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Zalloua P, Kadar H, Hariri E, et al., 2019, Untargeted mass spectrometry lipidomics identifies correlation between serum sphingomyelins and plasma cholesterol, Lipids in Health and Disease, Vol: 18, ISSN: 1476-511X
BackgroundLipoproteins are major players in the development and progression of atherosclerotic plaques leading to coronary stenosis and myocardial infarction. Epidemiological, genetic and experimental observations have implicated the association of sphingolipids and intermediates of sphingolipid synthesis in atherosclerosis. We aimed to investigate relationships between quantitative changes in serum sphingolipids, the regulation of the metabolism of lipoproteins (LDL, HDL), and endophenotypes of coronary artery disease (CAD).MethodsWe carried out untargeted liquid chromatography – mass spectrometry (UPLC-MS) lipidomics of serum samples of subjects belonging to a cross-sectional study and recruited on the basis of absence or presence of angiographically-defined CAD, and extensively characterized for clinical and biochemical phenotypes.ResultsAmong the 2998 spectral features detected in the serum samples, 1328 metabolic features were significantly correlated with at least one of the clinical or biochemical phenotypes measured in the cohort. We found evidence of significant associations between 34 metabolite signals, corresponding to a set of sphingomyelins, and serum HDL cholesterol. Many of these metabolite associations were also observed with serum LDL and total cholesterol levels but not as much with serum triglycerides.ConclusionAmong patients with CAD, sphingolipids in the form of sphingomyelins are directly correlated with serum levels of lipoproteins and total cholesterol. Results from this study support the fundamental role of sphingolipids in modulating lipid serum levels, highlighting the importance to identify novel targets in the sphingolipid metabolic pathway for anti-atherogenic therapies.
Gray N, Plumb RS, Wilson ID, et al., 2019, A validated UPLC-MS/MS assay for the quantification of amino acids and biogenic amines in rat urine, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, Vol: 1106, Pages: 50-57, ISSN: 1570-0232
A UPLC-MS/MS assay, employing a reversed-phase separation, has been applied to the analysis of a number of common amino acids and biogenic amines in rat urine. Analytes were derivatised, using 6‑aminoquinolyl‑N‑hydroxysuccinimidyl carbamate (AccQTag Ultra™). Derivatisation with this reagent, by increasing the hydrophobicity of the analytes, enables better retention by improving reversed-phase chromatographic properties and also improves ionisation efficiency to enhance MS-detection. The method allows for the determination of 38 amino compounds in 7.5 min, including baseline resolution of critical isomers. The assay has been validated for the absolute quantification of 29 amino compounds in rat urine, over a concentration range of 0.6–200 μM, for the purpose of exploratory metabolite phenotyping. Acceptable linearity (R2 > 0.995) and intra- and inter-day accuracy (<20.7%) and precision (<20.1%) for these analytes was achieved. The limits of detection ranged from 1.2–12 fmol on column with 20 μL of sample. The remaining nine amines examined were not accurately quantified by this method but can be monitored for relative/fold change in biological samples. The use of the method is exemplified by the monitoring of changes in healthy male Sprague-Dawley rat urinary amino acid concentrations over a 7-day period.
Lindon JC, Nicholson JK, 2019, Nuclear magnetic resonance (NMR) spectroscopy, Clarke's Analysis of Drugs and Poisons, Editors: Moffatt, Osselton, Widdop, London, Publisher: Pharmaceutical Press
Inglese P, Correia G, Takats Z, et al., 2019, SPUTNIK: an R package for filtering of spatially related peaks in mass spectrometry imaging data, Bioinformatics, Vol: 35, Pages: 178-180, ISSN: 1367-4803
Summary: SPUTNIK is an R package consisting of a series of tools to filter mass spectrometry imaging peaks characterized by a noisy or unlikely spatial distribution. SPUTNIK can produce mass spectrometry imaging datasets characterized by a smaller but more informative set of peaks, reduce the complexity of subsequent multi-variate analysis and increase the interpretability of the statistical results. Availability: SPUTNIK is freely available online from CRAN repository and at https://github.com/paoloinglese/SPUTNIK. The package is distributed under the GNU General Public License version 3 and is accompanied by example files and data. Supplementary information: Supplementary data are available at Bioinformatics online.
Bonner FW, Maslen L, Lindon JC, et al., 2019, Conception, Implementation and Operation of Large-Scale Metabolic Phenotyping Centres: Phenome Centres, HANDBOOK OF METABOLIC PHENOTYPING, Editors: Lindon, Nicholson, Holmes, Publisher: ELSEVIER SCIENCE BV, Pages: 385-405, ISBN: 978-0-12-812293-8
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Lindon JC, Holmes E, Nicholson JK, 2019, Metabolic Phenotyping: History, Status, and Prospects, HANDBOOK OF METABOLIC PHENOTYPING, Editors: Lindon, Nicholson, Holmes, Publisher: ELSEVIER SCIENCE BV, Pages: 571-583, ISBN: 978-0-12-812293-8
Holmes E, Wilson ID, Lindon JC, 2019, An Overview of Metabolic Phenotyping and Its Role in Systems Biology, HANDBOOK OF METABOLIC PHENOTYPING, Editors: Lindon, Nicholson, Holmes, Publisher: ELSEVIER SCIENCE BV, Pages: 1-51, ISBN: 978-0-12-812293-8
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- Citations: 9
Lindon JC, Holmes E, Nicholson JK, 2019, The Handbook of Metabolic Phenotyping Preface, HANDBOOK OF METABOLIC PHENOTYPING, Editors: Lindon, Nicholson, Holmes, Publisher: ELSEVIER SCIENCE BV, Pages: XXI-XXII, ISBN: 978-0-12-812293-8
Adesina-Georgiadis KN, Gray N, Plumb RS, et al., 2018, The metabolic fate and effects of 2-bromophenol in male Sprague-Dawley rats, Xenobiotica, ISSN: 0049-8254
1. The metabolic fate and urinary excretion of 2-bromophenol, a phenolic metabolite of bromobenzene, was investigated in male Sprague Dawley rats following single intraperitoneal doses at either 0, 100 or 200 mg/kg. 2. Urine was collected for seven days and samples analysed using 1H NMR spectroscopy, inductively coupled plasma (ICP)MS, and UPLC-MS. 3. 1H NMR spectroscopy of the urine samples showed that, at these doses, 2-bromophenol had little effect on endogenous metabolite profiles, supporting histopathology and clinical chemistry data which showed no changes associated with the administration of 2-bromophenol at these doses. 4. The use of ICP-MS Provided a means for the selective detection and quantification of bromine-containing species and showed that between 15 and 30% of the dose was excreted via the urine over the 7 days of the study for both the 100 and 200 mg doses respectively. 6. The bulk of the excretion of Br-containing material had occurred by 8 hr post administration. UPLC-MS of urine revealed a number of metabolites of 2-bromophenol, with 2-bromophenol glucuronide and 2-bromophenol sulphate identified as the major species. A number of minor hydroxylated metabolites were also detected as their glucuronide, sulphate or O-methyl conjugates. There was no evidence for the production of reactive metabolites.
Izzi-Engbeaya CN, Comninos AN, Clarke S, et al., 2018, The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans, Diabetes, Obesity and Metabolism, Vol: 20, Pages: 2800-2810, ISSN: 1462-8902
AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.
Jimenez B, Holmes E, Heude C, et al., 2018, Quantitative lipoprotein subclass and low molecular weight metabolite analysis in human serum and plasma by 1H NMR spectroscopy in a multilaboratory trial, Analytical Chemistry, Vol: 90, Pages: 11962-11971, ISSN: 0003-2700
We report an extensive 600 MHz NMR trial of a quantitative lipoprotein and small molecule measurements in human blood serum and plasma. Five centers with eleven 600 MHz NMR spectrometers were used to analyze 98 samples including: 20 QCs, 37 commercially sourced, paired serum and plasma samples and 2 National Institute of Science and Technology, NIST, reference material 1951c replicates. Samples were analyzed using rigorous protocols for sample preparation and experimental acquisition. A commercial lipoprotein subclass analysis was used to quantify 105 lipoprotein subclasses and 24 low molecular weight metabolites from the nuclear magnetic resonance, NMR, spectra. For all spectrometers, the instrument specific variance in measuring internal quality controls, QCs, was lower than the percentage described by the National Cholesterol Education Program, NCEP, criteria for lipid testing (triglycerides<2.7%, cholesterol<2.8%; LDL-cholesterol<2.8%; HDL-cholesterol<2.3%), showing exceptional reproducibility for direct quantitation of lipoproteins in both matrices. The average RSD for the 105 lipoprotein parameters in the 11 instruments was 4.6% and 3.9% for the two NIST samples while it was 38% and 40% for the 37 commercially sourced plasmas and sera, respectively, showing negligible analytical compared to biological variation. The coefficient of variance, CV, obtained for the quantification of the small molecules across the 11 spectrometers was below 15% for 20 out of the 24 metabolites analyzed. This study provides further evidence of the suitability of NMR for high-throughput lipoprotein subcomponent analysis and small molecule quantitation with the exceptional reproducibility required for clinical and other regulatory settings.
Chekmeneva E, Dos Santos Correia G, Gomez Romero M, et al., 2018, Ultra performance liquid chromatography-high resolution mass spectrometry and direct infusion-high resolution mass spectrometry for combined exploratory and targeted metabolic profiling of human urine, Journal of Proteome Research, Vol: 17, Pages: 3492-3502, ISSN: 1535-3893
The application of metabolic phenotyping to epidemiological studies involving thousands of biofluid samples presents a challenge for the selection of analytical platforms that meet the requirements of high-throughput precision analysis and cost-effectiveness. Here, direct infusion nanoelectrospray (DI-nESI)- was compared to an ultra-performance (UPLC)-high resolution mass spectrometry (HRMS) method for metabolic profiling of an exemplary set of 132 human urine samples from a large epidemiological cohort. Both methods were developed and optimised to allow simultaneous collection of high resolution urinary metabolic profiles and quantitative data for a selected panel of 35 metabolites. The total run time for measuring the sample set in both polarities by UPLC-HRMS was of 5 days compared to 9 hours by DI-nESI-HRMS. To compare the classification ability of the two MS methods we performed exploratory analysis of the full-scan HRMS profiles to detect sex-related differences in biochemical composition. Although metabolite identification is less specific in DI-nESI-HRMS, the significant features responsible for discrimination between sexes were mostly the same in both MS-based platforms. Using the quantitative data we showed that 10 metabolites have strong correlation (Pearson’s r > 0.9 and Passing-Bablok regression slope 0.8-1.3) and good agreement assessed by Bland-Altman plots between UPLC-HRMS and DI-nESI-HRMS and thus, can be measured using a cheaper and less sample- and time-consuming method. Only five metabolites showed weak correlation (Pearson’s r< 0.4) and poor agreement due to the overestimation of the results by DI-nESI-HRMS, and the rest of metabolites showed acceptable correlation between the two methods.
Dumas M-E, Chilloux J, Myridakis A, et al., 2018, Microbiome inhibition of IRAK-4 by trimethylamine mediates metabolic and immune benefits in high fat diet-induced insulin resistance, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S267-S268, ISSN: 0012-186X
Hoyles L, Fernandez-Real J-M, Federici M, et al., 2018, Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1628-1628, ISSN: 1078-8956
In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.
Abellona MRU, Mark P, Ladep N, et al., 2018, Elucidating Serum and Urinary Hepatocellular Carcinoma Diagnostic Biomarker Panels: Insight from the United Kingdom and West Africa, Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 37A-38A, ISSN: 0270-9139
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Domingo-Almenara X, Montenegro-Burke JR, Ivanisevic J, et al., 2018, CMS-MRM and METLIN-MRM: a cloud library and public resource for targeted analysis of small molecules, Nature Methods, Vol: 15, Pages: 681-684, ISSN: 1548-7091
We report XCMS-MRM and METLIN-MRM (http://xcmsonline-mrm.scripps.edu/ and http://metlin.scripps.edu/), a cloud-based data-analysis platform and a public multiple-reaction monitoring (MRM) transition repository for small-molecule quantitative tandem mass spectrometry. This platform provides MRM transitions for more than 15,500 molecules and facilitates data sharing across different instruments and laboratories.
Hoyles L, Fernández-Real JM, Federici M, et al., 2018, Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1-17, ISSN: 1078-8956
Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.
Seow WJ, Shu X-O, Nicholson J, et al., 2018, Prospective study of untargeted urinary metabolomics and risk of lung cancer among female never-smokers in Shanghai, China, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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McDonald JAK, Kimhofer T, West K, et al., 2018, Role of the gut microbiota in autism spectrum disorder, ISME17, Publisher: Nature Publishing Group
McDonald JAK, Mullish BH, Pechlivanis A, et al., 2018, 24 - A novel route to controlling Clostridioides Difficile growth via short chain fatty acid and bile acid modulation, Digestive Diseases Week, Publisher: Elsevier, Pages: S8-S8, ISSN: 0016-5085
Kinross JM, Li JV, Ocvirk S, et al., 2018, METABOLIC PHENOTYPING OF AFRICAN AND ALASKAN INDIGENOUS POPULATIONS DEMONSTRATES THAT URBANIZATION MODIFIES GUT MICROBIOME METABOLIC FUNCTIONS ASSOCIATED WITH COLON CANCER RISK, Annual Meeting of the American-Society-for-Gastrointestinal-Endoscopy / Digestive Disease Week, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S422-S422, ISSN: 0016-5085
Hoyles L, Jiménez-Pranteda MJ, Chilloux J, et al., 2018, Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota, Microbiome, Vol: 6, ISSN: 2049-2618
Background:The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). However, little is known about the use of trimethylamine N-oxide (TMAO) by this consortium of microbes.Results:A feeding study using deuterated TMAO in C57BL6/J mice demonstrated microbial conversion of TMAO to TMA, with uptake of TMA into the bloodstream and its conversion to TMAO. Microbial activity necessary to convert TMAO to TMA was suppressed in antibiotic-treated mice, with deuterated TMAO being taken up directly into the bloodstream. In batch-culture fermentation systems inoculated with human faeces, growth of Enterobacteriaceae was stimulated in the presence of TMAO. Human-derived faecal and caecal bacteria (n = 66 isolates) were screened on solid and liquid media for their ability to use TMAO, with metabolites in spent media analysed by 1H-NMR. As with the in vitro fermentation experiments, TMAO stimulated the growth of Enterobacteriaceae; these bacteria produced most TMA from TMAO. Caecal/small intestinal isolates of Escherichia coli produced more TMA from TMAO than their faecal counterparts. Lactic acid bacteria produced increased amounts of lactate when grown in the presence of TMAO but did not produce large amounts of TMA. Clostridia (sensu stricto), bifidobacteria, and coriobacteria were significantly correlated with TMA production in the mixed fermentation system but did not produce notable quantities of TMA from TMAO in pure culture.Conclusions:Reduction of TMAO by the gut microbiota (predominantly Enterobacteriaceae) to TMA followed by host uptake of TMA into the bloodstream from the intestine and its conversion back to TMAO by host hepatic enzymes is an example of metabolic retroconversion. TMAO influences microbial metabolism depending on isolation source and taxon of gut bacterium. Correlation of metabolomic and abundance data from mixed microbiota fermenta
Abellona U, Mark DP, Oleribe O, et al., 2018, Towards elucidating a universal panel of diagnostic biomarkers for early hepatocellular carcinoma, International Liver Congress (ILC), Publisher: ELSEVIER SCIENCE BV, Pages: S433-S433, ISSN: 0168-8278
Hoyles L, Snelling T, Umlai UK, et al., 2018, Microbiome–host systems interactions: protective effects of propionate upon the blood–brain barrier, Microbiome, Vol: 6, ISSN: 2049-2618
Background: Gut microbiota composition and function are symbiotically linked with host health, and altered in metabolic, inflammatory and neurodegenerative disorders. Three recognized mechanisms exist by which the microbiome influences the gut--brain axis: modification of autonomic/sensorimotor connections, immune activation, and neuroendocrine pathway regulation. We hypothesized interactions between circulating gut-derived microbial metabolites and the blood--brain barrier (BBB) also contribute to the gut--brain axis. Propionate, produced from dietary substrates by colonic bacteria, stimulates intestinal gluconeogenesis and is associated with reduced stress behaviours, but its potential endocrine role has not been addressed. Results: After demonstrating expression of the propionate receptor FFAR3 on human brain endothelium, we examined the impact of a physiologically relevant propionate concentration (1 μM) on BBB properties in vitro. Propionate inhibited pathways associated with non-specific microbial infections via a CD14-dependent mechanism, suppressed expression of LRP-1 and protected the BBB from oxidative stress via NRF2 (NFE2L2) signaling. Conclusions: Together, these results suggest gut-derived microbial metabolites interact with the BBB, representing a fourth facet of the gut--brain axis that warrants further attention.
Hoyles L, Snelling T, Umlai U-K, et al., 2018, Propionate has protective and anti-inflammatory effects on the blood–brain barrier, Alzheimer's Research UK Research Conference 2018
Propionate is a short-chain fatty acid (SCFA) produced by the human gut microbiota from dietary substrates, and is biologically active via the G protein coupled receptors FFAR2 and FFAR3. It is taken up from the gut and reaches systemic circulation in micromolar quantities. The blood–brain barrier (BBB) is the major interface between the circulation and central nervous system. FFAR3 is expressed on the vascular endothelium and a likely target for propionate in the BBB. We hypothesized exposure of the BBB to propionate influences barrier integrity and function.Methods and materialsWe investigated the in vitro effects of a physiologically relevant concentration (1 μM) of propionate upon the human immortalised cerebromicrovascular endothelial cell line hCMEC/D3. FFAR3 was present on these cells. We, therefore, performed an unbiased transcriptomic analysis of confluent hCMEC/D3 monolayers treated or not for 24 h with 1 μM propionate, supported by in vitro validation of key findings and assessment of functional endothelial permeability barrier properties.ResultsPropionate treatment had a significant (PFDR < 0.1) effect on the expression of 1136 genes. It inhibited several inflammation-associated pathways: TLR-specific signalling, NFkappaB signalling, and cytosolic DNA-sensing. Functional validation of these findings confirmed the down-regulation of TLR signalling by propionate, achieved primarily through down-regulation of endothelial CD14 expression. Accordingly, propionate prevented LPS-induced increases in paracellular permeability to 70 kDa FITC-dextran and loss of transendothelial electrical resistance. Propionate activated the NFE2L2 (NRF2)-driven protective response against oxidative stress. Confirming these data, propionate limited free reactive oxygen species induction by the mitochondrial respiratory inhibitor rotenone. ConclusionsOur data strongly suggest the SCFA propionate contributes to maintaining BBB integrity and protecting against inflamm
McArthur S, Carvalho A, Fonseca S, et al., 2018, Effects of gut-derived trimethylamines on the blood–brain barrier, Alzheimer's Research UK Research Conference 2018
Introduction: The gut microbiota and its metabolites exert significant effects on host health, with disturbances to composition and function associated with conditions including obesity, type II diabetes and, more recently, Alzheimer’s disease (AD). Communication between microbes and the host can take a number of forms, but central to all of them is a role for gut-derived microbial metabolites, with trimethylamine N-oxide (TMAO) and its precursor trimethylamine (TMA) being important examples. TMA produced by gut bacteria is converted to TMAO in the liver by flavin monooxygenases whereupon it enters the circulation. TMAO was recently identified as potentially important in genetic pathways associated with AD, and has been shown to influence peripheral vascular function. Given these links, the key position of the cerebral vasculature as the major interface between circulating molecules and the brain, and evidence that deficits in blood–brain barrier (BBB) function occur early in AD, we investigated the effects of TMAO and TMA on key BBB properties in vitro and in vivo.Materials and Methods: Male C57Bl/6 mice (n=4-5) were used to examine the effect of TMAO treatment (1.8 mg/kg, 2 h, dose equivalent to circulating human concentrations) upon BBB permeability in vivo, assessed by Evans’ blue dye extravasation. TMA was not investigated as the average mouse plasma concentration of this methylamine is substantially greater than that seen in humans (TMAO-to-TMA ratio 1:10 in mice, 10:1 in humans).Human hCMEC/D3 cerebromicrovascular cells were used as an in vitro model of the BBB to investigate the effects of 24 h treatment with human physiologically relevant doses of TMAO (40 μM) and TMA (0.4 μM), studying (i) functional barrier properties of cell monolayers and (ii) gene expression. Results: Administration of TMAO to mice enhanced BBB integrity above baseline after 2 h treatment (p<0.05). Similarly, in vitro exposure of hCMEC/D3 cells to TMAO enhanc
Hoyles L, Snelling T, Umlai U-K, et al., 2018, Microbiome–host interactions: protective effects of propionate upon the blood–brain barrier, Publisher: biorixiv
Breakdown of foodstuffs by the gut microbiota results in the production of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate. SFCAs are potent bioactive molecules, providing energy for intestinal cells, enhancing satiety and positively influencing metabolic health. They also influence the gut–brain axis. The gut microbiota and/or its bioactive molecules contribute to maintaining the integrity of the blood–brain barrier (BBB), the primary defensive structure of the brain. Propionate is produced by the gut microbiota from the breakdown of glucans found in whole grains, mushrooms and yeast products. It is found in the blood at ≤1 μM. At this physiologically relevant concentration, propionate enhances BBB integrity, mitigating against deleterious inflammatory and oxidative stimuli known to contribute to neurological and psychological diseases. Therefore, there is the potential that dietary supplementation with glucan-containing products may offer protection of the brain against detrimental stimuli.
Veselkov KA, Sleeman J, Claude E, et al., 2018, BASIS: High-performance bioinformatics platform for processing of large-scale mass spectrometry imaging data in chemically augmented histology, Scientific Reports, Vol: 8, ISSN: 2045-2322
Mass Spectrometry Imaging (MSI) holds significant promise in augmenting digital histopathologic analysis by generating highly robust big data about the metabolic, lipidomic and proteomic molecular content of the samples. In the process, a vast quantity of unrefined data, that can amount to several hundred gigabytes per tissue section, is produced. Managing, analysing and interpreting this data is a significant challenge and represents a major barrier to the translational application of MSI. Existing data analysis solutions for MSI rely on a set of heterogeneous bioinformatics packages that are not scalable for the reproducible processing of large-scale (hundreds to thousands) biological sample sets. Here, we present a computational platform (pyBASIS) capable of optimized and scalable processing of MSI data for improved information recovery and comparative analysis across tissue specimens using machine learning and related pattern recognition approaches. The proposed solution also provides a means of seamlessly integrating experimental laboratory data with downstream bioinformatics interpretation/analyses, resulting in a truly integrated system for translational MSI.
Athersuch TJ, Antoine DJ, Boobis AR, et al., 2018, Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective, Toxicology Research, Vol: 7, Pages: 347-357, ISSN: 2045-452X
After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (AM404) still a topic of debate. However, that the hepatotoxicity of APAP results from the production of the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI/NABQI) that can deplete glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of NAPQI provides a source of potential biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the microRNA miR-122 as well as mechanistic biomarkers associated with apoptosis, mitochondrial dysfunction, inflammation and tissue regeneration. Additionally, biomarkers of, and systems biology models for, glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to APAP-mediated toxicity. This perspective highlights some of the progress in current APAP-related research.
Loo RL, Zou X, Appel LJ, et al., 2018, Characterization of metabolic responses to healthy diets and association with blood pressure: application to the Optimal Macronutrient Intake Trial for Heart Health (OmniHeart), a randomized controlled study, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 107, Pages: 323-334, ISSN: 0002-9165
BackgroundInterindividual variation in the response to diet is common, but the underlying mechanism for such variation is unclear.ObjectiveThe objective of this study was to use a metabolic profiling approach to identify a panel of urinary metabolites representing individuals demonstrating typical (homogeneous) metabolic responses to healthy diets, and subsequently to define the association of these metabolites with improvement of risk factors for cardiovascular diseases (CVDs).Design24-h urine samples from 158 participants with pre-hypertension and stage 1 hypertension, collected at baseline and following the consumption of a carbohydrate-rich, a protein-rich, and a monounsaturated fat–rich healthy diet (6 wk/diet) in a randomized, crossover study, were analyzed by proton (1H) nuclear magnetic resonance (NMR) spectroscopy. Urinary metabolite profiles were interrogated to identify typical and variable responses to each diet. We quantified the differences in absolute excretion of metabolites, distinguishing between dietary comparisons within the typical response groups, and established their associations with CVD risk factors using linear regression.ResultsGlobally all 3 diets induced a similar pattern of change in the urinary metabolic profiles for the majority of participants (60.1%). Diet-dependent metabolic variation was not significantly associated with total cholesterol or low-density lipoprotein (LDL) cholesterol concentration. However, blood pressure (BP) was found to be significantly associated with 6 urinary metabolites reflecting dietary intake [proline-betaine (inverse), carnitine (direct)], gut microbial co-metabolites [hippurate (direct), 4-cresyl sulfate (inverse), phenylacetylglutamine (inverse)], and tryptophan metabolism [N-methyl-2-pyridone-5-carboxamide (inverse)]. A dampened clinical response was observed in some individuals with variable metabolic responses, which could be attributed to nonadherence to diet (≤25.3%), variation in gut mi
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