PubMed

Recon 2.2: from reconstruction to model of human metabolism. Metabolomics. 2016;12:109 Authors: Swainston N, Smallbone K, Hefzi H, Dobson PD, Brewer J, Hanscho M, Zielinski DC, Ang KS, Gardiner NJ, Gutierrez JM, Kyriakopoulos S, Lakshmanan M, Li S, Liu JK, Martínez VS, Orellana CA, Quek LE, Thomas A, Zanghellini J, Borth N, Lee DY, Nielsen LK, Kell DB, Lewis NE, Mendes P Abstract INTRODUCTION: The human genome-scale metabolic reconstruction details all known metabolic reactions occurring in humans, and thereby holds substantial promise for studying complex diseases and phenotypes. Capturing the whole human metabolic reconstruction is an on-going task and since the last community effort generated a consensus reconstruction, several updates have been developed. OBJECTIVES: We report a new consensus version, Recon 2.2, which integrates various alternative versions with significant additional updates. In addition to re-establishing a consensus reconstruction, further key objectives included providing more comprehensive annotation of metabolites and genes, ensuring full mass and charge balance in all reactions, and developing a model that correctly predicts ATP production on a range of carbon sources. METHODS: Recon 2.2 has been developed through a combination of manual curation and automated error checking. Specific and significant manual updates include a respecification of fatty acid metabolism, oxidative phosphorylation and a coupling of the electron transport chain to ATP synthase activity. All metabolites have definitive chemical formulae and charges specified, and these are used to ensure full mass and charge reaction balancing through an automated linear programming approach. Additionally, improved integration with transcriptomics and proteomics data has been facilitated with the updated curation of relationships between genes, proteins and reactions. RESULTS: Recon 2.2 now represents the most predictive model of human metabolism to date as demonstrated here. Extensive manual curation has increased the reconstruction size to 5324 metabolites, 7785 reactions and 1675 associated genes, which now are mapped to a single standard. The focus upon mass and charge balancing of all reactions, along with better representation of energy generation, has produced a flux model that correctly predicts ATP yield on different carbon sources. CONCLUSION: Through these updates we have achieved the most complete and best annotated consensus human metabolic reconstruction available, thereby increasing the ability of this resource to provide novel insights into normal and disease states in human. The model is freely available from the Biomodels database (http://identifiers.org/biomodels.db/MODEL1603150001). PMID: 27358602 [PubMed - as supplied by publisher]

Cold acclimation wholly reorganizes the Drosophila melanogaster transcriptome and metabolome. Sci Rep. 2016;6:28999 Authors: MacMillan HA, Knee JM, Dennis AB, Udaka H, Marshall KE, Merritt TJ, Sinclair BJ Abstract Cold tolerance is a key determinant of insect distribution and abundance, and thermal acclimation can strongly influence organismal stress tolerance phenotypes, particularly in small ectotherms like Drosophila. However, there is limited understanding of the molecular and biochemical mechanisms that confer such impressive plasticity. Here, we use high-throughput mRNA sequencing (RNA-seq) and liquid chromatography - mass spectrometry (LC-MS) to compare the transcriptomes and metabolomes of D. melanogaster acclimated as adults to warm (rearing) (21.5 °C) or cold conditions (6 °C). Cold acclimation improved cold tolerance and led to extensive biological reorganization: almost one third of the transcriptome and nearly half of the metabolome were differentially regulated. There was overlap in the metabolic pathways identified via transcriptomics and metabolomics, with proline and glutathione metabolism being the most strongly-supported metabolic pathways associated with increased cold tolerance. We discuss several new targets in the study of insect cold tolerance (e.g. dopamine signaling and Na(+)-driven transport), but many previously identified candidate genes and pathways (e.g. heat shock proteins, Ca(2+) signaling, and ROS detoxification) were also identified in the present study, and our results are thus consistent with and extend the current understanding of the mechanisms of insect chilling tolerance. PMID: 27357258 [PubMed - in process]

Why stay in a bad relationship? The effect of local host phenology on a generalist butterfly feeding on a low-ranked host. BMC Evol Biol. 2016;16(1):144 Authors: Audusseau H, de la Paz Celorio-Mancera M, Janz N, Nylin S Abstract BACKGROUND: In plant-feeding insects, the evolutionary retention of polyphagy remains puzzling. A better understanding of the relationship between these organisms and changes in the metabolome of their host plants is likely to suggest functional links between them, and may provide insights into how polyphagy is maintained. RESULTS: We investigated the phenological change of Cynoglossum officinale, and how a generalist butterfly species, Vanessa cardui, responded to this change. We used untargeted metabolite profiling to map plant seasonal changes in both primary and secondary metabolites. We compared these data to differences in larval performance on vegetative plants early and late in the season. We also performed two oviposition preference experiments to test females' ability to choose between plant developmental stages (vegetative and reproductive) early and late in the season. We found clear seasonal changes in plant primary and secondary metabolites that correlated with larval performance. The seasonal change in plant metabolome reflected changes in both nutrition and toxicity and resulted in zero survival in the late period. However, large differences among families in larval ability to feed on C. officinale suggest that there is genetic variation for performance on this host. Moreover, females accepted all plants for oviposition, and were not able to discriminate between plant developmental stages, in spite of the observed overall differences in metabolite profile potentially associated with differences in suitability as larval food. CONCLUSIONS: In V. cardui, migratory behavior, and thus larval feeding times, are not synchronized with plant phenology at the reproductive site. This lack of synchronization, coupled with the observed lack of discriminatory oviposition, obviously has potential fitness costs. However, this "opportunistic" behavior may as well function as a source of potential host plant evolution, promoting for example the acceptance of new plants. PMID: 27356867 [PubMed - in process]

Availability and dose response of phytophenols from a wheat bran-rich cereal product in healthy human volunteers. Mol Nutr Food Res. 2016 Jun 30; Authors: Neacsu M, McMonagle J, Fletcher R, Hulshof T, Duncan SH, Scobbie L, Duncan GJ, Cantlay L, Horgan G, de Roos B, Duthie GG, Russell WR Abstract SCOPE: Phytophenols present in cereals are metabolised to compounds that could be partly responsible for the reduced risk of chronic diseases and all-cause mortality associated with fibre-rich diets. The bioavailability, form and in vivo concentrations of these metabolites requires to be established. MATERIALS/METHODS: Eight healthy volunteers consumed a test meal containing a recommended dose (40 g) and high dose (120 g) of ready-to-eat wheat bran cereal and the systemic and colonic metabolites determined quantitatively by LC-MS. CONCLUSION: Analysis of the systemic metabolomes demonstrated that a wide range of phytophenols were absorbed/excreted (43 metabolites) within five hours of consumption. These included 16 of the 21 major parent compounds identified in the intervention product and several of these were also found to be significantly increased in the colon. Not all of the metabolites were increased with the higher dose, suggesting some limitation in absorption due to intrinsic factors and/or the food matrix. Many compounds identified (e.g. ferulic acid and major metabolites) exhibit anti-inflammatory activity and impact on redox pathways. The combination of postprandial absorption and delivery to the colon, as well as hepatic recycling of the metabolites at these concentrations is likely to be beneficial to both systemic and gut health. This article is protected by copyright. All rights reserved. PMID: 27356494 [PubMed - as supplied by publisher]

Related Articles Antimicrobial potential of Halophilic actinomycetes against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens. Pak J Pharm Sci. 2016 Mar;29(2):367-74 Authors: Aslam S, Sajid I Abstract A collection of forty halophilic actinomycetes isolated from water and mud samples of the saline lake at Kalar Kahar, salt range, Pakistan, was screened to investigate their antimicrobial potential against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens. The isolates exhibited significant tolerance to alkaline conditions and grew well at pH 9-11. The taxonomic status of the isolated strains was determined by morphological, biochemical and physiological characterization and by 16s rRNA gene sequencing. The results revealed that majority of the isolates (90%) belong to the genus Streptomyces. Most of the isolates exhibited remarkable antimicrobial activity up to 20mm zone of inhibition against MDR ventilator associated pneumonia causing bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Escherichia coli, Enterobacter and Acinetobacter spp. Additionally the isolates showed moderate to high cytotoxicity in the range of 40 to 80% larval mortality against Artemia salina in a micro well cytotoxicity assay. The chemical screening or the so called metabolic fingerprinting of the methanolic extracts of each isolate, by thin layer chromatography (TLC) using various staining reagents and by high performance liquid chromatography (HPLC-UV), indicated an impressive diversity of the compounds produced by these strains. The study reveals that these halophilic actinomycetes are a promising source of bioactive compounds. The preparative scale fermentation, isolation, purification and structure elucidation of the compounds produced by them may yield novel antimicrobial or chemotherapeutic agents. PMID: 27087086 [PubMed - indexed for MEDLINE]

Related Articles Caspases Connect Cell-Death Signaling to Organismal Homeostasis. Immunity. 2016 Feb 16;44(2):221-31 Authors: Galluzzi L, López-Soto A, Kumar S, Kroemer G Abstract Some forms of regulated cell death, such as apoptosis, are precipitated by the activation of cysteine proteases of the caspase family, including caspase 8, 9, and 3. Other caspases, such as caspase 1 and 4, are well known for their pro-inflammatory functions but regulate cell death in a limited number of pathophysiological settings. Accumulating evidence suggests that the most conserved function of mammalian caspases is not to control cell death sensu stricto, but to regulate inflammatory and immune reactions to dying cells and infectious challenges. Here, we review the molecular and cellular mechanisms though which mammalian caspases connect cell-death signaling to the maintenance of organismal homeostasis. PMID: 26885855 [PubMed - indexed for MEDLINE]

Related Articles IFNs Modify the Proteome of Legionella-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid. PLoS Pathog. 2016 Feb;12(2):e1005408 Authors: Naujoks J, Tabeling C, Dill BD, Hoffmann C, Brown AS, Kunze M, Kempa S, Peter A, Mollenkopf HJ, Dorhoi A, Kershaw O, Gruber AD, Sander LE, Witzenrath M, Herold S, Nerlich A, Hocke AC, van Driel I, Suttorp N, Bedoui S, Hilbi H, Trost M, Opitz B Abstract Macrophages can be niches for bacterial pathogens or antibacterial effector cells depending on the pathogen and signals from the immune system. Here we show that type I and II IFNs are master regulators of gene expression during Legionella pneumophila infection, and activators of an alveolar macrophage-intrinsic immune response that restricts bacterial growth during pneumonia. Quantitative mass spectrometry revealed that both IFNs substantially modify Legionella-containing vacuoles, and comparative analyses reveal distinct subsets of transcriptionally and spatially IFN-regulated proteins. Immune-responsive gene (IRG)1 is induced by IFNs in mitochondria that closely associate with Legionella-containing vacuoles, and mediates production of itaconic acid. This metabolite is bactericidal against intravacuolar L. pneumophila as well as extracellular multidrug-resistant Gram-positive and -negative bacteria. Our study explores the overall role IFNs play in inducing substantial remodeling of bacterial vacuoles and in stimulating production of IRG1-derived itaconic acid which targets intravacuolar pathogens. IRG1 or its product itaconic acid might be therapeutically targetable to fight intracellular and drug-resistant bacteria. PMID: 26829557 [PubMed - indexed for MEDLINE]

Related Articles LC-MS- and (1)H NMR-Based Metabolomic Analysis and in Vitro Toxicological Assessment of 43 Aristolochia Species. J Nat Prod. 2016 Jan 22;79(1):30-7 Authors: Michl J, Kite GC, Wanke S, Zierau O, Vollmer G, Neinhuis C, Simmonds MS, Heinrich M Abstract Species of Aristolochia are used as herbal medicines worldwide. They cause aristolochic acid nephropathy (AAN), a devastating disease associated with kidney failure and renal cancer. Aristolochic acids I and II (1 and 2) are considered to be responsible for these nephrotoxic and carcinogenic effects. A wide range of other aristolochic acid analogues (AAAs) exist, and their implication in AAN may have been overlooked. An LC-MS- and (1)H NMR-based metabolomic analysis was carried out on 43 medicinally used Aristolochia species. The cytotoxicity and genotoxicity of 28 Aristolochia extracts were measured in human kidney (HK-2) cells. Compounds 1 and 2 were found to be the most common AAAs. However, AA IV (3), aristolactam I (4), and aristolactam BI (5) were also widespread. No correlation was found between the amounts of 1 or 2 and extract cytotoxicity against HK-2 cells. The genotoxicity and cytotoxicity of the extracts could be linked to their contents of 5, AA D (8), and AA IIIa (10). These results undermine the assumption that 1 and 2 are exclusively responsible for the toxicity of Aristolochia species. Other analogues are likely to contribute to their toxicity and need to be considered as nephrotoxic agents. These findings facilitate understanding of the nephrotoxic mechanisms of Aristolochia and have significance for the regulation of herbal medicines. PMID: 26706944 [PubMed - indexed for MEDLINE]

Distinctive Metabolism of Flavonoid between Cultivated and Semi-wild Soybean Unveiled through Metabolomics Approach. J Agric Food Chem. 2016 Jun 29; Authors: Yun DY, Kang YG, Yun B, Kim EH, Kim M, Park JS, Lee J, Hong YS Abstract Soybeans are an important crop for agriculture and food, leading to increase of a range of its application. Recently, soybean leaves have been used not only for food products but also in the beauty industry. In order to provide useful and global metabolite information on the development of soy-based products, we investigated the metabolic evolution and cultivar-dependent metabolite variation in the leaves of cultivated (G. max) and semi-wild (G. gracilis) soybean, through a 1H NMR-based metabolomics approach, as they grew from V (vegetative) 1 to R (reproductive) 7 growth stages. The levels of primary metabolites, such as sucrose, amino acids, organic acids and fatty acids, were decreased both in the G. gracilis and G. max leaves. However, the secondary metabolites, such as pinitol, rutin and polyphenols, were increased, while synthesis of glucose was elevated as the leaves grew. Comparing metabolite variations between G. gracilis and G. max, it was noteworthy that rutin and its precursor, quercetin-3-O-glucoside, were found only in G. gracilis but not in G. max. Furthermore, levels of pinitol, proline, -alanine and acetic acid, a metabolite related to adaptation toward environmental stress, were different between the two soybean cultivars. These results highlight their distinct metabolism for adaptation to environmental conditions and their intrinsic metabolic phenotype. This study therefore provides important information on the metabolic evolution and cultivar-dependent metabolites of soybean leaves for better understanding of plant physiology to develop soy-based products. PMID: 27356159 [PubMed - as supplied by publisher]

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins. PLoS One. 2016;11(6):e0158568 Authors: Pallister T, Jennings A, Mohney RP, Yarand D, Mangino M, Cassidy A, MacGregor A, Spector TD, Menni C Abstract Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations. PMID: 27355821 [PubMed - as supplied by publisher]

Novel insights into development of diabetic bladder disorder provided by metabolomic analysis of the rat non-diabetic and diabetic detrusor and urothelial layer. Am J Physiol Endocrinol Metab. 2016 Jun 28;:ajpendo.00134.2016 Authors: Wang Y, Deng GG, Davies KP Abstract There are at present no published studies providing a global overview of changes in bladder metabolism resulting from diabetes. Such studies have the potential to provide mechanistic insight into the development of diabetic bladder disorder (DBD). In the present study we compared the metabolome of detrusor and urothelial layer in a one month streptozotocin-induced rat model of Type I diabetes with non-diabetic controls. Our studies revealed diabetes caused both common and differential changes in the detrusor and urothelial layer's metabolome. Diabetes resulted in similar changes in levels of previously described diabetic markers in both tissues, such as glucose, lactate, 2-hydroxybutyrate, branched-chain amino acid degradation products, bile acids and 1,5-anhydroglucitol, as well as markers of oxidative stress. In detrusor (but not urothelial layer) diabetes caused activation of the pentose-phosphate and polyol pathways, concomitant with a reduction in the TCA cycle and β-oxidation. Changes in detrusor energy generating pathways resulted in an accumulation of sorbitol which, through generation of advanced glycation end products, is likely to play a central role in the development of DBD. In the diabetic urothelial layer there was decreased flux of glucose via glycolysis and changes in lipid metabolism, particularly prostaglandin synthesis, which also potentially contributes to detrusor dysfunction. PMID: 27354236 [PubMed - as supplied by publisher]

Enzyme-driven metabolomic screening: a proof-of-principle method for discovery of plant defence compounds targeted by pathogens. New Phytol. 2016 Jun 29; Authors: Carere J, Colgrave ML, Stiller J, Liu C, Manners JM, Kazan K, Gardiner DM Abstract Plants produce a variety of secondary metabolites to defend themselves from pathogen attack, while pathogens have evolved to overcome plant defences by producing enzymes that degrade or modify these defence compounds. However, many compounds targeted by pathogen enzymes currently remain enigmatic. Identifying host compounds targeted by pathogen enzymes would enable us to understand the potential importance of such compounds in plant defence and modify them to make them insensitive to pathogen enzymes. Here, a proof of concept metabolomics-based method was developed to discover plant defence compounds modified by pathogens using two pathogen enzymes with known targets in wheat and tomato. Plant extracts treated with purified pathogen enzymes were subjected to LC-MS, and the relative abundance of metabolites before and after treatment were comparatively analysed. Using two enzymes from different pathogens the in planta targets could be found by combining relatively simple enzymology with the power of untargeted metabolomics. Key to the method is dataset simplification based on natural isotope occurrence and statistical filtering, which can be scripted. The method presented here will aid in our understanding of plant-pathogen interactions and may lead to the development of new plant protection strategies. PMID: 27353742 [PubMed - as supplied by publisher]

Related Articles Characterization of Non-Anthocyanic Flavonoids in Some Hybrid Red Grape Extracts Potentially Interesting for Industrial Uses. Molecules. 2015;20(10):18095-106 Authors: De Rosso M, Panighel A, Vedova AD, Gardiman M, Flamini R Abstract Previous studies showed that hybrid grapes often have qualitatively and quantitatively higher polyphenolic contents than the common V. vinifera grape varieties. In general, these compounds are studied for grape chemotaxonomy and for nutraceutical purposes due to their relevant antioxidant activity. Non-anthocyanic flavonoid composition of five red hybrid grape varieties produced by crossing of V. vinifera, V. aestivalis, V. cinerea, V. berlandieri, V. labrusca, V. lincecumii, and V. rupestris were studied by liquid chromatography/high-resolution mass spectrometry. Thirty-one compounds were identified, including methylnaringenin, a tetrahydroxy-dimethoxyflavanone-hexoside, two flavonols (quercetin and a pentahydroxyflavone isomer), 20 glycoside flavonols (four quercetin, two myricetin, two kaempferol, three isorhamnetin, one laricitrin, two syringetin, one kaempferide and two dihydroflavonol derivatives; myricetin-glucoside-glucuronide; myricetin-diglucoside; syringetin-dihexoside), three flavan-3-ols (-)-epicatechin, (+)-catechin, (-)-epicatechin gallate) and four proantocyanidins (procyanidin B1, procyanidin B2, procyanidin B3 or B4/B5, procyanidin T2 or T3/T4/C1). Seibel 19881, Seyve Villard 12-347 and Seyve Villard 29-399 were particularly rich in polyphenols. These findings emphasize that these grapes are especially interesting for the production of antioxidant extracts for nutraceutical and pharmaceutical uses. PMID: 26445038 [PubMed - indexed for MEDLINE]

Related Articles Increased PUFA Content and 5-Lipoxygenase Pathway Expression Are Associated with Subcutaneous Adipose Tissue Inflammation in Obese Women with Type 2 Diabetes. Nutrients. 2015 Sep;7(9):7676-90 Authors: Heemskerk MM, Giera M, Bouazzaoui FE, Lips MA, Pijl H, van Dijk KW, van Harmelen V Abstract Obese women with type 2 diabetes mellitus (T2DM) have more inflammation in their subcutaneous white adipose tissue (sWAT) than age-and-BMI similar obese women with normal glucose tolerance (NGT). We aimed to investigate whether WAT fatty acids and/or oxylipins are associated with the enhanced inflammatory state in WAT of the T2DM women. Fatty acid profiles were measured in both subcutaneous and visceral adipose tissue (vWAT) of 19 obese women with NGT and 16 age-and-BMI similar women with T2DM. Oxylipin levels were measured in sWAT of all women. Arachidonic acid (AA) and docosahexaenoic acid (DHA) percentages were higher in sWAT, but not vWAT of the T2DM women, and AA correlated positively to the gene expression of macrophage marker CD68. We found tendencies for higher oxylipin concentrations of the 5-LOX leukotrienes in sWAT of T2DM women. Gene expression of the 5-LOX leukotriene biosynthesis pathway was significantly higher in sWAT of T2DM women. In conclusion, AA and DHA content were higher in sWAT of T2DM women and AA correlated to the increased inflammatory state in sWAT. Increased AA content was accompanied by an upregulation of the 5-LOX pathway and seems to have led to an increase in the conversion of AA into proinflammatory leukotrienes in sWAT. PMID: 26378572 [PubMed - indexed for MEDLINE]

Related Articles A Novel Urinary Metabolite Signature for Non-invasive Post-stroke Depression Diagnosis. Cell Biochem Biophys. 2015 Jul;72(3):661-667 Authors: Zhang W, Zhang XA Abstract Post-stroke depression (PSD) is the most common psychiatric complication in stroke survivors that has been associated with increased physical disability, distress, poor rehabilitation, and suicidal ideation. However, there are still no biomarkers available to support objective laboratory testing for this disorder. Here, a GC-MS-based urinary metabolomics approach was used to characterize the urinary metabolic profiling of PSD (stroke) subjects and non-PSD (health controls) subjects in order to identify and validate urinary metabolite biomarkers for PSD. Six metabolites, azelaic acid, glyceric acid, pseudouridine, 5-hydroxyhexanoic acid, tyrosine, and phenylalanine, were defined as biomarkers. A combined panel of these six urinary metabolites could effectively discriminate between PSD subjects and non-PSD subjects, achieving an area under the receiver-operating characteristic curve (AUC) of 0.961 in a training set (n = 72 PSD subjects and n = 146 non-PSD subjects). Moreover, this urinary biomarker panel was capable of discriminating blinded test samples (n = 58 PSD patients and n = 109 non-PSD subjects) with an AUC of 0.954. These findings suggest that a urine-based laboratory test using these biomarkers may be useful in the diagnosis of PSD. PMID: 27352185 [PubMed - as supplied by publisher]

Related Articles Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease. Expert Opin Drug Metab Toxicol. 2016 Jun 28; Authors: Bizzarri M, Fuso A, Dinicola S, Cucina A, Bevilacqua A Abstract INTRODUCTION: Inositol and its derivatives comprise a huge field of biology. Myo-inositol is not only a prominent component of membrane-incorporated phosphatidylinositol, but participates in its free form, with its isomers or its phosphate derivatives, to a multitude of cellular processes, including ion channel permeability, metabolic homeostasis, mRNA export and translation, cytoskeleton remodeling, stress response. AREAS COVERED: Bioavailability, safety, uptake and metabolism of inositol is discussed emphasizing the complexity of interconnected pathways leading to phosphoinositides, inositol phosphates and more complex molecules, like glycosyl-phosphatidylinositols. EXPERT OPINION: Besides being a structural element, myo-inositol exerts unexpected functions, mostly unknown. However, several reports indicate that inositol plays a key role during phenotypic transitions and developmental phases. Furthermore, dysfunctions in the regulation of inositol metabolism have been implicated in several chronic diseases. Clinical trials using inositol in pharmacological doses provide amazing results in the management of gynecological diseases, respiratory stress syndrome, Alzheimer's disease, metabolic syndrome, and cancer, for which conventional treatments are disappointing. However, despite the widespread studies carried out to identify inositol-based effects, no comprehensive understanding of inositol-based mechanisms has been achieved. An integrated metabolomics-genomic study to identify the cellular fate of therapeutically administered myo-inositol and its genomic/enzymatic targets is urgently warranted. PMID: 27351907 [PubMed - as supplied by publisher]

Related Articles Xenobiotic/medium chain fatty acid: CoA ligase - a critical review on its role in fatty acid metabolism and the detoxification of benzoic acid and aspirin. Expert Opin Drug Metab Toxicol. 2016 Jun 28; Authors: van der Sluis R, Erasmus E Abstract INTRODUCTION: Activation of fatty acids by the acyl-CoA synthetases (ACSs) is the vital first step in fatty acid metabolism. The enzymatic and physiological characterization of the human xenobiotic/medium chain fatty acid: CoA ligases (ACSMs) has been severely neglected even though xenobiotics, such as benzoate and salicylate, are detoxified through this pathway. AREAS COVERED: This review will focus on the nomenclature and substrate specificity of the human ACSM ligases; the biochemical and enzymatic characterization of ACSM1 and ACSM2B; the high sequence homology of the ACSM2 genes (ACSM2A and ACSM2B) as well as what is currently known regarding disease association studies. Expert opinion Several discrepancies exist in the current literature that should be taken note of. For example, the single nucleotide polymorphisms (SNPs) reported to be associated with aspirin metabolism and multiple risk factors of metabolic syndrome are incorrect. Kinetic data on the substrate specificity of the human ACSM ligases are non-existent and currently no data exist on the influence of SNPs on the enzyme activity of these ligases. One of the biggest obstacles currently in the field is that glycine conjugation is continuously studied as a one-step process, which means that key regulatory factors of the two individual steps remain unknown. PMID: 27351777 [PubMed - as supplied by publisher]

Related Articles Comprehensive and Quantitative Profiling of the Human Sweat Submetabolome Using High-Performance Chemical Isotope Labeling LC-MS. Anal Chem. 2016 Jun 28; Authors: Hooton K, Han W, Li L Abstract Human sweat can be noninvasively collected and used as a media for diagnosis of certain diseases as well as for drug detection. However, because of very low concentrations of endogenous metabolites present in sweat, metabolomic analysis of sweat with high coverage is difficult, making it less widely used for metabolomics research. In this work, a high-performance method for profiling the human sweat submetabolome based on chemical isotope labeling (CIL) LC-MS is reported. Sweat was collected using a gauze sponge style patch and extracted from the gauze by centrifugation and then derivatized using CIL. Differential (12)C- and (13)C-dansylation labeling was used to target the amine/phenol submetabolome. Because of large variations in the total amount of sweat metabolites in individual samples, sample amount normalization was first performed using LC-UV after dansylation. The (12)C-labeled individual sample was then mixed with an equal amount of (13)C-labeled pooled sample. The mixture was subjected to LC-MS analysis. Over 2707 unique metabolites were detected across 54 sweat samples from six individuals with an average of 2002±165 metabolites detected per sample from a total of 108 LC-MS runs. Using a dansyl standard library, we were able to identify 83 metabolites with high confidence; many of them have never been reported to be present in sweat. Using accurate mass search against human metabolome libraries, we putatively identified an additional 2411 metabolites. Uni- and multivariate analyses of these metabolites showed significant differences in the sweat submetabolomes between male and female, as well as between early and late exercise. These results demonstrate that the CIL LC-MS method described can be used to profile the human sweat submetabolome with high metabolomic coverage and high quantification accuracy to reveal metabolic differences in different sweat samples, thereby allowing the use of sweat as another human biofluid for comprehensive and quantitative metabolomics research. PMID: 27351466 [PubMed - as supplied by publisher]

Related Articles Metabolic clusters of breast cancer in relation to gene- and protein expression subtypes. Cancer Metab. 2016;4:12 Authors: Haukaas TH, Euceda LR, Giskeødegård GF, Lamichhane S, Krohn M, Jernström S, Aure MR, Lingjærde OC, Schlichting E, Garred Ø, Due EU, Mills GB, Sahlberg KK, Børresen-Dale AL, Bathen TF, Oslo Breast Cancer Consortium (OSBREAC) Abstract BACKGROUND: The heterogeneous biology of breast cancer leads to high diversity in prognosis and response to treatment, even for patients with similar clinical diagnosis, histology, and stage of disease. Identifying mechanisms contributing to this heterogeneity may reveal new cancer targets or clinically relevant subgroups for treatment stratification. In this study, we have merged metabolite, protein, and gene expression data from breast cancer patients to examine the heterogeneity at a molecular level. METHODS: The study included primary tumor samples from 228 non-treated breast cancer patients. High-resolution magic-angle spinning magnetic resonance spectroscopy (HR MAS MRS) was performed to extract the tumors metabolic profiles further used for hierarchical cluster analysis resulting in three significantly different metabolic clusters (Mc1, Mc2, and Mc3). The clusters were further combined with gene and protein expression data. RESULTS: Our result revealed distinct differences in the metabolic profile of the three metabolic clusters. Among the most interesting differences, Mc1 had the highest levels of glycerophosphocholine (GPC) and phosphocholine (PCho), Mc2 had the highest levels of glucose, and Mc3 had the highest levels of lactate and alanine. Integrated pathway analysis of metabolite and gene expression data uncovered differences in glycolysis/gluconeogenesis and glycerophospholipid metabolism between the clusters. All three clusters had significant differences in the distribution of protein subtypes classified by the expression of breast cancer-related proteins. Genes related to collagens and extracellular matrix were downregulated in Mc1 and consequently upregulated in Mc2 and Mc3, underpinning the differences in protein subtypes within the metabolic clusters. Genetic subtypes were evenly distributed among the three metabolic clusters and could therefore contribute to additional explanation of breast cancer heterogeneity. CONCLUSIONS: Three naturally occurring metabolic clusters of breast cancer were detected among primary tumors from non-treated breast cancer patients. The clusters expressed differences in breast cancer-related protein as well as genes related to extracellular matrix and metabolic pathways known to be aberrant in cancer. Analyses of metabolic activity combined with gene and protein expression provide new information about the heterogeneity of breast tumors and, importantly, the metabolic differences infer that the clusters may be susceptible to different metabolically targeted drugs. PMID: 27350877 [PubMed]

Related Articles Positive effects of proline addition on the central metabolism of wild-type and lactic acid-producing Saccharomyces cerevisiae strains. Bioprocess Biosyst Eng. 2016 Jun 27; Authors: Nugroho RH, Yoshikawa K, Matsuda F, Shimizu H Abstract In Saccharomyces cerevisiae, proline is a stress protectant interacting with other substrate uptake systems against oxidative stress under low pH conditions. In this study, we performed metabolomics analysis to investigate the response associated with an increase in cell growth rates and maximum densities when cells were treated with proline under normal and acid stress conditions. Metabolome data show that concentrations of components of central metabolism are increased in proline-treated S. cerevisiae. No consumption of proline was observed, suggesting that proline does not act as a nutrient but regulates metabolic state and growth of cells. Treatment of lactic acid-producing yeast with proline during lactic acid bio-production improved growth rate and increased the final concentration of lactic acid. PMID: 27350544 [PubMed - as supplied by publisher]