PubMed

Molecular histology of arteries: mass spectrometry imaging as a novel ex vivo tool to investigate atherosclerosis. Expert Rev Proteomics. 2015 Nov 11; Authors: Martin-Lorenzo M, Alvarez-Llamas G, McDonnell LA, Vivanco F Abstract Atherosclerosis is usually the underlying cause of a fatal event such as myocardial infarction or ictus. The atherome plaque develops silently and asymptomatically within the arterial intima layer. In this context, the possibility to analyze the molecular content of arterial tissue while preserving each molecule's specific localization is of great interest as it may reveal further insights into the physiopathological changes taking place. Mass spectrometry imaging (MSI) enables the spatially-resolved molecular analysis of proteins, peptides, metabolites, lipids and drugs directly in tissue, with a resolution sufficient to reveal molecular features specific to distinct arterial structures. MSI represents a novel ex vivo imaging tool still underexplored in cardiovascular diseases. This review focuses on the MSI technique applied to cardiovascular disease and covers the main contributions to date, ongoing efforts, the main challenges and current limitations of MSI. PMID: 26558814 [PubMed - as supplied by publisher]

1H-NMR-Based Metabolomic Study for Identifying Serum Profiles Associated with the Response to Etanercept in Patients with Rheumatoid Arthritis. PLoS One. 2015;10(11):e0138537 Authors: Priori R, Casadei L, Valerio M, Scrivo R, Valesini G, Manetti C Abstract OBJECTIVE: A considerable proportion of patients with rheumatoid arthritis (RA) do not have a satisfactory response to biological therapies. We investigated the use of metabolomics approach to identify biomarkers able to anticipate the response to biologics in RA patients. METHODS: Due to gender differences in metabolomic profiling, the analysis was restricted to female patients starting etanercept as the first biological treatment and having a minimum of six months' follow-up. Each patient was evaluated by the same rheumatologist before and after six months of treatment. At this time, the clinical response (good, moderate, none) was determined according to the EUropean League Against Rheumatism (EULAR) criteria, based on both erythrocyte sedimentation rate (EULAR-ESR) and C-reactive protein (EULAR-CRP). Sera collected prior and after six months of etanercept were analyzed by 1H-nuclear magnetic resonance (NMR) spectroscopy in combination with multivariate data analysis. RESULTS: Twenty-seven patients were enrolled: 18 had a good/moderate response and 9 were non responders according to both EULAR-ESR and EULAR-CRP after six months of etanercept. Metabolomic analysis at baseline was able to discriminate good, moderate, and non-responders with a very good predictivity (Q2 = 0.68) and an excellent sensitivity, specificity, and accuracy (100%). In good responders, we found an increase in isoleucine, leucine, valine, alanine, glutamine, tyrosine, and glucose levels and a decrease in 3-hydroxybutyrate levels after six months of treatment with etanercept with respect to baseline. CONCLUSION: Our study confirms the potential of metabolomic analysis to predict the response to biological agents. Changes in metabolic profiles during treatment may help elucidate their mechanism of action. PMID: 26558759 [PubMed - in process]

Related Articles Discriminating precursors of common fragments for large-scale metabolite profiling by triple quadrupole mass spectrometry. Bioinformatics. 2015 Jun 15;31(12):2017-23 Authors: Nikolskiy I, Siuzdak G, Patti GJ Abstract MOTIVATION: The goal of large-scale metabolite profiling is to compare the relative concentrations of as many metabolites extracted from biological samples as possible. This is typically accomplished by measuring the abundances of thousands of ions with high-resolution and high mass accuracy mass spectrometers. Although the data from these instruments provide a comprehensive fingerprint of each sample, identifying the structures of the thousands of detected ions is still challenging and time intensive. An alternative, less-comprehensive approach is to use triple quadrupole (QqQ) mass spectrometry to analyze predetermined sets of metabolites (typically fewer than several hundred). This is done using authentic standards to develop QqQ experiments that specifically detect only the targeted metabolites, with the advantage that the need for ion identification after profiling is eliminated. RESULTS: Here, we propose a framework to extend the application of QqQ mass spectrometers to large-scale metabolite profiling. We aim to provide a foundation for designing QqQ multiple reaction monitoring (MRM) experiments for each of the 82 696 metabolites in the METLIN metabolite database. First, we identify common fragmentation products from the experimental fragmentation data in METLIN. Then, we model the likelihoods of each precursor structure in METLIN producing each common fragmentation product. With these likelihood estimates, we select ensembles of common fragmentation products that minimize our uncertainty about metabolite identities. We demonstrate encouraging performance and, based on our results, we suggest how our method can be integrated with future work to develop large-scale MRM experiments. AVAILABILITY AND IMPLEMENTATION: Our predictions, Supplementary results, and the code for estimating likelihoods and selecting ensembles of fragmentation reactions are made available on the lab website at http://pattilab.wustl.edu/FragPred. PMID: 25691443 [PubMed - indexed for MEDLINE]

Flatography: Detection of gastrointestinal diseases by faecal gas analysis. World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):111-3 Authors: de Groot EF, de Meij TG, Berkhout DJ, van der Schee MP, de Boer NK Abstract Patients presenting with gastro-intestinal symptoms might suffer from a range of possible underlying diseases. An unmet need exists for novel cost-effective, reproducible, easy-to-perform and non-invasive tests. Hippocrates used body odours to diagnose diseases circa 460 before Christ. The art of diagnostic smelling is making a promising high-tech come-back with portable "electronic diagnostic noses". Analysis of faecal volatile organic compounds is a novel field in metabolomics with considerable potential to improve the diagnosis, phenotyping and monitoring of gastro-intestinal disease. Challenges will be to mature over the coming years by development of a standardized methodology for stool sample collection, storage, handling and analysis. Furthermore, key volatiles need to be identified to improve test accuracy and sensitivity by development of sensors tailored toward the accurate identification of disease specific volatiles. If these challenges are adequately faced, analysis of faecal volatiles has realistic potential to considerably improve screening, diagnosis and disease monitoring for gastro-intestinal diseases. PMID: 26558144 [PubMed]

Metabolomics, Standards, and Metabolic Modeling for Synthetic Biology in Plants. Front Bioeng Biotechnol. 2015;3:167 Authors: Hill CB, Czauderna T, Klapperstück M, Roessner U, Schreiber F Abstract Life on earth depends on dynamic chemical transformations that enable cellular functions, including electron transfer reactions, as well as synthesis and degradation of biomolecules. Biochemical reactions are coordinated in metabolic pathways that interact in a complex way to allow adequate regulation. Biotechnology, food, biofuel, agricultural, and pharmaceutical industries are highly interested in metabolic engineering as an enabling technology of synthetic biology to exploit cells for the controlled production of metabolites of interest. These approaches have only recently been extended to plants due to their greater metabolic complexity (such as primary and secondary metabolism) and highly compartmentalized cellular structures and functions (including plant-specific organelles) compared with bacteria and other microorganisms. Technological advances in analytical instrumentation in combination with advances in data analysis and modeling have opened up new approaches to engineer plant metabolic pathways and allow the impact of modifications to be predicted more accurately. In this article, we review challenges in the integration and analysis of large-scale metabolic data, present an overview of current bioinformatics methods for the modeling and visualization of metabolic networks, and discuss approaches for interfacing bioinformatics approaches with metabolic models of cellular processes and flux distributions in order to predict phenotypes derived from specific genetic modifications or subjected to different environmental conditions. PMID: 26557642 [PubMed]

Exposure to ionizing radiation reveals global dose- and time-dependent changes in the urinary metabolome of rat. Metabolomics. 2015 Oct 1;11(5):1082-1094 Authors: Mak TD, Tyburski JB, Krausz KW, Kalinich JF, Gonzalez FJ, Fornace AJ Abstract The potential for exposures to ionizing radiation has increased in recent years. Although advances have been made, understanding the global metabolic response as a function of both dose and exposure time is challenging considering the complexity of the responses. Herein we report our findings on the dose- and time-dependency of the urinary response to ionizing radiation in the male rat using radiation metabolomics. Urine samples were collected from adult male rats, exposed to 0.5 to 10 Gy γ-radiation, both before from 6 to 72 h following exposures. Samples were analyzed by liquid chromatography coupled with time-of-flight mass spectrometry, and deconvoluted mass chromatographic data were initially analyzed by principal component analysis. However, the breadth and complexity of the data necessitated the development of a novel approach to summarizing biofluid constituents after exposure, called Visual Analysis of Metabolomics Package (VAMP). VAMP revealed clear urine metabolite profile differences to as little as 0.5 Gy after 6 h exposure. Via VAMP, it was discovered that the response to radiation exposure found in rat urine is characterized by an overall net down-regulation of ion excretion with only a modest number of ions excreted in excess over pre-exposure levels. Our results show both similarities and differences with the published mouse urine response and a dose- and time-dependent net decrease in urine ion excretion associated with radiation exposure. These findings mark an important step in the development of minimally invasive radiation biodosimetry. VAMP should have general applicability in metabolomics to visualize overall differences and trends in many sample sets. PMID: 26557048 [PubMed - as supplied by publisher]

Chemical Shifts to Metabolic Pathways: Identifying Metabolic Pathways Directly from a Single 2D NMR Spectrum. Anal Chem. 2015 Nov 10; Authors: Dubey A, Rangarajan A, Pal D, Atreya HS Abstract Identifying cellular processes in terms of metabolic pathways is one of the avowed goals of metabolomics studies. Currently this is done after relevant metabolites are identified to allow their mapping onto specific pathways. This task is daunting due to the complex nature of cellular processes and the difficulty in establishing the identity of individual metabolites. We propose here a new method: ChemSMP (Chemical Shifts to Metabolic Pathways), which facilitates rapid analysis by identifying the active metabolic pathways directly from chemical shifts obtained from a single two-dimensional (2D) [13C-1H] correlation NMR spectrum, without the need for identification and assignment of individual metabolites. ChemSMP uses a novel indexing and scoring system comprising of a 'uniqueness score' and a 'coverage score'. Our method is demonstrated on metabolic pathways data from Small Molecule Pathway Database (SMPDB) and chemical shifts from Human Metabolome Database (HMDB). Benchmarks show that ChemSMP has a positive prediction rate of >90% in presence of de-cluttered data and can sustain the same at 60 - 70% even in presence of noise such as deletions of peaks and chemical shift deviations. The method tested on NMR data acquired for a mixture of 20 amino acids shows a success rate of 93% in correct recovery of pathways. When used on data obtained from cell lysate of an unexplored oncogenic cell line, it revealed active metabolic pathways responsible for regulating energy homeostasis of cancer cells. Our unique tool is thus expected to significantly enhance analysis of NMR based metabolomics data by reducing existing impediments. PMID: 26556218 [PubMed - as supplied by publisher]

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study. J Lipid Res. 2015 Nov 10; Authors: Oni-Orisan A, Edin ML, Lee JA, Wells MA, Christensen ES, Vendrov KC, Lih FB, Tomer KB, Bai X, Taylor JM, Stouffer GA, Zeldin DC, Lee CR Abstract Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD (no apparent CAD [N=39], nonobstructive CAD [N=51], obstructive CAD [N=72]) were evaluated. A significant relationship between free EET levels and CAD extent was observed (P=0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P=0.013), and with a biomarker of EET biosynthesis (P<0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared to other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise in patients with obstructive CAD. PMID: 26555503 [PubMed - as supplied by publisher]

ANALYTICAL APPROACHES FOR LIPIDOMICS AND ITS POTENTIAL APPLICATIONS IN NEUROPSYCHIATRIC DISORDERS. World J Biol Psychiatry. 2015 Nov 10;:1-49 Authors: Sethi S, Hayashi M, Sussulini A, Tasic L, Brietzke E Abstract OBJECTIVES: In this review, the authors discuss an overview of lipidomics followed by in-depth discussion of its application to the study of human diseases, including extraction methods of lipids, analytical techniques and clinical research in neuropsychiatric disorders. METHODS: Lipidomics is a lipid-targeted metabolomics approach aiming at the comprehensive analysis of lipids in biological systems. Recent technological advancements in mass spectrometry and chromatography have greatly enhanced the development and applications of metabolic profiling of diverse lipids in complex biological samples. RESULTS: An effective evaluation of the clinical course of diseases requires the application of very precise diagnostic and assessment approaches as early as possible. In order to achieve this, "omics" strategies offer new opportunities for biomarker identification and/or discovery in complex diseases and may provide pathological pathways understanding for diseases beyond traditional methodologies. CONCLUSIONS: This review highlights the importance of lipidomics for the future perspectives as a tool for biomarker identification and discovery and its clinical application. PMID: 26555297 [PubMed - as supplied by publisher]

Human plasma protein N-glycosylation. Glycoconj J. 2015 Nov 10; Authors: Clerc F, Reiding KR, Jansen BC, Kammeijer GS, Bondt A, Wuhrer M Abstract Glycosylation is the most abundant and complex protein modification, and can have a profound structural and functional effect on the conjugate. The oligosaccharide fraction is recognized to be involved in multiple biological processes, and to affect proteins physical properties, and has consequentially been labeled a critical quality attribute of biopharmaceuticals. Additionally, due to recent advances in analytical methods and analysis software, glycosylation is targeted in the search for disease biomarkers for early diagnosis and patient stratification. Biofluids such as saliva, serum or plasma are of great use in this regard, as they are easily accessible and can provide relevant glycosylation information. Thus, as the assessment of protein glycosylation is becoming a major element in clinical and biopharmaceutical research, this review aims to convey the current state of knowledge on the N-glycosylation of the major plasma glycoproteins alpha-1-acid glycoprotein, alpha-1-antitrypsin, alpha-1B-glycoprotein, alpha-2-HS-glycoprotein, alpha-2-macroglobulin, antithrombin-III, apolipoprotein B-100, apolipoprotein D, apolipoprotein F, beta-2-glycoprotein 1, ceruloplasmin, fibrinogen, immunoglobulin (Ig) A, IgG, IgM, haptoglobin, hemopexin, histidine-rich glycoprotein, kininogen-1, serotransferrin, vitronectin, and zinc-alpha-2-glycoprotein. In addition, the less abundant immunoglobulins D and E are included because of their major relevance in immunology and biopharmaceutical research. Where available, the glycosylation is described in a site-specific manner. In the discussion, we put the glycosylation of individual proteins into perspective and speculate how the individual proteins may contribute to a total plasma N-glycosylation profile determined at the released glycan level. PMID: 26555091 [PubMed - as supplied by publisher]

A cost-effectiveness model for evaluating new diagnostic tests in the work-up of patients with inflammatory arthritis at risk of having Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2015 Nov 10; Authors: Luime JJ, Buisman LR, Oppe M, Hazes JM, Rutten-van Mölken MP Abstract New opportunities have emerged for early diagnosis with the arrival of new technologies that assess the impact of genomics, proteomics, metabolomics and cytomics on rheumatoid arthritis (RA) risk. OBJECTIVE: This early Health Technology Assessment study assesses the short term cost-effectiveness of 4 add-on diagnostic tests in early inflammatory arthritis patients at risk of RA. METHODS: We modeled four diagnostic add-on tests to the ACR/EULAR 2010 RA classification criteria covering the first year after diagnosis, using REACH data. Sensitivity (Se), specificity (Sp) and costs were assigned to the magnetic resonance imaging (MRI) of hands and feet (Se 0.90;Sp 0.60;€756), IL6 serum level test (Se 0.70;Sp 0.53;€50), B-cell related gene expression (Se 0.60;Sp 0.90;€150,) and gene assay for RA (Se 0.40;Sp 0.85;€750), based on literature and expert opinion. Outcomes were evaluated using the unweighted diagnostic Net Benefit (udNB) and the incremental costs per quality-adjusted life year gained (ICER) in all patients (n=552), intermediate risk patients (n=263) and seronegative patients (n=329). RESULTS: The highest udNB was found when using B-cell assay in intermediate risk patients (43%; ICER €5,314), while the IL6 test in seronegative patients resulted in the lowest udNB (-11.4%; ICER €7,650). If a threshold of €20,000 is applied, the B-cell assay would be preferred over the other alternatives with a probability of being cost-effective of 78% for intermediate risk patients, 57% for all patients and 73% for seronegative patients. CONCLUSION: Diagnostic add-on tests favoring specificity over sensitivity with a headroom less than €370 per test are cost-effective, with the largest diagnostic benefit occurring in intermediate risk patients. This article is protected by copyright. All rights reserved. PMID: 26555013 [PubMed - as supplied by publisher]

Comparing two metabolic profiling approaches (liquid chromatography and gas chromatography coupled to mass spectrometry) for extra-virgin olive oil phenolic compounds analysis: A botanical classification perspective. J Chromatogr A. 2015 Oct 26; Authors: Bajoub A, Pacchiarotta T, Hurtado-Fernández E, Olmo-García L, García-Villalba R, Fernández-Gutiérrez A, Mayboroda OA, Carrasco-Pancorbo A Abstract Over the last decades, the phenolic compounds from virgin olive oil (VOO) have become the subject of intensive research because of their biological activities and their influence on some of the most relevant attributes of this interesting matrix. Developing metabolic profiling approaches to determine them in monovarietal virgin olive oils could help to gain a deeper insight into olive oil phenolic compounds composition as well as to promote their use for botanical origin tracing purposes. To this end, two approaches were comparatively investigated (LC-ESI-TOF MS and GC-APCI-TOF MS) to evaluate their capacity to properly classify 25 olive oil samples belonging to five different varieties (Arbequina, Cornicabra, Hojiblanca, Frantoio and Picual), using the entire chromatographic phenolic profiles combined to chemometrics (principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA)). The application of PCA to LC-MS and GC-MS data showed the natural clustering of the samples, seeing that 2 varieties were dominating the models (Arbequina and Frantoio), suppressing any possible discrimination among the other cultivars. Afterwards, PLS-DA was used to build four different efficient predictive models for varietal classification of the samples under study. The varietal markers pointed out by each platform were compared. In general, with the exception of one GC-MS model, all exhibited proper quality parameters. The models constructed by using the LC-MS data demonstrated superior classification ability. PMID: 26554295 [PubMed - as supplied by publisher]

Identification and Annotation of Lipid Species in Metabolomics Studies Needs Improvement. Clin Chem. 2015 Nov 9; Authors: Liebisch G, Ejsing CS, Ekroos K PMID: 26553790 [PubMed - as supplied by publisher]

The Physiological Regulation of Skeletal Muscle Fatty Acid Supply and Oxidation During Moderate-Intensity Exercise. Sports Med. 2015 Nov 9; Authors: van Hall G Abstract Energy substrates that are important to the working muscle at moderate intensities are the non-esterified fatty acids (NEFAs) taken up from the circulation and NEFAs originating from lipolysis of the intramuscular triacylglycerol (IMTAG). Moreover, NEFA from lipolysis via lipoprotein lipase (LPL) in the muscle of the very-low-density lipoproteins and in the (semi) post-prandial state chylomicrons may also contribute. In this review, the NEFA fluxes and oxidation by skeletal muscle during prolonged moderate-intensity exercise are described in terms of the integration of physiological systems. Steps involved in the regulation of the active muscle NEFA uptake include (1) increased energy demand; (2) delivery of NEFA to the muscle; (3) transport of NEFA into the muscle by NEFA transporters; and (4) activation of the NEFAs and either oxidation or re-esterification into IMTAG. The increased metabolic demand of the exercising muscle is the main driving force for all physiological regulatory processes. It elicits functional hyperemia, increasing the recruitment of capillaries and muscle blood flow resulting in increased NEFA delivery and accessibility to NEFA transporters and LPL. It also releases epinephrine that augments adipose tissue NEFA release and thereby NEFA delivery to the active muscle. Moreover, NEFA transporters translocate to the plasma membrane, further increasing the NEFA uptake. The majority of the NEFAs taken up by the active muscle is oxidized and a minor portion is re-esterified to IMTAG. Net IMTAG lipolysis occurs; however, the IMTAG contribution to total fat oxidation is rather limited compared to plasma-derived NEFA oxidation, suggesting a complex role and regulation of IMTAG utilization. PMID: 26553490 [PubMed - as supplied by publisher]

Metal and metalloid containing natural products and a brief overview of their applications in biology, biotechnology and biomedicine. Biometals. 2015 Nov 9; Authors: Dias DA, Kouremenos KA, Beale DJ, Callahan DL, Jones OA Abstract Bioinorganic natural product chemistry is a relatively unexplored but rapidly developing field with enormous potential for applications in biology, biotechnology (especially in regards to nanomaterial development, synthesis and environmental cleanup) and biomedicine. In this review the occurrence of metals and metalloids in natural products and their synthetic derivatives are reviewed. A broad overview of the area is provided followed by a discussion on the more common metals and metalloids found in natural sources, and an overview of the requirements for future research. Special attention is given to metal hyperaccumulating plants and their use in chemical synthesis and bioremediation, as well as the potential uses of metals and metalloids as therapeutic agents. The potential future applications and development in the field are also discussed. PMID: 26553050 [PubMed - as supplied by publisher]

[The mechanism of action of valsartan studied by HPLC-TOF/MS]. Yao Xue Xue Bao. 2015 Jul;50(7):875-81 Authors: Yang WQ, Li YL, Jiang HQ Abstract High performance liquid chromatography-time-off-flight mass spectrometer (HPLC-TOFMS) technology coupled with partial least squares discriminant analysis (PLS-DA) processed by SIMCA-P software was applied to investigate serum endogenous metabolites alternations of valsartan in spontaneous hypertension rats (SHR). And MetPA platform was used to connect identified potential biomarkers in corresponding metabolic pathways to find possible therapeutic mechanism of valsartan. Valsartan significantly declined the blood pressure of SHRs (P < 0.05) at fourth week. The metabolic profiling significantly changed and four metabolites involved in G protein-coupled pathway were identified. Metabolomics is able to detect holistic and microcosmic alternations in organism, so as to elucidate therapeutic mechanism of drugs. PMID: 26552150 [PubMed - in process]

[The action mechanisms of Morus alba leaves extract for the treatment of diabetes based on plasma metabolomics]. Yao Xue Xue Bao. 2015 Jul;50(7):830-5 Authors: Ji T, Zhang LL, Huang XC, Su SL, Ouyang Z, Zhu ZH, Guo S, Shang EX, Qian DW, Duan JA Abstract In order to evaluate the effect and mechanism of the mulberry leaf alkaloid, flavones, and polysaccharide intervention on diabetes, the overall metabolite profiling characteristics for the plasma of diabetic mouse was performed by using an ultra-performance liquid chromatography/electrospray-tandem mass spectrometry (UPLC-ESI-MS). The 8 potential biomarkers were found in diabetic mice plasma based on the data of MS/MS characteristics obtained from the UPLC-OrbitrapMS analysis, which mainly involved in sphingolipids, amino acid metabolic pathway. The principal component analysis showed that the normal group and model group were obviously distinguished and implied that metabolic disturbance was happened in diabetic mice plasma. The extracts of mulberry leaf flavonoids, polysaccharide, alkaloid had exhibited the effects of callback function for diabetic mice through regulating the amino acid metabolism and sphingolipid metabolism. PMID: 26552143 [PubMed - in process]

Related Articles Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4410-7 Authors: Daemen A, Peterson D, Sahu N, McCord R, Du X, Liu B, Kowanetz K, Hong R, Moffat J, Gao M, Boudreau A, Mroue R, Corson L, O'Brien T, Qing J, Sampath D, Merchant M, Yauch R, Manning G, Settleman J, Hatzivassiliou G, Evangelista M Abstract Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼ 200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors. PMID: 26216984 [PubMed - indexed for MEDLINE]

Related Articles A recycling pathway for cyanogenic glycosides evidenced by the comparative metabolic profiling in three cyanogenic plant species. Biochem J. 2015 Aug 1;469(3):375-89 Authors: Pičmanová M, Neilson EH, Motawia MS, Olsen CE, Agerbirk N, Gray CJ, Flitsch S, Meier S, Silvestro D, Jørgensen K, Sánchez-Pérez R, Møller BL, Bjarnholt N Abstract Cyanogenic glycosides are phytoanticipins involved in plant defence against herbivores by virtue of their ability to release toxic hydrogen cyanide (HCN) upon tissue disruption. In addition, endogenous turnover of cyanogenic glycosides without the liberation of HCN may offer plants an important source of reduced nitrogen at specific developmental stages. To investigate the presence of putative turnover products of cyanogenic glycosides, comparative metabolic profiling using LC-MS/MS and high resolution MS (HR-MS) complemented by ion-mobility MS was carried out in three cyanogenic plant species: cassava, almond and sorghum. In total, the endogenous formation of 36 different chemical structures related to the cyanogenic glucosides linamarin, lotaustralin, prunasin, amygdalin and dhurrin was discovered, including di- and tri-glycosides derived from these compounds. The relative abundance of the compounds was assessed in different tissues and developmental stages. Based on results common to the three phylogenetically unrelated species, a potential recycling endogenous turnover pathway for cyanogenic glycosides is described in which reduced nitrogen and carbon are recovered for primary metabolism without the liberation of free HCN. Glycosides of amides, carboxylic acids and 'anitriles' derived from cyanogenic glycosides appear as common intermediates in this pathway and may also have individual functions in the plant. The recycling of cyanogenic glycosides and the biological significance of the presence of the turnover products in cyanogenic plants open entirely new insights into the multiplicity of biological roles cyanogenic glycosides may play in plants. PMID: 26205491 [PubMed - indexed for MEDLINE]

Related Articles Nutrikinetic modeling reveals order of genistein phase II metabolites appearance in human plasma. Mol Nutr Food Res. 2014 Nov;58(11):2111-21 Authors: Smit S, Szymańska E, Kunz I, Gomez Roldan V, van Tilborg MW, Weber P, Prudence K, van der Kloet FM, van Duynhoven JP, Smilde AK, de Vos RC, Bendik I Abstract SCOPE: Genistein from foods or supplements is metabolized by the gut microbiota and the human body, thereby releasing many different metabolites into systemic circulation. The order of their appearance in plasma and the possible influence of food format are still unknown. This study compared the nutrikinetic profiles of genistein metabolites. METHODS AND RESULTS: In a randomized cross-over trial, 12 healthy young volunteers were administered a single dose of 30 mg genistein provided as a genistein tablet, a genistein tablet in low fat milk, and soy milk containing genistein glycosides. A high mass resolution LC-LTQ-Orbitrap FTMS platform detected and quantified in human plasma: free genistein, seven of its phase-II metabolites and 15 gut-derived metabolites. Interestingly, a novel metabolite, genistein-4'-glucuronide-7-sulfate (G-4'G-7S) was identified. Nutrikinetic analysis using population-based modeling revealed the order of appearance of five genistein phase II metabolites in plasma: (1) genistein-4',7-diglucuronide, (2) genistein-7-sulfate, (3) genistein-4'-sulfate-7-glucuronide, (4) genistein-4'-glucuronide, and (5) genistein-7-glucuronide, independent of the food matrix. CONCLUSION: The conjugated genistein metabolites appear in a distinct order in human plasma. The specific early appearance of G-4',7-diG suggests a multistep formation process for the mono and hetero genistein conjugates, involving one or two deglucuronidation steps. PMID: 25045152 [PubMed - indexed for MEDLINE]