PubMed

Broadening Our Portfolio in the Genetic Improvement of Maize Chemical Composition. Trends Genet. 2016 May 24; Authors: Wen W, Brotman Y, Willmitzer L, Yan J, Fernie AR Abstract The adoption of recombinant inbred line and introgression line populations, as well as the study of association mapping panels, has greatly accelerated our ability to identify the genes underlying plant phenotypic variance. In tandem, the development of metabolomics approaches has greatly enhanced our ability to comprehensively define cellular chemical composition. As a consequence, breeding for chemical composition is being extended beyond our traditional targets of oil and protein to include components such as essential amino acids, vitamins, and antioxidant secondary metabolites with considerable purported consequences for human health. Here, we review the above-mentioned developments paying particular attention to the genetic architecture of metabolic traits as well as updating the perspective for utilizing metabolomics in maize improvement. PMID: 27235112 [PubMed - as supplied by publisher]

Characterisation of the metabolome of ocular tissues and post-mortem changes in the rat retina. Exp Eye Res. 2016 May 24; Authors: Tan SZ, Mullard G, Hollywood KA, Dunn WB, Bishop PN Abstract Time-dependent post-mortem biochemical changes have been demonstrated in donor cornea and vitreous, but there have been no published studies to date that objectively measure post-mortem changes in the retinal metabolome over time. The aim of the study was firstly, to investigate post-mortem, time-dependent changes in the rat retinal metabolome and secondly, to compare the metabolite composition of healthy rat ocular tissues. To study post-mortem changes in the rat retinal metabolome, globes were enucleated and stored at 4 °C and sampled at 0, 2, 4, 8, 24 and 48 h post-mortem. To study the metabolite composition of rat ocular tissues, eyes were dissected immediately after culling to isolate the cornea, lens, vitreous and retina, prior to storing at -80 °C. Tissue extracts were subjected to Gas Chromatograph Mass Spectrometry (GC-MS) and Ultra High Performance Liquid Chromatography Mass Spectrometry (UHPLC-MS). Generally, the metabolic composition of the retina was stable for 8 h post-mortem when eyes were stored at 4 °C, but showed increasing changes thereafter. However, some more rapid changes were observed such as increases in TCA cycle metabolites after 2 h post-mortem, whereas some metabolites such as fatty acids only showed decreases in concentration from 24 h. A total of 42 metabolites were identified across the ocular tissues by GC-MS (MSI level 1) and 2782 metabolites were annotated by UHPLC-MS (MSI level 2) according to MSI reporting standards. Many of the metabolites detected were common to all of the tissues but some metabolites showed partitioning between different ocular structures with 655, 297, 93 and 13 metabolites being uniquely detected in the retina, lens, cornea and vitreous respectively. Only a small percentage (1.6%) of metabolites found in the vitreous were exclusively found in the retina and not other tissues. In conclusion, mass spectrometry-based techniques have been used for the first time to compare the metabolic composition of different ocular tissues. The metabolite composition of the retina of eyes kept at 4 °C post-mortem is mostly stable for at least 8 h. PMID: 27233448 [PubMed - as supplied by publisher]

Intermittent energy restriction induces changes in breast gene expression and systemic metabolism. Breast Cancer Res. 2016;18(1):57 Authors: Harvie MN, Sims AH, Pegington M, Spence K, Mitchell A, Vaughan AA, Allwood JW, Xu Y, Rattray NJ, Goodacre R, Evans DG, Mitchell E, McMullen D, Clarke RB, Howell A Abstract BACKGROUND: Observational studies suggest weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight to the same extent as, or more than equivalent continuous energy restriction (CER) but the effects of IER on normal breast tissue and systemic metabolism as indicators of breast cancer risk are unknown. METHODS: We assessed the effect of IER (two days of 65 % energy restriction per week) for one menstrual cycle on breast tissue gene expression using Affymetrix GeneChips, adipocyte size by morphometry, and systemic metabolism (insulin resistance, lipids, serum and urine metabolites, lymphocyte gene expression) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised and supervised analyses of matched pre and post IER biopsies in 20 subjects were performed, whilst liquid and gas chromatography mass spectrometry assessed corresponding changes in serum and urine metabolites in all subjects after the two restricted and five unrestricted days of the IER. RESULTS: Women lost 4.8 % (±2.0 %) of body weight and 8.0 % (±5.0 %) of total body fat. Insulin resistance (homeostatic model assessment (HOMA)) reduced by 29.8 % (±17.8 %) on the restricted days and by 11 % (±34 %) on the unrestricted days of the IER. Five hundred and twenty-seven metabolites significantly increased or decreased during the two restricted days of IER. Ninety-one percent of these returned to baseline after 5 days of normal eating. Eleven subjects (55 %) displayed reductions in energy restriction-associated metabolic gene pathways including lipid synthesis, gluconeogenesis and glycogen synthesis. Some of these women also had increases in genes associated with breast epithelial cell differentiation (secretoglobulins, milk proteins and mucins) and decreased collagen synthesis (TNMD, PCOLCE2, TIMP4). There was no appreciable effect of IER on breast gene expression in the other nine subjects. These groups did not differ in the degree of changes in weight, total body fat, fat cell size or serum or urine metabolomic markers. Corresponding gene changes were not seen in peripheral blood lymphocytes. CONCLUSION: The transcriptional response to IER is variable in breast tissue, which was not reflected in the systemic response, which occurred in all subjects. The mechanisms of breast responsiveness/non-responsiveness require further investigation. TRIAL REGISTRATION: ISRCTN77916487 31/07/2012. PMID: 27233359 [PubMed - as supplied by publisher]

Feasibility Study of NMR Based Serum Metabolomic Profiling to Animal Health Monitoring: A Case Study on Iron Storage Disease in Captive Sumatran Rhinoceros (Dicerorhinus sumatrensis). PLoS One. 2016;11(5):e0156318 Authors: Watanabe M, Roth TL, Bauer SJ, Lane A, Romick-Rosendale LE Abstract A variety of wildlife species maintained in captivity are susceptible to iron storage disease (ISD), or hemochromatosis, a disease resulting from the deposition of excess iron into insoluble iron clusters in soft tissue. Sumatran rhinoceros (Dicerorhinus sumatrensis) is one of the rhinoceros species that has evolutionarily adapted to a low-iron diet and is susceptible to iron overload. Hemosiderosis is reported at necropsy in many African black and Sumatran rhinoceroses but only a small number of animals reportedly die from hemochromatosis. The underlying cause and reasons for differences in susceptibility to hemochromatosis within the taxon remains unclear. Although serum ferritin concentrations have been useful in monitoring the progression of ISD in many species, there is some question regarding their value in diagnosing hemochromatosis in the Sumatran rhino. To investigate the metabolic changes during the development of hemochromatosis and possibly increase our understanding of its progression and individual susceptibility differences, the serum metabolome from a Sumatran rhinoceros was investigated by nuclear magnetic resonance (NMR)-based metabolomics. The study involved samples from female rhinoceros at the Cincinnati Zoo (n = 3), including two animals that died from liver failure caused by ISD, and the Sungai Dusun Rhinoceros Conservation Centre in Peninsular Malaysia (n = 4). Principal component analysis was performed to visually and statistically compare the metabolic profiles of the healthy animals. The results indicated that significant differences were present between the animals at the zoo and the animals in the conservation center. A comparison of the 43 serum metabolomes of three zoo rhinoceros showed two distinct groupings, healthy (n = 30) and unhealthy (n = 13). A total of eighteen altered metabolites were identified in healthy versus unhealthy samples. Results strongly suggest that NMR-based metabolomics is a valuable tool for animal health monitoring and may provide insight into the progression of this and other insidious diseases. PMID: 27232336 [PubMed - as supplied by publisher]

Applications of Fourier Transform Ion Cyclotron Resonance (FT-ICR) and Orbitrap Based High Resolution Mass Spectrometry in Metabolomics and Lipidomics. Int J Mol Sci. 2016;17(6) Authors: Ghaste M, Mistrik R, Shulaev V Abstract Metabolomics, along with other "omics" approaches, is rapidly becoming one of the major approaches aimed at understanding the organization and dynamics of metabolic networks. Mass spectrometry is often a technique of choice for metabolomics studies due to its high sensitivity, reproducibility and wide dynamic range. High resolution mass spectrometry (HRMS) is a widely practiced technique in analytical and bioanalytical sciences. It offers exceptionally high resolution and the highest degree of structural confirmation. Many metabolomics studies have been conducted using HRMS over the past decade. In this review, we will explore the latest developments in Fourier transform mass spectrometry (FTMS) and Orbitrap based metabolomics technology, its advantages and drawbacks for using in metabolomics and lipidomics studies, and development of novel approaches for processing HRMS data. PMID: 27231903 [PubMed - as supplied by publisher]

Metabolic Phenotypes of Carotid Atherosclerotic Plaques Relate to Stroke Risk: An Exploratory Study. Eur J Vasc Endovasc Surg. 2016 May 23; Authors: Vorkas PA, Shalhoub J, Lewis MR, Spagou K, Want EJ, Nicholson JK, Davies AH, Holmes E Abstract OBJECTIVE: Stroke is a major cause of death and disability. That three-quarters of stroke patients will never have previously manifested cerebrovascular symptoms demonstrates the unmet clinical need for new biomarkers able to stratify patient risk and elucidation of the biological dysregulations. In this study, the utility of comprehensive metabolic phenotyping is assessed to provide candidate biomarkers that relate to stroke risk in stenosing carotid plaque tissue samples. METHOD: Carotid plaque tissue samples were obtained from patients with cerebrovascular symptoms of carotid origin (n = 5), and from asymptomatic patients (n = 5). Two adjacent biological replicates were obtained from each tissue. Organic and aqueous metabolite extracts were obtained separately and analysed using two ultra performance liquid chromatography coupled to mass spectrometry metabolic profiling methods. Multivariate and univariate tools were used for statistical analysis. RESULTS: The two study groups demonstrated distinct plaque phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the two groups with a strong statistical significance (p = 10(-4)-10(-5)). Specifically, metabolites related to the eicosanoid pathway (arachidonic acid and arachidonic acid precursors), and three acylcarnitine species (butyrylcarnitine, hexanoylcarnitine, and palmitoylcarnitine), intermediates of the β-oxidation, were detected in higher intensities in symptomatic patients. However, metabolites implicated in the process of cell death, a process known to be upregulated in the formation of the vulnerable plaque, were unaffected. CONCLUSIONS: Discrimination between symptomatic and asymptomatic carotid plaque tissue is demonstrated for the first time using metabolic profiling technologies. Two biological pathways (eicosanoid and β-oxidation) were implicated in differentiating symptomatic from asymptomatic patients and will be further investigated. These results indicate that metabolic phenotyping should be further explored to investigate the chemistry of the unstable plaque, in the pursuit of candidate biomarkers for risk-stratification and targets for pharmacotherapeutic intervention. PMID: 27231199 [PubMed - as supplied by publisher]

Microfluidics meets metabolomics to reveal the impact of Campylobacter jejuni infection on biochemical pathways. Biomed Microdevices. 2016 Jun;18(3):51 Authors: Mortensen NP, Mercier KA, McRitchie S, Cavallo TB, Pathmasiri W, Stewart D, Sumner SJ Abstract Microfluidic devices that are currently being used in pharmaceutical research also have a significant potential for utilization in investigating exposure to infectious agents. We have established a microfluidic device cultured with Caco-2 cells, and utilized metabolomics to investigate the biochemical responses to the bacterial pathogen Campylobacter jejuni. In the microfluidic devices, Caco-2 cells polarize at day 5, are uniform, have defined brush borders and tight junctions, and form a mucus layer. Metabolomics analysis of cell culture media collected from both Caco-2 cell culture systems demonstrated a more metabolic homogenous biochemical profile in the media collected from microfluidic devices, compared with media collected from transwells. GeneGo pathway mapping indicated that aminoacyl-tRNA biosynthesis was perturbed by fluid flow, suggesting that fluid dynamics and shear stress impacts the cells translational quality control. Both microfluidic device and transwell culturing systems were used to investigate the impact of Campylobacter jejuni infection on biochemical processes. Caco-2 cells cultured in either system were infected at day 5 with C. jejuni 81-176 for 48 h. Metabolomics analysis clearly differentiated C. jejuni 81-176 infected and non-infected medias collected from the microfluidic devices, and demonstrated that C. jejuni 81-176 infection in microfluidic devices impacts branched-chain amino acid metabolism, glycolysis, and gluconeogenesis. In contrast, no distinction was seen in the biochemical profiles of infected versus non-infected media collected from cells cultured in transwells. Microfluidic culturing conditions demonstrated a more metabolically homogenous cell population, and present the opportunity for studying host-pathogen interactions for extended periods of time. PMID: 27231016 [PubMed - in process]

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016;6:26933 Authors: Trammell SA, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, Obrosov A, Kardon RH, Yorek MA, Brenner C Abstract Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID: 27230286 [PubMed - in process]

The use of mass spectrometry for analysing metabolite biomarkers in epidemiology: methodological and statistical considerations for application to large numbers of biological samples. Eur J Epidemiol. 2016 May 26; Authors: Lind MV, Savolainen OI, Ross AB Abstract Data quality is critical for epidemiology, and as scientific understanding expands, the range of data available for epidemiological studies and the types of tools used for measurement have also expanded. It is essential for the epidemiologist to have a grasp of the issues involved with different measurement tools. One tool that is increasingly being used for measuring biomarkers in epidemiological cohorts is mass spectrometry (MS), because of the high specificity and sensitivity of MS-based methods and the expanding range of biomarkers that can be measured. Further, the ability of MS to quantify many biomarkers simultaneously is advantageously compared to single biomarker methods. However, as with all methods used to measure biomarkers, there are a number of pitfalls to consider which may have an impact on results when used in epidemiology. In this review we discuss the use of MS for biomarker analyses, focusing on metabolites and their application and potential issues related to large-scale epidemiology studies, the use of MS "omics" approaches for biomarker discovery and how MS-based results can be used for increasing biological knowledge gained from epidemiological studies. Better understanding of the possibilities and possible problems related to MS-based measurements will help the epidemiologist in their discussions with analytical chemists and lead to the use of the most appropriate statistical tools for these data. PMID: 27230258 [PubMed - as supplied by publisher]

Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis. Clin Chest Med. 2016 Jun;37(2):321-31 Authors: Englert JA, Rogers AJ Abstract Sepsis is characterized by profound changes in systemic and cellular metabolism that disrupt normal metabolic homeostasis. These metabolic changes can serve as biomarkers for disease severity. Lactate, a metabolite of anaerobic metabolism, is the most widely used ICU biomarker and it is incorporated into multiple management algorithms. Technological advances now make broader metabolic profiling possible, with early studies identifying metabolic changes associated with sepsis mortality. Finally, given the marked changes in metabolism in sepsis and the association of worse prognosis in patients with severe metabolic derangements, we summarize the seminal trials conducted to optimize nutrition in the ICU. PMID: 27229648 [PubMed - in process]

Plasma metabolomic profile and potential biomarkers for missed abortion. Biomed Chromatogr. 2016 May 26; Authors: Fei H, Hou J, Wu Z, Zhang L, Zhao H, Dong X, Chen Y Abstract A missed abortion(MA)is an in utero death of the embryo or foetus before the 20th week of gestation with retained products of conception, and this condition is currently common in China. In order to discover novel biomarkers for MA, ultrahigh performance liquid chromatography (UHPLC-MS) was applied to study plasma metabolite profiles for 33 patients with MA and 29 control subjects. Thirty-seven differential plasma metabolites were found to discriminate between the two groups in the initial cohort (15 subjects with MA and 15 healthy controls). The feasibility of using these potential biomarkers to predict MA was further evaluated in the validation cohort (18 subjects with MA and 14 healthy controls) and 15 had an area under the receiver operating characteristic curve (AUC) of >0.80, making them satisfactory. Tryptophan metabolism and sphingolipid metabolism were identified as important potential target pathways for MA using metabolic pathway impact analysis. Furthermore, 3 of the 15 satisfactory metabolites (glyceric acid, indole and sphingosine) were combined to establish a predictive model with 100% sensitivity and 100% specificity in the validation cohort. Taken together, these results suggest that MA results in significant disturbance of metabolism and those various novel biomarkers have satisfactory diagnostic and predictive power for MA. PMID: 27229294 [PubMed - as supplied by publisher]

Related Articles Ancient Wheat Diet Delays Diabetes Development in a Type 2 Diabetes Animal Model. Rev Diabet Stud. 2014 Fall-Winter;11(3-4):245-57 Authors: Thorup AC, Gregersen S, Jeppesen PB Abstract AIM: The main objective was to investigate the physiological effects of ancient wheat whole grain flour diets on the development and progression of type 2 diabetes in Zucker diabetic fatty (ZDF) rats, and specifically to look at the acute glycemic responses. METHODS: An intervention study was conducted, involving 40 ZDF rats consuming one of 5 different diets (emmer, einkorn, spelt, rye and refined wheat) for 9 weeks. Refined wheat flour and whole grain rye flour were included as negative and positive controls, respectively. RESULTS: After 9 weeks of intervention, a downregulation of the hepatic genes PPAR-α, GLUT2, and SREBP-1c was observed in the emmer group compared to the control wheat group. Likewise, expression of hepatic SREBP-2 was lower for emmer, einkorn, and rye compared with the control group. Furthermore, spelt and rye induced a low acute glycemic response. The wheat group had higher HDL- and total cholesterol levels. CONCLUSIONS: Ancient wheat diets caused a downregulation of key regulatory genes involved in glucose and fat metabolism, equivalent to a prevention or delay of diabetes development. Spelt and rye induced a low acute glycemic response compared to wheat. PMID: 26177485 [PubMed - indexed for MEDLINE]

Related Articles Recent Advances and Understanding of Using Probiotic-Based Interventions to Restore Homeostasis of the Microbiome for the Prevention/Therapy of Bacterial Diseases. Microbiol Spectr. 2016 Apr;4(2) Authors: Suchodolski JS, Jergens AE Abstract The importance of the microbiome in health and disease has galvanized interest in using manipulations of the gastrointestinal ecosystem to prevent and/or combat gut bacterial infections and to restore mucosal homeostasis in patients with generalized microbial imbalances (i.e., dysbiosis), including the human inflammatory bowel diseases, Crohn's disease, and ulcerative colitis. Probiotics, prebiotics, or their combination use (i.e., synbiotics) are one mechanism for modifying the microbiota and exerting direct and indirect effects on the host immune responses and metabolomics profiles. These beneficial effects are transferred through various pathways, including the production of antimicrobial peptides, promoting the growth of beneficial microbes and enhancing immunomodulatory functions via various metabolites. While probiotic therapy has been used empirically for decades with mixed success, the recent advances in molecular and mass spectrophotometric techniques for the characterization of the complexity and diversity of the intestinal microbiome has aided in better understanding of host-microbe interactions. It is important to better understand the functional properties of the microbiome, because it is now clear that the microbiota secretes many metabolites that have a direct impact on host immune responses. This information will improve selection of the most appropriate probiotic strains that selectively target intestinal disease processes. PMID: 27227298 [PubMed - as supplied by publisher]

Related Articles Circadian regulation of lipid metabolism. Proc Nutr Soc. 2016 May 26;:1-11 Authors: Gooley JJ Abstract The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases. PMID: 27225642 [PubMed - as supplied by publisher]

Related Articles Editorial on "Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations" by Fabienne Jeanneret, David Tonoli, Michel F. Rossier, Martial Saugy, Julien Boccard and S. Rudaz. J Chromatogr A. 2016 Jan 22;1430:96 Authors: Fanali S PMID: 26627585 [PubMed - indexed for MEDLINE]

Phamacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer. Oncotarget. 2016 May 19; Authors: Miolo G, Muraro E, Caruso D, Crivellari D, Ash A, Scalone S, Lombardi D, Rizzolio F, Giordano A, Corona G Abstract Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. In the present study, we applied a pharmacometabolomics approach to identify biomarkers potentially associated with pathological complete response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer patients. Based on histological response the 34 patients enrolled in the study were subdivided into two groups: good responders (n = 15) and poor responders (n = 19). The pre-treatment serum targeted metabolomics profile of all patients were analyzed by liquid chromatography tandem mass spectrometry and the differences in the metabolomics profile between the two groups was investigated by multivariate partial least squares discrimination analysis. The most relevant metabolites that differentiate the two groups of patients were spermidine and tryptophan. The Good responders showed higher levels of spermidine and lower amounts of tryptophan compared with the poor responders (p < 0.001, q < 0.05). The serum level of these two metabolites identified patients who achieved a pathological complete response with a sensitivity of 90% [0.79-1.00] and a specificity of 0.87% [0.67-1.00]. These preliminary results support the role played by the individual patients' metabolism in determining the response to cancer treatments and may be a useful tool to select patients that are more likely to benefit from the trastuzumab-paclitaxel treatment. PMID: 27223427 [PubMed - as supplied by publisher]

Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients. JAMA Surg. 2016 May 25;:e160853 Authors: Parent BA, Seaton M, Sood RF, Gu H, Djukovic D, Raftery D, O'Keefe GE Abstract Importance: Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient. Objective: To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury. Design, Setting, and Participants: Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry. Main Outcomes and Measures: Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites. Results: Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) µM to 79.37 (50.29-106.37) µM (P = .002), leucine levels increased from 69.21 (48.36-99.89) µM to 114.16 (92.89-143.52) µM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) µM to 48.72 (36.28-64.84) µM (P < .001), and valine levels increased from 122.56 (95.63-140.61) µM to 190.52 (136.68-226.07) µM (P = .004). There was an incomplete reversal of oxidative stress. Conclusions and Relevance: Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients. PMID: 27223119 [PubMed - as supplied by publisher]

Future paradigms for precision oncology. Oncotarget. 2016 May 19; Authors: Klement GL, Arkun K, Valik D, Roffidal T, Hashemi A, Klement C, Carmassi P, Rietman E, Slaby O, Mazanek P, Mudry P, Kovacs G, Kiss C, Norga K, Konstantinov D, André N, Slavc I, Berg HV, Kolenova A, Kren L, Tuma J, Skotakova J, Sterba J Abstract Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used. PMID: 27223079 [PubMed - as supplied by publisher]

Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery. Diabetes Care. 2016 Jun;39(6):893-901 Authors: Batterham RL, Cummings DE Abstract More than 20 years ago, Pories et al. published a seminal article, "Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus." This was based on their observation that bariatric surgery rapidly normalized blood glucose levels in obese people with type 2 diabetes mellitus (T2DM), and 10 years later, almost 90% remained diabetes free. Pories et al. suggested that caloric restriction played a key role and that the relative contributions of proximal intestinal nutrient exclusion, rapid distal gut nutrient delivery, and the role of gut hormones required further investigation. These findings of T2DM improvement/remission after bariatric surgery have been widely replicated, together with the observation that bariatric surgery prevents or delays incident T2DM. Over the ensuing two decades, important glucoregulatory roles of the gastrointestinal (GI) tract have been firmly established. However, the physiological and molecular mechanisms underlying the beneficial glycemic effects of bariatric surgery remain incompletely understood. In addition to the mechanisms proposed by Pories et al., changes in bile acid metabolism, GI tract nutrient sensing and glucose utilization, incretins, possible anti-incretin(s), and the intestinal microbiome are implicated. These changes, acting through peripheral and/or central pathways, lead to reduced hepatic glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced β-cell function. A constellation of factors, rather than a single overarching mechanism, likely mediate postoperative glycemic improvement, with the contributing factors varying according to the surgical procedure. Thus, different bariatric/metabolic procedures provide us with experimental tools to probe GI tract physiology. Embracing this approach through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic regulation and help identify novel therapeutic targets. PMID: 27222547 [PubMed - in process]

Screening of Intestinal Bacterial Metabolites of Platycodin D Using Ultra-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry. Am J Chin Med. 2016 May 24;:1-17 Authors: Zhang W, Qian SH, Qian DW, Li SL Abstract Platycodin D (PD), a bioactive triterpenoid saponin isolated from Platycodi Radix (PR), possesses a vast range of biological activities. Although the pharmacological activities and pharmacokinetics of PD have been well demonstrated, information regarding the intestinal metabolisms of PD is very limited. In this study, human and rat fecal microflora were prepared and anaerobically incubated with PD at 37(∘)C for 48 h, respectively. A highly sensitive and specific ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was developed for the analysis of PD and related metabolites in the reaction samples. A liquid-liquid extraction method was used for sample pretreatment and the chromatographic separation was performed on a 1.7 μm particle size Syncronis C18 column using gradient elution system. Finally, a total of seven metabolites were detected and tentatively identified, such as the demethylation metabolite (M1), deoxidation metabolites (M3, M7) and hydrolysis at the C-28 oligosaccharide metabolites (M5, M6), which were first discovered in this experiment. The results indicate that hydrolysis, demethylation, dehydroxylation, and acetylation were the major metabolic pathways of PDin vitro. Additionally, four bacterial strains from human feces including Enterococcus sp.41, Bacillus sp.46, Escherichia sp.49A andEscherichia sp.64 were detected and further identified with 16S rRNA gene sequencing due to their relatively strong metabolic capacity toward PD. The present study provides important information about the metabolism of PD, which will help elucidate the impact of intestinal bacteria on this active component. PMID: 27222071 [PubMed - as supplied by publisher]