schmidt F, Völker U Abstract Infectious diseases caused by pathogens such as Staphylococcus aureus are still a major threat for human health. Proteome analyses allow detailed monitoring of the molecular interplay between pathogen and host upon internalization. However, the investigation of the responses of both partners is complicated by the large excess of host cell proteins compared to bacterial proteins as well as by the fact that only a fraction of host cells are infected. In the present study we infected human alveolar epithelial A549 cells with S. aureus HG001 pMV158GFP and separated intact bacteria from host cell debris or infected from non-infected A549 cells by cell sorting to enable detailed proteome analysis. During the first 6.5h in the intracellular milieu S. aureus displayed reduced growth rate, induction of the stringent response, adaptation to microaerobic conditions as well as cell wall stress. Interestingly, both truly infected host cells and those not infected but exposed to secreted S. aureus proteins and host cell factors showed differences in the proteome pattern compared to A549 cells which had never been in contact with S. aureus. However, adaptation reactions were more pronounced in infected compared to non-infected A549 bystander cells. Biological significance When studying interactions between pathogen and host, proteome analyses of internalization models in cell culture provide valuable information about the adaptation of both, host and pathogen, to infection. A comprehensive understanding of the bacterial invasion, spreading, and survival mechanisms within the host as well as of the defense strategies of infected host cells will provide new options to prevent and combat bacterial infections. However, such proteome studies are complicated by the low amount of bacterial proteins available in such models as well as by the fact that only a fraction of eukaryotic host cells are indeed infected. Thus, in previous studies, either the adaptation reactions of the pathogen or the host were investigated separately. Using bacteria continuously expressing GFP, we are now able to enrich the intra-cellular S. aureus bacteria after lysis of the infected host cells and also to separate infected from non-infected airway epithelial cells (A549). Thus, we could simultaneously monitor the responses of the host and the pathogen after infection. In the future such studies could be extended to comparative analysis of different S. aureus strains/ mutants after co-infection to explore the specific influence of virulence factors or regulatory proteins on the outcome of infection. PMID: 26244908 [PubMed - as supplied by publisher]

Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis. Sci Rep. 2015;5:12757 Authors: Ivanisevic J, Elias D, Deguchi H, Averell PM, Kurczy M, Johnson CH, Tautenhahn R, Zhu Z, Watrous J, Jain M, Griffin J, Patti GJ, Siuzdak G Abstract The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology. PMID: 26244428 [PubMed - as supplied by publisher]

Related Articles Metabolomic profiling of hormone-dependent cancers: a bird's eye view. Trends Endocrinol Metab. 2015 Aug 1; Authors: Lloyd SM, Arnold J, Sreekumar A Abstract Hormone-dependent cancers present a significant public health challenge, because they are among the most common cancers in the world. One factor associated with cancer development and progression is metabolic reprogramming. By understanding these alterations, we can identify potential markers and novel biochemical therapeutic targets. Metabolic profiling is an advanced technology that allows investigators to assess low-molecular-weight compounds that reflect physiological alterations. Current research in metabolomics on prostate (PCa) and breast cancer (BCa) have made great strides in uncovering specific metabolic pathways that are associated with cancer development, progression, and resistance. In this review, we highlight some of the major findings and potential therapeutic advances that have been reported utilizing this technology. PMID: 26242817 [PubMed - as supplied by publisher]

Related Articles Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary (13)C-glucose labeling metabolomics. J Transl Med. 2015;13:253 Authors: D'Alessandro A, Slaughter AL, Peltz ED, Moore EE, Silliman CC, Wither M, Nemkov T, Bacon AW, Fragoso M, Banerjee A, Hansen KC Abstract BACKGROUND: Metabolic derangement is a key hallmark of major traumatic injury. The recent introduction of mass spectrometry-based metabolomics technologies in the field of trauma shed new light on metabolic aberrations in plasma that are triggered by trauma and hemorrhagic shock. Alteration in metabolites associated with catabolism, acidosis and hyperglycemia have been identified. However, the mechanisms underlying fluxes driving such metabolic adaptations remain elusive. METHODS: A bolus of U-(13)C-glucose was injected in Sprague-Dawley rats at different time points. Plasma extracts were analyzed via ultra-high performance liquid chromatography-mass spectrometry to detect quantitative fluctuations in metabolite levels as well as to trace the distribution of heavy labeled carbon isotopologues. RESULTS: Rats experiencing trauma did not show major plasma metabolic aberrations. However, trauma/hemorrhagic shock triggered severe metabolic derangement, resulting in increased glucose levels, lactate and carboxylic acid accumulation. Isotopologue distributions in late Krebs cycle metabolites (especially succinate) suggested a blockade at complex I and II of the electron transport chain, likely due to mitochondrial uncoupling. Urate increased after trauma and hemorrhage. Increased levels of unlabeled mannitol and citramalate, metabolites of potential bacterial origin, were also observed in trauma/hemorrhagic shock rats, but not trauma alone or controls. CONCLUSIONS: These preliminary results are consistent with observations we have recently obtained in humans, and expand upon our early results on rodent models of trauma and hemorrhagic shock by providing the kinetics of glucose fluxes after trauma and hemorrhage. Despite the preliminary nature of this study, owing to the limited number of biological replicates, results highlight a role for shock, rather than trauma alone, in eliciting systemic metabolic aberrations. This study provides the foundation for tracing experiments in rat models of trauma. The goal is to improve our understanding of substrate specific metabolic derangements in trauma/hemorrhagic shock, so as to design resuscitative strategies tailored toward metabolic alterations and the severity of trauma. PMID: 26242576 [PubMed - in process]

Related Articles [Metabolomics Study on Non-Small Cell Lung Cancer Patients with Different Chinese Medical Syndromes]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2015 Jun;35(6):659-63 Authors: Ma JJ, Wang XL, Liu HP Abstract OBJECTIVE: To study the relationship between Chinese medical syndrome types and metabolomics of non-small cell lung cancer (NSCLC) patients. METHODS: Totally 120 NSCLC patients were assigned to asthenia syndrome group and sthenia syndrome group, 60 in each group. Meanwhile, 60 cases of benign pulmonary nodules in physical examinations were recruited as the control group. Tumor tissues or benign pulmonary nodules tissues were obtained by thoracoscope. Changes of their metabolites were observed using gas chromatography-mass spectrometry (GC-MS). Their differences were studied using principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA). ROC curve analysis was performed in different metabolic compounds of sthenia and asthenia syndromes groups. The area under the curve (AUC) was calculated to evaluate the sensitivity of diagnosing syndrome types. RESULTS: Compared with the control group, difference existed in 16 compounds. Of them , contents of citric acid, pyruvic acid, alanine, choline phosphate, glycerol phosphate choline, linoleic acid, oleic acid, lactic acid, inositol were more in the two tumors group than in the control group. Difference existed in 10 compounds between the sthenia syndrome group and the asthenia syndrome group. Of them, citric acid, pyruvic acid, alanine, choline phosphate, glycerol phosphate choline, lactic acid, and inositol were more in the asthenia syndrome group than in the sthenia syndrome group. Contents of valine, glucose, and glutamine were more in the sthenia syndrome group than in the asthenia syndrome group. ROC curve analyses of different compounds indicated that AUC of lactic acid and glucose was more than 0.8 (P < 0.01); AUC of inositol, choline phosphate, and glycerol phosphate choline was more than 0.7 (P < 0.01); AUC of valine, citric acid, glutamine, alanine, and pyruvic acid was more than 0.6 (P < 0.05). CONCLUSIONS: There existed certain correlation between CM syndrome types and metabolomics of lung cancer. Lactic acid, glucose, inositol, choline phosphate, glycerol phosphate choline, valine, citric acid, glutamine, alanine, pyruvic acid were sensitive diagnostic compounds, and the first four kinds were most sensitive compounds. PMID: 26242114 [PubMed - in process]

Related Articles Characterizing the in vivo role of trehalose in Saccharomyces cerevisiae using the AGT1 transporter. Proc Natl Acad Sci U S A. 2015 May 12;112(19):6116-21 Authors: Gibney PA, Schieler A, Chen JC, Rabinowitz JD, Botstein D Abstract Trehalose is a highly stable, nonreducing disaccharide of glucose. A large body of research exists implicating trehalose in a variety of cellular phenomena, notably response to stresses of various kinds. However, in very few cases has the role of trehalose been examined directly in vivo. Here, we describe the development and characterization of a system in Saccharomyces cerevisiae that allows us to manipulate intracellular trehalose concentrations independently of the biosynthetic enzymes and independently of any applied stress. We found that many physiological roles heretofore ascribed to intracellular trehalose, including heat resistance, are not due to the presence of trehalose per se. We also found that many of the metabolic and growth defects associated with mutations in the trehalose biosynthesis pathway are not abolished by providing abundant intracellular trehalose. Instead, we made the observation that intracellular accumulation of trehalose or maltose (another disaccharide of glucose) is growth-inhibitory in a carbon source-specific manner. We conclude that the physiological role of the trehalose pathway is fundamentally metabolic: i.e., more complex than simply the consequence of increased concentrations of the sugar and its attendant physical properties (with the exception of the companion paper where Tapia et al. [Tapia H, et al. (2015) Proc Natl Acad Sci USA, 10.1073/pnas.1506415112] demonstrate a direct role for trehalose in protecting cells against desiccation). PMID: 25918382 [PubMed - indexed for MEDLINE]

Related Articles Characterization and study of transgenic cultivars by capillary and microchip electrophoresis. Int J Mol Sci. 2014;15(12):23851-77 Authors: Domínguez Vega E, Marina ML Abstract Advances in biotechnology have increased the demand for suitable analytical techniques for the analysis of genetically modified organisms. Study of the substantial equivalence, discrimination between transgenic and non-transgenic cultivars, study of the unintended effects caused by a genetic modification or their response to diverse situations or stress conditions (e.g., environmental, climatic, infections) are some of the concerns that need to be addressed. Capillary electrophoresis (CE) is emerging as an alternative to conventional techniques for the study and characterization of genetically modified organisms. This article reviews the most recent applications of CE for the analysis and characterization of transgenic cultivars in the last five years. Different strategies have been described depending on the level analyzed (DNA, proteins or metabolites). Capillary gel electrophoresis (CGE) has shown to be particularly useful for the analysis of DNA fragments amplified by PCR. Metabolites and proteins have been mainly separated using capillary zone electrophoresis (CZE) using UV and MS detection. Electrophoretic chips have also proven their ability in the analysis of transgenic cultivars and a section describing the new applications is also included. PMID: 25535077 [PubMed - indexed for MEDLINE]

Related Articles Peroxiredoxin 3 levels regulate a mitochondrial redox setpoint in malignant mesothelioma cells. Redox Biol. 2014;3:79-87 Authors: Cunniff B, Wozniak AN, Sweeney P, DeCosta K, Heintz NH Abstract Peroxiredoxin 3 (PRX3), a typical 2-Cys peroxiredoxin located exclusively in the mitochondrial matrix, is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide, a byproduct of cellular respiration originating from the mitochondrial electron transport chain. Mitochondrial oxidants are produced in excess in cancer cells due to oncogenic transformation and metabolic reorganization, and signals through FOXM1 and other redox-responsive factors to support a hyper-proliferative state. Over-expression of PRX3 in cancer cells has been shown to counteract oncogene-induced senescence and support tumor cell growth and survival making PRX3 a credible therapeutic target. Using malignant mesothelioma (MM) cells stably expressing shRNAs to PRX3 we show that decreased expression of PRX3 alters mitochondrial structure, function and cell cycle kinetics. As compared to control cells, knockdown of PRX3 expression increased mitochondrial membrane potential, basal ATP production, oxygen consumption and extracellular acidification rates. shPRX3 MM cells failed to progress through the cell cycle compared to wild type controls, with increased numbers of cells in G2/M phase. Diminished PRX3 expression also induced mitochondrial hyperfusion similar to the DRP1 inhibitor mdivi-1. Cell cycle progression and changes in mitochondrial networking were rescued by transient expression of either catalase or mitochondrial-targeted catalase, indicating high levels of hydrogen peroxide contribute to perturbations in mitochondrial structure and function in shPRX3 MM cells. Our results indicate that PRX3 levels establish a redox set point that permits MM cells to thrive in response to increased levels of mROS, and that perturbing the redox status governed by PRX3 impairs proliferation by altering cell cycle-dependent dynamics between mitochondrial networking and energy metabolism. PMID: 25462069 [PubMed - indexed for MEDLINE]

Related Articles LocFuse: human protein-protein interaction prediction via classifier fusion using protein localization information. Genomics. 2014 Dec;104(6 Pt B):496-503 Authors: Zahiri J, Mohammad-Noori M, Ebrahimpour R, Saadat S, Bozorgmehr JH, Goldberg T, Masoudi-Nejad A Abstract UNLABELLED: Protein-protein interaction (PPI) detection is one of the central goals of functional genomics and systems biology. Knowledge about the nature of PPIs can help fill the widening gap between sequence information and functional annotations. Although experimental methods have produced valuable PPI data, they also suffer from significant limitations. Computational PPI prediction methods have attracted tremendous attentions. Despite considerable efforts, PPI prediction is still in its infancy in complex multicellular organisms such as humans. Here, we propose a novel ensemble learning method, LocFuse, which is useful in human PPI prediction. This method uses eight different genomic and proteomic features along with four types of different classifiers. The prediction performance of this classifier selection method was found to be considerably better than methods employed hitherto. This confirms the complex nature of the PPI prediction problem and also the necessity of using biological information for classifier fusion. The LocFuse is available at: http://lbb.ut.ac.ir/Download/LBBsoft/LocFuse. BIOLOGICAL SIGNIFICANCE: The results revealed that if we divide proteome space according to the cellular localization of proteins, then the utility of some classifiers in PPI prediction can be improved. Therefore, to predict the interaction for any given protein pair, we can select the most accurate classifier with regard to the cellular localization information. Based on the results, we can say that the importance of different features for PPI prediction varies between differently localized proteins; however in general, our novel features, which were extracted from position-specific scoring matrices (PSSMs), are the most important ones and the Random Forest (RF) classifier performs best in most cases. LocFuse was developed with a user-friendly graphic interface and it is freely available for Linux, Mac OSX and MS Windows operating systems. PMID: 25458812 [PubMed - indexed for MEDLINE]

Discovery of nutritional biomarkers: future directions based on omics technologies. Int J Food Sci Nutr. 2015 Jul;66(S1):S31-S40 Authors: Odriozola L, Corrales FJ Abstract Understanding the interactions between food and human biology is of utmost importance to facilitate the development of more efficient nutritional interventions that might improve our wellness status and future health outcomes by reducing risk factors for non-transmittable chronic diseases, such as cardiovascular diseases, cancer, obesity and metabolic syndrome. Dissection of the molecular mechanisms that mediate the physiological effects of diets and bioactive compounds is one of the main goals of current nutritional investigation and the food industry as might lead to the discovery of novel biomarkers. It is widely recognized that the availability of robust nutritional biomarkers represents a bottleneck that delays the innovation process of the food industry. In this regard, omics sciences have opened up new avenues of research and opportunities in nutrition. Advances in mass spectrometry, nuclear magnetic resonance, next generation sequencing and microarray technologies allow massive genome, gene expression, proteomic and metabolomic profiling, obtaining a global and in-depth analysis of physiological/pathological scenarios. For this reason, omics platforms are most suitable for the discovery and characterization of novel nutritional markers that will define the nutritional status of both individuals and populations in the near future, and to identify the nutritional bioactive compounds responsible for the health outcomes. PMID: 26241009 [PubMed - as supplied by publisher]

Nutridynamics: mechanism(s) of action of bioactive compounds and their effects. Int J Food Sci Nutr. 2015 Jul;66(S1):S22-S30 Authors: Serrano JC, Jove M, Gonzalo H, Pamplona R, Portero-Otin M Abstract Mechanism of action of bioactive compounds may be multiple, especially in the food matrix. Therefore, the interplay between these compounds and hosts' physiology, and the consequences of its continuous intake should be considered. In analogy with pharmacodynamics, the bioactive compounds should have both defined targets and mechanisms of action. However, several essential differences arise when considering the heterogeneous nature of the food matrix, the multiplicity of mechanisms and the variety of responses. In order to ascertain a potential mechanism of activity, one should consider both the intended use of the food, the biomarker that will support this claim and previous evidences, examined from current information sources. Once these have been examined, several experimental strategies should be considered, ranging from the choice of preclinical or experimental model, the use of samples from pilot interventional studies and the application of system's biology derived techniques, such as transcriptomics or metabolomics. PMID: 26241008 [PubMed - as supplied by publisher]

An essential poison: Synthesis and degradation of cyclic di-AMP in Bacillus subtilis. J Bacteriol. 2015 Aug 3; Authors: Gundlach J, Mehne FM, Herzberg C, Kampf J, Valerius O, Kaever V, Stülke J Abstract Gram-positive bacteria synthesize the second messenger cyclic di-AMP to control cell wall and potassium homeostasis and to secure the integrity of their DNA. In the firmicutes, c-di-AMP is essential for growth. The model organism Bacillus subtilis encodes three diadenylate cyclases and two potential phosphodiesterases to produce and degrade c-di-AMP, respectively. Among the three cyclases, CdaA is conserved in nearly all firmicutes, and this enzyme seems to be responsible for the c-di-AMP that is required for cell wall homeostasis. Here, we demonstrate that CdaA localizes to the membrane and that it forms a complex with the regulatory protein CdaR and the glucosamine-6-phosphate mutase GlmM. Interestingly, cdaA, cdaR, and glmM form a gene cluster that is conserved throughout the firmicutes. This conserved arrangement and the observed interaction between the three proteins suggests a functional relation. Our data suggest that GlmM and GlmS are involved in the control of c-di-AMP synthesis. These enzymes convert glutamine and fructose-6-phosphate to glutamate and glucosamine-1-phosphate. c-di-AMP synthesis is enhanced if the cells are grown in the presence of glutamate as compared to glutamine-grown cells. Thus, the quality of the nitrogen source is an important signal for c-di-AMP production. In the analysis of c-di-AMP-degrading phosphodiesterases, we observed that both phosphodiesterases, GdpP and PgpH (previously YqfF), contribute to the degradation of the second messenger. Accumulation of c-di-AMP in a gdpP pgpH double mutant is toxic for the cells, and the cells respond to this accumulation by inactivation of the diadenylate cyclase CdaA. IMPORTANCE: Bacteria use second messengers for signal transduction. Cyclic di-AMP is the only second messenger that is essential for a large group of bacteria known so far. We have studied the regulation of c-di-AMP synthesis and the role of the phosphodiesterases that degrade the second messenger. C-di-AMP synthesis strongly depends on the nitrogen source: glutamate-grown cell produce more c-di-AMP than glutamine-grown cells. The accumulation of c-di-AMP in a strain lacking both phosphodiesterases is toxic, and results in inactivation of the diadenylate cyclase CdaA. Our results suggest that CdaA is the critical diadenylate cyclase that produces the c-di-AMP that is both essential and toxic upon accumulation. PMID: 26240071 [PubMed - as supplied by publisher]

Pharmacological inhibition of fatty acid oxidation synergistically enhances the effect of L-asparaginase in childhood ALL cells. Leukemia. 2015 Aug 4; Authors: Heřmanová I, Arruabarrena-Aristorena A, Vališ K, Nůsková H, Jorda MA, Fišer K, Fernández-Ruiz S, Kavan D, Pecinová A, Niso-Santano M, Žaliová M, Novák P, Houštěk J, Mráček T, Kroemer G, Carracedo A, Trka J, Starková J Abstract L-asparaginase (ASNase), a key component in the treatment of childhood acute lymphoblastic leukemia (ALL), hydrolyzes plasma asparagine and glutamine and thereby disturbs metabolic homeostasis of leukemic cells. The efficacy of such therapeutic strategy will depend on the capacity of cancer cells to adapt to the metabolic challenge, which could relate to the activation of compensatory metabolic routes. Therefore, we studied the impact of ASNase on the main metabolic pathways in leukemic cells. Treating leukemic cells with ASNase increased fatty acid oxidation (FAO) and cell respiration and inhibited glycolysis. FAO, together with the decrease in protein translation and pyrimidine synthesis, was positively regulated through inhibition of the RagB-mTORC1 pathway, whereas the effect on glycolysis was RagB-mTORC1 independent. Since FAO has been suggested to have a pro-survival function in leukemic cells, we tested its contribution to cell survival following ASNase treatment. Pharmacological inhibition of FAO significantly increased the sensitivity of ALL cells to ASNase. Moreover, constitutive activation of the mTOR pathway increased apoptosis in leukemic cells treated with ASNase, but did not increase FAO. Our study uncovers a novel therapeutic option based on the combination of ASNase and FAO inhibitors.Leukemia accepted article preview online, 04 August 2015. doi:10.1038/leu.2015.213. PMID: 26239197 [PubMed - as supplied by publisher]

Vitroprocines, new antibiotics against Acinetobacter baumannii, discovered from marine Vibrio sp. QWI-06 using mass-spectrometry-based metabolomics approach. Sci Rep. 2015;5:12856 Authors: Liaw CC, Chen PC, Shih CJ, Tseng SP, Lai YM, Hsu CH, Dorrestein PC, Yang YL Abstract A robust and convenient research strategy integrating state-of-the-art analytical techniques is needed to efficiently discover novel compounds from marine microbial resources. In this study, we identified a series of amino-polyketide derivatives, vitroprocines A-J, from the marine bacterium Vibrio sp. QWI-06 by an integrated approach using imaging mass spectroscopy and molecular networking, as well as conventional bioactivity-guided fractionation and isolation. The structure-activity relationship of vitroprocines against Acinetobacter baumannii is proposed. In addition, feeding experiments with (13)C-labeled precursors indicated that a pyridoxal 5'-phosphate-dependent mechanism is involved in the biosynthesis of vitroprocines. Elucidation of amino-polyketide derivatives from a species of marine bacteria for the first time demonstrates the potential of this integrated metabolomics approach to uncover marine bacterial biodiversity. PMID: 26238555 [PubMed - as supplied by publisher]

Alteration of Amino Acid and Biogenic Amine Metabolism in Hepatobiliary Cancers: Findings from a Prospective Cohort Study. Int J Cancer. 2015 Aug 3; Authors: Stepien M, Duarte-Salles T, Fedirko V, Floegel A, Barupal DK, Rinaldi S, Achaintre D, Assi N, Tjønneland A, Overvad K, Bastide N, Boutron-Ruault MC, Severi G, Kühn T, Kaaks R, Aleksandrova K, Boeing H, Trichopoulou A, Bamia C, Lagiou P, Saieva C, Agnoli C, Panico S, Tumino R, Naccarati A, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Quirós JR, Agudo A, Sánchez MJ, Dorronsoro M, Gavrila D, Barricarte A, Ohlsson B, Sjöberg K, Werner M, Sund M, Wareham N, Khaw KT, Travis RC, Schmidt JA, Gunter M, Cross A, Vineis P, Romieu I, Scalbert A, Jenab M Abstract Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean=0, SD=1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which 7 metabolites and 4 ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development. This article is protected by copyright. All rights reserved. PMID: 26238458 [PubMed - as supplied by publisher]

Related Articles Roseomics: a blank slate. Curr Opin Virol. 2014 Dec;9:188-93 Authors: Moorman NJ, Murphy EA Abstract Recent technological advances have led to an explosion in the system-wide profiling of biological processes in the study of herpesvirus biology, herein referred to as '-omics'. In many cases these approaches have revealed novel virus-induced changes to host cell biology that can be targeted with new antiviral therapeutics. Despite these successes, -omics approaches are not widely applied in the study of roseoloviruses. Here we describe examples of how -omics studies have shaped our understanding of herpesvirus biology, and discuss how these approaches might be used to identify host and viral factors that mediate roseolovirus pathogenesis. PMID: 25437230 [PubMed - indexed for MEDLINE]

Related Articles An in planta-expressed polyketide synthase produces (R)-mellein in the wheat pathogen Parastagonospora nodorum. Appl Environ Microbiol. 2015 Jan;81(1):177-86 Authors: Chooi YH, Krill C, Barrow RA, Chen S, Trengove R, Oliver RP, Solomon PS Abstract Parastagonospora nodorum is a pathogen of wheat that affects yields globally. Previous transcriptional analysis identified a partially reducing polyketide synthase (PR-PKS) gene, SNOG_00477 (SN477), in P. nodorum that is highly upregulated during infection of wheat leaves. Disruption of the corresponding SN477 gene resulted in the loss of production of two compounds, which we identified as (R)-mellein and (R)-O-methylmellein. Using a Saccharomyces cerevisiae yeast heterologous expression system, we successfully demonstrated that SN477 is the only enzyme required for the production of (R)-mellein. This is the first identification of a fungal PKS that is responsible for the synthesis of (R)-mellein. The P. nodorum ΔSN477 mutant did not show any significant difference from the wild-type strain in its virulence against wheat. However, (R)-mellein at 200 μg/ml inhibited the germination of wheat (Triticum aestivum) and barrel medic (Medicago truncatula) seeds. Comparative sequence analysis identified the presence of mellein synthase (MLNS) homologues in several Dothideomycetes and two sodariomycete genera. Phylogenetic analysis suggests that the MLNSs in fungi and bacteria evolved convergently from fungal and bacterial 6-methylsalicylic acid synthases. PMID: 25326302 [PubMed - indexed for MEDLINE]

Rapid on-line analysis of single cyanobacteria and algae cells under nitrogen-limited conditions using aerosol time-of-flight mass spectrometry. Anal Chem. 2015 Aug 3; Authors: Cahill JF, Darlington TK, Fitzgerald CK, Schoepp NG, Beld J, Burkart MD, Prather KA Abstract Metabolomics studies typically perform measurements on populations of whole cells which provide the average representation of a collection of many cells. However key mechanistic information can be lost using this approach. Investigating chemistry at the single cell level yields a more accurate representation of the diversity of populations within a cell sample, however this approach has many analytical challenges. In this study, an aerosol time-of-flight mass spectrometer (ATOFMS) was used for rapid analysis of single algae and cyanobacteria cells with diameters ranging from 1-8 µm. Cells were aerosolized by nebulization and directly transmitted into the ATOFMS. Whole cells were determined to remain intact inside the instrument through a combination of particle sizing and imaging measurements. Differences in cell populations were observed after perturbing Chlamydomonas reinhardtii cells via nitrogen deprivation. Thousands of single cells were measured over a period of 4 days for nitrogen-replete and nitrogen-limited conditions. A comparison of the single cell mass spectra of the cells sampled under the two conditions revealed an increase in the dipalmitic acid sulfolipid sulfoquinovosyldiacylglycerol (SQDG), a chloroplast membrane lipid, under nitrogen-limited conditions. Single cell peak intensity distributions demonstrate the ability of the ATOFMS to measure metabolic differences of single cells. The ATOFMS provides an unprecedented maximum throughput of 50 Hz, enabling the rapid on-line measurement of thousands of single cell mass spectra. PMID: 26237223 [PubMed - as supplied by publisher]