PubMed

Related Articles Stable Isotope Resolved Metabolomics Studies in Ex Vivo TIssue Slices. Bio Protoc. 2016 Feb 5;6(3) Authors: Fan TW, Lane AN, Higashi RM Abstract An important component of this methodology is to assess the role of the tumor microenvironment on tumor growth and survival. To tackle this problem, we have adapted the original approach of Warburg (1), by combining thin tissue slices with Stable Isotope Resolved Metabolomics (SIRM) to determine detailed metabolic activity of human tissues. SIRM enables the tracing of metabolic transformations of source molecules such as glucose or glutamine over defined time periods, and is a requirement for detailed pathway tracing and flux analysis. In our approach, we maintain freshly resected tissue slices (both cancerous and non- cancerous from the same organ of the same subject) in cell culture media, and treat with appropriate stable isotope-enriched nutrients, e.g. (13)C6-glucose or (13)C5, (15)N2 -glutamine. These slices are viable for at least 24 h, and make it possible to eliminate systemic influence on the target tissue metabolism while maintaining the original 3D cellular architecture. It is therefore an excellent pre-clinical platform for assessing the effect of therapeutic agents on target tissue metabolism and their therapeutic efficacy on individual patients (2,3). PMID: 27158639 [PubMed - as supplied by publisher]

Related Articles Dying cell recognition shapes the pathophysiology of cell death. Cell Death Differ. 2016 Jun;23(6):913-4 Authors: Kroemer G PMID: 27157319 [PubMed - in process]

Related Articles Commentary: High-resolution magic angle spinning (1)H nuclear magnetic resonance spectroscopy metabolomics of hyperfunctioning parathyroid glands. Surgery. 2016 May 5; Authors: Thompson GB PMID: 27157122 [PubMed - as supplied by publisher]

Related Articles Precision Treatment and Precision Prevention: Integrating "Below and Above the Skin". JAMA Pediatr. 2016 Jan;170(1):9-10 Authors: Gillman MW, Hammond RA PMID: 26595371 [PubMed - indexed for MEDLINE]

Related Articles Biomarkers of Ectopic Fat Deposition: The Next Frontier in Serum Lipidomics. J Clin Endocrinol Metab. 2016 Jan;101(1):176-82 Authors: Perreault L, Starling AP, Glueck D, Brozinick JT, Sanders P, Siddall P, Kuo MS, Dabelea D, Bergman BC Abstract CONTEXT: Strong evidence suggests that ectopic fat rather than fat mass per se drives risk for type 2 diabetes. Nonetheless, biomarkers of ectopic fat have gone unexplored. OBJECTIVE: To determine the utility of serum lipidomics to predict ectopic lipid deposition. DESIGN: Cross-sectional. SETTING: The Clinical Translational Research Center at the University of Colorado Anschutz Medical Campus. PARTICIPANTS: Endurance-trained athletes (n = 15, 41 ± 0.9 y old; body mass index 24 ± 0.6 kg/m(2)) and obese people with or without type 2 diabetes (n = 29, 42 ± 1.4 y old; body mass index 32 ± 2.5 kg/m(2)). INTERVENTION: Blood sampling and skeletal muscle biopsy. MAIN OUTCOME MEASURES: Multivariable models determined the ability of serum lipids to predict intramuscular (im) lipid accumulation of triacylglycerol (TAG), diacylglycerol (DAG), and ceramide (liquid chromatography tandem mass spectroscopy). RESULTS: Among people with obesity, serum ganglioside C22:0 and lactosylceramide C14:0 predicted muscle TAG (overall model R(2) = 0.48), whereas serum DAG C36:1 and free fatty acid (FFA) C18:4 were strong predictors of muscle DAG (overall model R(2) = 0.77), as were serum TAG C58:5, FFA C14:2 and C14:3, phosphotidylcholine C38:1, and cholesterol ester C24:1 to predict muscle ceramide (overall model R(2) = 0.85). Among endurance-trained athletes, serum FFA C14:1 and sphingosine were significant predictors of muscle TAG (overall model R(2) = 0.81), whereas no models could predict intramuscular DAG or ceramide in this group. CONCLUSIONS: Different serum lipids predict intramuscular TAG accumulation in obese people vs athletes. The ability of serum lipidomics to predict intramuscular DAG and ceramide in insulin-resistant humans may prove a new biomarker to determine risk for diabetes. PMID: 26574956 [PubMed - indexed for MEDLINE]

Related Articles Animal Models and "Omics" Technologies for Identification of Novel Biomarkers and Drug Targets to Prevent Heart Failure. Biomed Res Int. 2015;2015:212910 Authors: Hou Y, Adrian-Segarra JM, Richter M, Kubin N, Shin J, Werner I, Walther T, Schönburg M, Pöling J, Warnecke H, Braun T, Kostin S, Kubin T Abstract It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an "omics" toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future. PMID: 26236717 [PubMed - indexed for MEDLINE]

Proteomics and metabolomics analyses reveal the cucurbit sieve tube system as a complex metabolic space. Plant J. 2016 May 7; Authors: Hu C, Ham BK, El-Shabrawi HM, Alexander D, Zhang D, Ryals J, Lucas WJ Abstract The plant vascular system, and specifically the phloem plays a pivotal role in allocation of fixed carbon to developing sink organs. Although the processes involved in loading and unloading of sugars and amino acids are well characterized, in contrast, little information is available regarding the nature of other metabolites in the sieve tube system (STS), at specific sites long the pathway. Here, we elucidate spatial features of metabolite composition mapped with phloem enzymes along the cucurbit STS. Phloem sap (PS) was collected from the loading (source), unloading (apical sink region) and shoot-root junction regions of cucumber, watermelon and pumpkin. Our PS analyses revealed significant differences in the metabolic and proteomic profiles, both along the source-to-sink pathway and between the STSs of these three cucurbits. In addition, metabolite profiles established for PS and vascular tissue indicated the presence of distinct compositions, consistent with the operation of the STS as a unique symplasmic domain. In this regard, at various locations along the STS, we could map metabolites and their related enzymes to specific metabolic pathways. These findings are discussed regarding the function of the STS as a unique and highly complex metabolic space within the plant vascular system. This article is protected by copyright. All rights reserved. PMID: 27155400 [PubMed - as supplied by publisher]

Identification of line-specific strategies for improving carotenoid production in synthetic maize through data-driven mathematical modelling. Plant J. 2016 May 7; Authors: Comas J, Benfeitas R, Vilaprinyo E, Sorribas A, Solsona F, Farré G, Berman J, Zorrilla U, Capell T, Sandmann G, Zhu C, Christou P, Alves R Abstract Plant Synthetic Biology is still in its infancy. However, Synthetic Biology approaches have been used to manipulate and improve the nutritional and health value of staple food crops, such as rice, potato, or maize. With current technologies, production yields of the synthetic nutrients are a result of trial and error, and systematic rational strategies to optimize those yields are still lacking. Here, we present a workflow that combines gene expression and quantitative metabolomics with mathematical modeling to identify strategies for increasing production yields of nutritionally important carotenoids in the seed endosperm synthesized through alternative biosynthetic pathways in synthetic lines of white maize, which is normally devoid of carotenoids. Quantitative metabolomics and gene expression data are used to create and fit parameters of mathematical models that are specific for four independent maize lines. Sensitivity analysis and simulation of each model is used to predict which gene activities should be further engineered in order to increase production yields for carotenoid accumulation in each line. Some of these predictions (e.g. increasing Zmlycb/Gllycb will increase accumulated β-carotenes) are valid across the four maize lines and consistent with experimental observations in other systems. Other predictions are line-specific. The workflow is adaptable to any other biological system for which appropriate quantitative information is available. Furthermore, we validate some of the predictions using experimental data from additional synthetic maize lines for which no models were developed. This article is protected by copyright. All rights reserved. PMID: 27155093 [PubMed - as supplied by publisher]

Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice. Diabetologia. 2016 May 6; Authors: Radović B, Vujić N, Leopold C, Schlager S, Goeritzer M, Patankar JV, Korbelius M, Kolb D, Reindl J, Wegscheider M, Tomin T, Birner-Gruenberger R, Schittmayer M, Groschner L, Magnes C, Diwoky C, Frank S, Steyrer E, Du H, Graier WF, Madl T, Kratky D Abstract AIMS/HYPOTHESIS: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). METHODS: We studied metabolic adaptations in Lal (-/-) mice. RESULTS: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels. CONCLUSIONS/INTERPRETATION: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply. PMID: 27153842 [PubMed - as supplied by publisher]

Proteometabolomic analysis of transgenic tomato overexpressing oxalate decarboxylase uncovers novel proteins potentially involved in defense mechanism against Sclerotinia. J Proteomics. 2016 May 3; Authors: Ghosh S, Narula K, Sinha A, Ghosh R, Jawa P, Chakraborty N, Chakraborty S Abstract Oxalic acid (OA) plays dual role in fungal pathogenicity in a concentration dependent manner. While at higher concentration it induces programmed cell death leading to fungal invasion, low oxalate build resistance in plant. Although OA has been identified as a virulence determinant for rot disease caused by Sclerotinia sp., our understanding of how oxalate downregulation impart host immunity is limited. We have earlier shown that ectopic expression of oxalate decarboxylase (FvOXDC) specifically degrades OA in tomato (Solanum lycopersicum). To elucidate low oxalate regulated molecular mechanism imparting immunity, a comparative proteomics approach has been applied to E8.2-OXDC tomato fruit displaying fungal resistance. Mass spectrometric analyses identified 92 OXDC-responsive immunity related protein spots (ORIRPs) presumably associated with acid metabolism, defense signaling and endoplasmic reticulum stress. Metabolome study indicated increased abundance of some of the organic acids paralleling the proteomic analysis. Further, we interrogated the proteome data using network analysis that identified modules enriched in known and novel immunity-related prognostic proteins centered around 14-3-3, translationally controlled tumor protein, annexin and chaperonin. Taken together, our data demonstrate that low oxalate may act as metabolic and immunity determinant through translational reprogramming. BIOLOGICAL SIGNIFICANCE: Although OA plays critical role as fungal elicitor, our understanding of how oxalate downregulation by decarboxylative degradation impart immunity is limited. Our study confirms the impact of oxalate down-regulation on overall cellular physiology and provides new perspectives to study plant immunity. The network representation may facilitate the prioritization of candidate proteins for patho-stress tolerance in crop plant. These findings are of great importance for future work towards functional determination and exploitation of target proteins in crop improvement program. PMID: 27153761 [PubMed - as supplied by publisher]

NMRPro: an integrated web component for interactive processing and visualization of NMR spectra. Bioinformatics. 2016 Feb 26; Authors: Mohamed A, Nguyen CH, Mamitsuka H Abstract The popularity of using NMR spectroscopy in metabolomics and natural products has driven the development of an array of NMR spectral analysis tools and databases. Particularly, web applications are well used recently because they are platform-independent and easy to extend through reusable web components. Currently available web applications provide the analysis of NMR spectra. However, they still lack the necessary processing and interactive visualization functionalities. To overcome these limitations, we present NMRPro, a web component that can be easily incorporated into current web applications, enabling easy-to-use online interactive processing and visualization. NMRPro integrates server-side processing with client-side interactive visualization through three parts: a python package to efficiently process large NMR datasets on the server-side, a Django App managing server-client interaction, and SpecdrawJS for client-side interactive visualization. AVAILABILITY AND IMPLEMENTATION: Demo and installation instructions are available at http://mamitsukalab.org/tools/nmrpro/ CONTACT: mohamed@kuicr.kyoto-u.ac.jpSupplementary information: Supplementary data are available at Bioinformatics online. PMID: 27153725 [PubMed - as supplied by publisher]

metaCCA: summary statistics-based multivariate meta-analysis of genome-wide association studies using canonical correlation analysis. Bioinformatics. 2016 Feb 19; Authors: Cichonska A, Rousu J, Marttinen P, Kangas AJ, Soininen P, Lehtimäki T, Raitakari OT, Järvelin MR, Salomaa V, Ala-Korpela M, Ripatti S, Pirinen M Abstract MOTIVATION: A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. RESULTS: We introduce metaCCA, a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness.Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA, using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies. AVAILABILITY AND IMPLEMENTATION: Code is available at https://github.com/aalto-ics-kepaco CONTACTS: anna.cichonska@helsinki.fi or matti.pirinen@helsinki.fiSupplementary information: Supplementary data are available at Bioinformatics online. PMID: 27153689 [PubMed - as supplied by publisher]

RIPPER: a framework for MS1 only metabolomics and proteomics label-free relative quantification. Bioinformatics. 2016 Feb 18; Authors: Van Riper SK, Higgins L, Carlis JV, Griffin TJ Abstract RIPPER is a framework for mass-spectrometry-based label-free relative quantification for proteomics and metabolomics studies. RIPPER combines a series of previously described algorithms for pre-processing, analyte quantification, retention time alignment, and analyte grouping across runs. It is also the first software framework to implement proximity-based intensity normalization. RIPPER produces lists of analyte signals with their unnormalized and normalized intensities that can serve as input to statistical and directed mass spectrometry (MS) methods for detecting quantitative differences between biological samples using MS. AVAILABILITY AND IMPLEMENTATION: http://www.z.umn.edu/ripper CONTACT: vanr0014@umn.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID: 27153682 [PubMed - as supplied by publisher]

Purine metabolism is dysregulated in patients with major depressive disorder. Psychoneuroendocrinology. 2016 Apr 30;70:25-32 Authors: Ali-Sisto T, Tolmunen T, Toffol E, Viinamäki H, Mäntyselkä P, Valkonen-Korhonen M, Honkalampi K, Ruusunen A, Velagapudi V, Lehto SM Abstract INTRODUCTION: The purine cycle and altered purinergic signaling have been suggested to play a role in major depressive disorder (MDD). Nevertheless, data on this topic are scarce. Based on previous studies, we hypothesized that compared with non-depressed controls, MDD patients have distinct purine metabolite profiles. METHODS: The samples comprised 99 MDD patients and 253 non-depressed controls, aged 20-71 years. Background data were collected with questionnaires. Fasting serum samples were analyzed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS) to determine seven purine cycle metabolites belonging to the purine cycle. We investigated the levels of these metabolites in three settings: (1) MDD patients vs. non-depressed controls and (2) remitted vs. non-remitted MDD patients, and also (3) within-group changes in metabolite levels during the follow-up period. RESULTS: In logistic regression adjusted for age, gender, smoking, alcohol use, physical exercise, glycosylated hemoglobin, and high-density lipoprotein cholesterol, lower levels of inosine (OR 0.89, 95% CI 0.82-0.97) and guanosine (OR 0.32, 95% CI 0.17-0.59), and higher levels of xanthine (OR 2.21, 95% CI 1.30-3.75) were associated with MDD vs. the non-depressed group. Levels of several metabolites changed significantly during the follow-up period in the MDD group, but there were no differences between remitted and non-remitted groups. CONCLUSIONS: We observed altered purine metabolism in MDD patients compared with non-depressed controls. Furthermore, our observations suggest that circulating xanthine may accumulate in MDD patients. PMID: 27153521 [PubMed - as supplied by publisher]

Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis. Cell. 2016 May 5;165(4):896-909 Authors: Masri S, Papagiannakopoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, Jacks T, Sassone-Corsi P Abstract The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous "zeitgebers," such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here, we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK, and SREBP signaling, leading to altered insulin, glucose, and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver. PAPERCLIP. PMID: 27153497 [PubMed - as supplied by publisher]

Plasma sphingolipid changes with autopsy-confirmed Lewy Body or Alzheimer's pathology. Alzheimers Dement (Amst). 2016;3:43-50 Authors: Savica R, Murray ME, Persson XM, Kantarci K, Parisi JE, Dickson DW, Petersen RC, Ferman TJ, Boeve BF, Mielke MM Abstract INTRODUCTION: The clinical and pathological phenotypes of Dementia with Lewy Bodies (DLB) and Alzheimer's disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy-confirmed Lewy Body pathology or AD pathology. METHODS: We identified four groups with available plasma two years prior to death: high (n=12) and intermediate likelihood DLB (n=14) based on the third report of the DLB consortium; dementia with Alzheimer's pathology (AD; n=18); and cognitively normal with normal aging pathology (n=21). Lipids were measured using ESI/MS/MS. RESULTS: There were overall group differences in plasma ceramides C16:0, C18:1, C20:0 and C24:1 and monohexosylceramides C18:1 and C24:1. These lipids did not differ between the high likelihood DLB and AD groups, but both groups had higher levels than normals. Plasma fatty acid levels did not differ by group. DISCUSSION: Plasma ceramides and monohexosylceramides are elevated in people with dementia with either high likelihood DLB or AD pathology. PMID: 27152320 [PubMed - as supplied by publisher]

Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem. 2016 May 5; Authors: Salabei JK, Lorkiewicz PK, Mehra P, Gibb AA, Haberzettl P, Hong KU, Wei X, Zhang X, Li Q, Wysoczynski M, Bolli R, Bhatnagar A, Hill BG Abstract Type 2 diabetes is associated with increased mortality and progression to heart failure. Recent studies suggest that diabetes also impairs reparative responses after cell therapy. In this study, we examined potential mechanisms by which diabetes affects cardiac progenitor cells (CPCs). CPCs isolated from the diabetic heart showed diminished proliferation, a propensity for cell death, and a pro-adipogenic phenotype. The diabetic CPCs were insulin resistant, and they showed higher energetic reliance on glycolysis, which was associated with upregulation of the pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). In WT CPCs, expression of a mutant form of PFKFB, which mimics PFKFB3 activity and increases glycolytic rate, was sufficient to phenocopy the mitochondrial and proliferative deficiencies found in diabetic cells. Consistent with activation of phosphofructokinase in diabetic cells, stable isotope carbon tracing in diabetic CPCs showed dysregulation of the pentose phosphate and glycero(phospho)lipid synthesis pathways. We describe diabetes-induced dysregulation of carbon partitioning using stable isotope metabolomics-based coupling quotients, which relate relative flux values between metabolic pathways. These findings suggest that diabetes causes an imbalance in glucose carbon allocation by uncoupling biosynthetic pathway activity, which could diminish the efficacy of CPCs for myocardial repair. PMID: 27151219 [PubMed - as supplied by publisher]

In vivo gene expression in a Staphylococcus aureus prosthetic joint infection characterized by RNA sequencing and metabolomics: a pilot study. BMC Microbiol. 2016;16(1):80 Authors: Xu Y, Maltesen RG, Larsen LH, Schønheyder HC, Le VQ, Nielsen JL, Nielsen PH, Thomsen TR, Nielsen KL Abstract BACKGROUND: Staphylococcus aureus gene expression has been sparsely studied in deep-sited infections in humans. Here, we characterized the staphylococcal transcriptome in vivo and the joint fluid metabolome in a prosthetic joint infection with an acute presentation using deep RNA sequencing and nuclear magnetic resonance spectroscopy, respectively. We compared our findings with the genome, transcriptome and metabolome of the S. aureus joint fluid isolate grown in vitro. RESULT: From the transcriptome analysis we found increased expression of siderophore synthesis genes and multiple known virulence genes. The regulatory pattern of catabolic pathway genes indicated that the bacterial infection was sustained on amino acids, glycans and nucleosides. Upregulation of fermentation genes and the presence of ethanol in joint fluid indicated severe oxygen limitation in vivo. CONCLUSION: This single case study highlights the capacity of combined transcriptome and metabolome analyses for elucidating the pathogenesis of prosthetic infections of major clinical importance. PMID: 27150914 [PubMed - in process]

Related Articles Stereotypical Metabolic Response to Endoscopic Retrograde Cholangiopancreatography Show Alterations in Pancreatic Function Regardless of Post-Procedure Pancreatitis. Clin Transl Gastroenterol. 2016;7:e169 Authors: Lusczek ER, Colling K, Muratore S, Conwell D, Freeman M, Beilman G Abstract OBJECTIVES: Metabolomics-based diagnosis or prediction of risk may improve patient outcomes and improve understanding of the pathogenesis of acute pancreatitis (AP). Endoscopic retrograde cholangiopancreatography (ERCP) is a risk factor for developing AP. This pilot study examined metabolomes of patients before and after ERCP, hypothesizing that metabolomics could differentiate between patients who did and did not develop post-ERCP pancreatitis, and that biomarkers associated with development of AP could be identified. METHODS: Patients at high risk for developing post-ERCP pancreatitis were prospectively enrolled at the University of Minnesota from October 2012 to February 2014. Urine and serum samples were collected before ERCP, 2 h after ERCP, and daily thereafter if patients were admitted to the hospital with AP. Pancreatitis severity was calculated with Bedside Index for Severity in Acute Pancreatitis (BISAP) and Modified Glasgow scores. Patients who developed AP (n=9) were matched to patients who did not develop AP (n=18) by age and gender. Urine and serum metabolites were profiled with nuclear magnetic resonance spectroscopy. Partial least squares discriminant analysis (PLS-DA) was performed to detect changes in metabolic profiles associated with development of pancreatitis. Metabolic networks were constructed to probe functional relationships among metabolites. RESULTS: Of the 113 enrolled patients, 9 developed mild AP according to BISAP and modified Glasglow scores. PLS-DA showed common differences between pre- and post-ERCP metabolic profiles in urine and serum regardless of AP status, characterized by increases in serum and urine ketones and serum glucose. Pre-ERCP lipase levels were somewhat elevated in those who went on to develop AP, though this did not reach statistical significance. Metabolic networks differed between patients with AP and those without after ERCP; however, metabolomics did not identify specific prognostic or diagnostic markers of ERCP-induced AP. Aspartate and asparagine were identified as well-connected hubs in post-ERCP serum networks of cases and were correlated with aspartate transaminase (AST) and white blood cell count levels. These features were not evident in controls. Serum aspartate was elevated in AP patients relative to those without AP after ERCP (P=0.03). CONCLUSIONS: In this pilot study, ERCP was found to induce global changes in urine and serum metabolomes indicative of alterations in pancreatic function and insulin resistance. This should be taken into consideration in future research on this topic. Post-ERCP serum metabolic networks indicate functional differences surrounding aspartate metabolism between patients with AP and those without. Further study must be done in larger patient populations to test elevated lipase as a prognostic biomarker associated with risk of developing AP and to examine active metabolic mechanisms at work. PMID: 27148850 [PubMed]

Related Articles Reliability of Serum Metabolites over a Two-Year Period: A Targeted Metabolomic Approach in Fasting and Non-Fasting Samples from EPIC. PLoS One. 2015;10(8):e0135437 Authors: Carayol M, Licaj I, Achaintre D, Sacerdote C, Vineis P, Key TJ, Onland Moret NC, Scalbert A, Rinaldi S, Ferrari P Abstract OBJECTIVE: Although metabolic profiles have been associated with chronic disease risk, lack of temporal stability of metabolite levels could limit their use in epidemiological investigations. The present study aims to evaluate the reliability over a two-year period of 158 metabolites and compare reliability over time in fasting and non-fasting serum samples. METHODS: Metabolites were measured with the AbsolueIDQp180 kit (Biocrates, Innsbruck, Austria) by mass spectrometry and included acylcarnitines, amino acids, biogenic amines, hexoses, phosphatidylcholines and sphingomyelins. Measurements were performed on repeat serum samples collected two years apart in 27 fasting men from Turin, Italy, and 39 non-fasting women from Utrecht, The Netherlands, all participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Reproducibility was assessed by estimating intraclass correlation coefficients (ICCs) in multivariable mixed models. RESULTS: In fasting samples, a median ICC of 0.70 was observed. ICC values were <0.50 for 48% of amino acids, 27% of acylcarnitines, 18% of lysophosphatidylcholines and 4% of phosphatidylcholines. In non-fasting samples, the median ICC was 0.54. ICC values were <0.50 for 71% of acylcarnitines, 48% of amino acids, 44% of biogenic amines, 36% of sphingomyelins, 34% of phosphatidylcholines and 33% of lysophosphatidylcholines. Overall, reproducibility was lower in non-fasting as compared to fasting samples, with a statistically significant difference for 19-36% of acylcarnitines, phosphatidylcholines and sphingomyelins. CONCLUSION: A single measurement per individual may be sufficient for the study of 73% and 52% of the metabolites showing ICCs >0.50 in fasting and non-fasting samples, respectively. ICCs were higher in fasting samples that are preferable to non-fasting. PMID: 26274920 [PubMed - indexed for MEDLINE]