PubMed

Use of Metabolomics to Advance Research on Environmental Exposures and the Human Exposome: Workshop in Brief Book. 2016 03 22Authors: Board on Life Sciences, Division on Earth and Life Studies, National Academies of Sciences, Engineering, and Medicine Abstract Metabolomics, the scientific study of small molecules produced from metabolism (metabolites) is a rapidly expanding area of research that enables scientists to better understand the physiological state of an organism and its response to different types of stimuli, including nutrients and pollutants. Metabolism is the array of chemical reactions that occur within a living organism to support its ability to grow, reproduce, and respond to environmental exposures, among other processes necessary to sustain life. Metabolites can be created in response to chemicals that originate endogenously (inside the body) or exogenously (outside of the body). Preliminary research suggests that metabolomics holds promise to advance understanding of the exposome. The exposome includes all of the environmental compounds an individual is exposed to from conception to death. This environmental correlate to the genome, first described in 2005 by Christopher Wild, includes people's exposure to complex mixtures of chemicals, as well as the substances that can be produced in the body when chemicals are metabolized. For this reason, the National Academies of Sciences, Engineering, and Medicine held a workshop to examine the potential for using metabolomics to characterize human environmental exposures and the exposome. Proofs-of-concept were discussed in two case studies on the cause of human Eosinophilic esophagitis and the effect of toxic pollutants on pregnancy in rats. Key workshop themes included technical capabilities and limitations to collect metabolomics data and the implications of this new source of data for future environmental and public health research and public health policies. PMID: 27054232

Targeted lipidomics distinguishes patient subgroups in mild cognitive impairment (MCI) and late onset Alzheimer's disease (LOAD). BBA Clin. 2016 Jun;5:25-28 Authors: Wood PL, Locke VA, Herling P, Passaro A, Vigna GB, Volpato S, Valacchi G, Cervellati C, Zuliani G Abstract BACKGROUND: Diverse research approaches support the concept that a clinical diagnosis of Late-Onset Alzheimer's Disease (LOAD) does not distinguish between subpopulations with differing neuropathologies, including dementia patients with amyloid deposition and dementia patients without amyloid deposition but with cortical thinning. Mild cognitive impairment (MCI) is generally considered the prodromal phase for LOAD, however, while a number of studies have attempted to define plasma biomarkers for the conversion of MCI to LOAD, these studies have not taken into account the heterogeneity of patient cohorts within a clinical phenotype. METHODS: Studies of MCI and LOAD in several laboratories have demonstrated decrements in ethanolamine plasmalogen levels in plasma and brain and increased levels of diacylglycerols in plasma and brain. To further extend these studies and to address the issue of heterogeneity in MCI and LOAD patient groups we investigated the levels of diacylglycerols and ethanolamine plasmalogens in larger cohorts of patients utilizing, high-resolution (0.2 to 2 ppm mass error) mass spectrometry. RESULTS: For the first time, our lipidomics data clearly stratify both MCI and LOAD subjects into 3 different patient cohorts within each clinical diagnosis. These include i) patients with lower circulating ethanolamine plasmalogen levels; ii) patients with augmented plasma diacylglycerol levels; and iii) patients with neither of these lipid alterations. CONCLUSIONS: These represent the first serum biochemical data to stratify MCI and LOAD patients, advancing efforts to biochemically define patient heterogeneity in cognitive disorders. GENERAL SIGNIFICANCE: Lipidomics offers a new approach for identifying biomarkers and biological targets in cognitive disorders. PMID: 27051586 [PubMed - as supplied by publisher]

Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A. 2016 Apr 5; Authors: Sadhukhan S, Liu X, Ryu D, Nelson OD, Stupinski JA, Li Z, Chen W, Zhang S, Weiss RS, Locasale JW, Auwerx J, Lin H Abstract Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart. This interesting observation has prompted us to examine protein lysine succinylation in different mouse tissues in the presence and absence of SIRT5. Protein lysine succinylation predominantly accumulates in the heart whenSirt5is deleted. Using proteomic studies, we have identified many cardiac proteins regulated by SIRT5. Our data suggest that ECHA, a protein involved in fatty acid oxidation, is a major enzyme that is regulated by SIRT5 and affects heart function.Sirt5knockout (KO) mice have lower ECHA activity, increased long-chain acyl-CoAs, and decreased ATP in the heart under fasting conditions.Sirt5KO mice develop hypertrophic cardiomyopathy, as evident from the increased heart weight relative to body weight, as well as reduced shortening and ejection fractions. These findings establish that regulating heart metabolism and function is a major physiological function of lysine succinylation and SIRT5. PMID: 27051063 [PubMed - as supplied by publisher]

Plasma metabolomic changes following PI3K inhibition as pharmacodynamic biomarkers: preclinical discovery to Phase I trial evaluation. Mol Cancer Ther. 2016 Apr 5; Authors: Ang JE, Pandher R, Ang JC, Asad YJ, Henley A, Valenti M, Box G, De Haven Brandon A, Baird RR, Friedman L, Derynck M, Vanhaesebroeck B, Eccles SA, Kaye SB, Workman P, de Bono JS, Raynaud FI Abstract Phosphoinositide-3-kinase (PI3K) plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor bearing controls and in addition were increased following dosing with Class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a Phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids and related metabolites following PI3K inhibition. PMID: 27048952 [PubMed - as supplied by publisher]

Integrated Metabolomics Study of the Milk of Heat-stressed Lactating Dairy Cows. Sci Rep. 2016;6:24208 Authors: Tian H, Zheng N, Wang W, Cheng J, Li S, Zhang Y, Wang J Abstract Heat stress (HS) damages the global dairy industry by reducing milk yields and quality, harming health, and damaging the reproduction of dairy cows, causing huge economic losses each year. However, an understanding of the physiological mechanism of HS lactating dairy cows remains elusive. Here, a metabolomics study using LC-MS and (1)H NMR spectroscopy was performed to analyze the metabolomic differences in the milk between HS-free and HS dairy cows, and discover diagnostic biomarkers and changes in the metabolic pathway. A total of 53 discriminating metabolites were significantly up- or down-regulated in the HS group compared with the HS-free group (P < 0.05). These biomarkers were involved in pathways of carbohydrate, amino acid, lipid, and gut microbiome-derived metabolism. Comparing these potential biomarkers with previously identified HS candidate biomarkers in plasma, significant correlations between the levels of lactate, pyruvate, creatine, acetone, β-hydroxybutyrate, trimethylamine, oleic acid, linoleic acid, lysophosphatidylcholine 16:0, and phosphatidylcholine 42:2 in milk and plasma were found, indicating that the blood-milk barrier became leaky and the levels of these 10 biomarkers in milk can reflect HS-induced metabolomic alterations in blood. These novel findings can support more in-depth research to elucidate the milk-based changes in metabolic pathways in HS lactating dairy cows. PMID: 27048914 [PubMed - in process]

Dysbiosis in gastrointestinal disorders. Best Pract Res Clin Gastroenterol. 2016 Feb;30(1):3-15 Authors: Chang C, Lin H Abstract The recent development of advanced sequencing techniques has revealed the complexity and diverse functions of the gut microbiota. Furthermore, alterations in the composition or balance of the intestinal microbiota, or dysbiosis, are associated with many gastrointestinal diseases. The looming question is whether dysbiosis is a cause or effect of these diseases. In this review, we will evaluate the contribution of intestinal microbiota in obesity, fatty liver, inflammatory bowel disease, and irritable bowel syndrome. Promising results from microbiota or metabolite transfer experiments in animals suggest the microbiota may be sufficient to reproduce disease features in the appropriate host in certain disorders. Less compelling causal associations may reflect complex, multi-factorial disease pathogenesis, in which dysbiosis is a necessary condition. Understanding the contributions of the microbiota in GI diseases should offer novel insight into disease pathophysiology and deliver new treatment strategies such as therapeutic manipulation of the microbiota. PMID: 27048892 [PubMed - in process]

Regulated cell death and adaptive stress responses. Cell Mol Life Sci. 2016 Apr 5; Authors: Galluzzi L, Bravo-San Pedro JM, Kepp O, Kroemer G Abstract Eukaryotic cells react to potentially dangerous perturbations of the intracellular or extracellular microenvironment by activating rapid (transcription-independent) mechanisms that attempt to restore homeostasis. If such perturbations persist, cells may still try to cope with stress by activating delayed and robust (transcription-dependent) adaptive systems, or they may actively engage in cellular suicide. This regulated form of cell death can manifest with various morphological, biochemical and immunological correlates, and constitutes an ultimate attempt of stressed cells to maintain organismal homeostasis. Here, we dissect the general organization of adaptive cellular responses to stress, their intimate connection with regulated cell death, and how the latter operates for the preservation of organismal homeostasis. PMID: 27048813 [PubMed - as supplied by publisher]

Approximating the stabilization of cellular metabolism by compartmentalization. Theory Biosci. 2016 Apr 5; Authors: Fürtauer L, Nägele T Abstract Biochemical regulation in compartmentalized metabolic networks is highly complex and non-intuitive. This is particularly true for cells of higher plants showing one of the most compartmentalized cellular structures across all kingdoms of life. The interpretation and testable hypothesis generation from experimental data on such complex systems is a challenging step in biological research and biotechnological applications. While it is known that subcellular compartments provide defined reaction spaces within a cell allowing for the tight coordination of complex biochemical reaction sequences, its role in the coordination of metabolic signals during metabolic reprogramming due to environmental fluctuations is less clear. In the present study, we numerically analysed the effects of environmental fluctuations in a subcellular metabolic network with regard to the stability of an experimentally observed steady state in the genetic model plant Arabidopsis thaliana. Applying a method for kinetic parameter normalization, several millions of probable enzyme kinetic parameter constellations were simulated and evaluated with regard to the stability information of the metabolic homeostasis. Information about the stability of the metabolic steady state was derived from real parts of eigenvalues of Jacobian matrices. Our results provide evidence for a differential stabilizing contribution of different subcellular compartments. We could identify stabilizing and destabilizing network components which we could classify according to their subcellular localization. The findings prove that a highly dynamic interplay between intracellular compartments is preliminary for an efficient stabilization of a metabolic homeostasis after environmental perturbation. Further, our results provide evidence that feedback-inhibition originating from the cytosol and plastid seem to stabilize the sucrose homeostasis more efficiently than vacuolar control. In summary, our results indicate stabilizing and destabilizing network components in context of their subcellular organization. PMID: 27048513 [PubMed - as supplied by publisher]

The importance of GC-MS date processing and analysis strategies suitable for plant and environmental metabolomics : with references to Changes in the abundance of sugars and sugar-like compounds in tall fescue (Festuca arundinacea) due to growth in naphthalene-treated sand. Environ Sci Pollut Res Int. 2016 Apr 6; Authors: Law KP, Han TL PMID: 27048323 [PubMed - as supplied by publisher]

Related Articles The Frog Skin-Derived Antimicrobial Peptide Esculentin-1a(1-21)NH2 Promotes the Migration of Human HaCaT Keratinocytes in an EGF Receptor-Dependent Manner: A Novel Promoter of Human Skin Wound Healing? PLoS One. 2015;10(6):e0128663 Authors: Di Grazia A, Cappiello F, Imanishi A, Mastrofrancesco A, Picardo M, Paus R, Mangoni ML Abstract One of the many functions of skin is to protect the organism against a wide range of pathogens. Antimicrobial peptides (AMPs) produced by the skin epithelium provide an effective chemical shield against microbial pathogens. However, whereas antibacterial/antifungal activities of AMPs have been extensively characterized, much less is known regarding their wound healing-modulatory properties. By using an in vitro re-epithelialisation assay employing special cell-culture inserts, we detected that a derivative of the frog-skin AMP esculentin-1a, named esculentin-1a(1-21)NH2, significantly stimulates migration of immortalized human keratinocytes (HaCaT cells) over a wide range of peptide concentrations (0.025-4 μM), and this notably more efficiently than human cathelicidin (LL-37). This activity is preserved in primary human epidermal keratinocytes. By using appropriate inhibitors and an enzyme-linked immunosorbent assay we found that the peptide-induced cell migration involves activation of the epidermal growth factor receptor and STAT3 protein. These results suggest that esculentin-1a(1-21)NH2 now deserves to be tested in standard wound healing assays as a novel candidate promoter of skin re-epithelialisation. The established ability of esculentin-1a(1-21)NH2 to kill microbes without harming mammalian cells, namely its high anti-Pseudomonal activity, makes this AMP a particularly attractive candidate wound healing promoter, especially in the management of chronic, often Pseudomonas-infected, skin ulcers. PMID: 26068861 [PubMed - indexed for MEDLINE]

Global Isotope Metabolomics Reveals Adaptive Strategies for Nitrogen Assimilation in Pseudomonas. ACS Chem Biol. 2016 Apr 5; Authors: Kurczy ME, Forsberg EM, Thorgersen MP, Poole FL, Benton HP, Ivanisevic J, Tran ML, Wall JD, Elias DA, Adams MW, Siuzdak G Abstract Nitrogen cycling is a microbial metabolic process essential for global ecological/agricultural balance. To investigate the link between the well-established ammonium and the alternative nitrate assimilation metabolic pathways, global isotope metabolomics was employed to examine three nitrate reducing bacteria using 15NO3 as a nitrogen source.  In contrast to a control (Pseudomonas stutzeri RCH2), the results show that two of the isolates from Oak Ridge, Tennessee (Pseudomonas N2A2 and N2E2) utilize nitrate and ammonia for assimilation concurrently with differential labeling observed across multiple classes of metabolites including amino acids and nucleotides. The data reveal that the N2A2 and N2E2 strains conserve nitrogen-containing metabolites indicating the nitrate assimilation pathway is an inefficient mechanism for the assimilation of nitrogen. Co-utilization of nitrate and ammonia are likely an adaption to manage higher levels of nitrite since the denitrification pathways utilized by the N2A2 and N2E2 strains from the Oak Ridge site are predisposed to the accumulation of the toxic nitrite. The use of global isotope metabolomics allowed for this adaptive strategy to be investigated, which would otherwise not have been possible to decipher. PMID: 27045776 [PubMed - as supplied by publisher]

Construction of a metabolomics profile of arsenic trioxide effect in gastric carcinoma cell line SGC7901. Acta Biochim Biophys Sin (Shanghai). 2016 Apr 3; Authors: Chen Z, Zhang H, Yang L, Jiang H, Guo S, Li Y, Tao S Abstract Arsenic trioxide (ATO) is highly effective for treating acute promyelocytic leukemia. It also holds the promise for treating solid tumors, including gastric carcinoma. However, the molecular mechanism of the effectiveness of ATO to solid tumor is still poorly understood. In this study, we chosed gastric carcinoma as an example and tried to reveal the antitumor mechanism through metabolomics. Gastric carcinoma cell line SGC7901 was treated with ATO for 6, 12, and 24 h. The global metabolite profiles were monitored by metabolomics analysis using gas chromatography (GC)/mass spectrometry (MS) and liquid chromatography/MS/MS. A total of 281 certified metabolites were reliably detected. Bioinformatics analysis showed that glycerophospholipid synthesis, one-carbon synthesis, and glutathione synthesis were affected dramatically. Other cellular functions/pathways that had been affected included inflammatory response, nicotinamide adenine dinucleotide (NAD(+)), and polyamine biosynthesis pathway. The metabolomics data from this study, in combination with previous transcriptomics and proteomics data, could serve as valuable resources for the understanding of the specific antitumor mechanism of ATO treatment. PMID: 27044562 [PubMed - as supplied by publisher]

Related Articles Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun. 2015;6:7320 Authors: Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ, Roberts LK, Wong CH, Shim R, Robert R, Chevalier N, Tan JK, Mariño E, Moore RJ, Wong L, McConville MJ, Tull DL, Wood LG, Murphy VE, Mattes J, Gibson PG, Mackay CR Abstract Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to prevent asthma, including during pregnancy. PMID: 26102221 [PubMed - indexed for MEDLINE]

Related Articles TRANSCRIPTION ACTIVATOR-LIKE EFFECTOR NUCLEASE-Mediated Generation and Metabolic Analysis of Camalexin-Deficient cyp71a12 cyp71a13 Double Knockout Lines. Plant Physiol. 2015 Jul;168(3):849-58 Authors: Müller TM, Böttcher C, Morbitzer R, Götz CC, Lehmann J, Lahaye T, Glawischnig E Abstract In Arabidopsis (Arabidopsis thaliana), a number of defense-related metabolites are synthesized via indole-3-acetonitrile (IAN), including camalexin and indole-3-carboxylic acid (ICOOH) derivatives. Cytochrome P450 71A13 (CYP71A13) is a key enzyme for camalexin biosynthesis and catalyzes the conversion of indole-3-acetaldoxime (IAOx) to IAN. The CYP71A13 gene is located in tandem with its close homolog CYP71A12, also encoding an IAOx dehydratase. However, for CYP71A12, indole-3-carbaldehyde and cyanide were identified as major reaction products. To clarify CYP71A12 function in vivo and to better understand IAN metabolism, we generated two cyp71a12 cyp71a13 double knockout mutant lines. CYP71A12-specific transcription activator-like effector nucleases were introduced into the cyp71a13 background, and very efficient somatic mutagenesis was achieved. We observed stable transmission of the cyp71a12 mutation to the following generations, which is a major challenge for targeted mutagenesis in Arabidopsis. In contrast to cyp71a13 plants, in which camalexin accumulation is partially reduced, double mutants synthesized only traces of camalexin, demonstrating that CYP71A12 contributes to camalexin biosynthesis in leaf tissue. A major role of CYP71A12 was identified for the inducible biosynthesis of ICOOH. Specifically, the ICOOH methyl ester was reduced to 12% of the wild-type level in AgNO3-challenged cyp71a12 leaves. In contrast, indole-3-carbaldehyde derivatives apparently are synthesized via alternative pathways, such as the degradation of indole glucosinolates. Based on these results, we present a model for this surprisingly complex metabolic network with multiple IAN sources and channeling of IAOx-derived IAN into camalexin biosynthesis. In conclusion, transcription activator-like effector nuclease-mediated mutation is a powerful tool for functional analysis of tandem genes in secondary metabolism. PMID: 25953104 [PubMed - indexed for MEDLINE]

Related Articles An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei. PLoS Pathog. 2015 May;11(5):e1004875 Authors: de Macêdo JP, Schumann Burkard G, Niemann M, Barrett MP, Vial H, Mäser P, Roditi I, Schneider A, Bütikofer P Abstract Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug action or targeting. PMID: 25946070 [PubMed - indexed for MEDLINE]

Related Articles Glycomic Analysis of Life Stages of the Human Parasite Schistosoma mansoni Reveals Developmental Expression Profiles of Functional and Antigenic Glycan Motifs. Mol Cell Proteomics. 2015 Jul;14(7):1750-69 Authors: Smit CH, van Diepen A, Nguyen DL, Wuhrer M, Hoffmann KF, Deelder AM, Hokke CH Abstract Glycans present on glycoproteins and glycolipids of the major human parasite Schistosoma mansoni induce innate as well as adaptive immune responses in the host. To be able to study the molecular characteristics of schistosome infections it is therefore required to determine the expression profiles of glycans and antigenic glycan-motifs during a range of critical stages of the complex schistosome lifecycle. We performed a longitudinal profiling study covering schistosome glycosylation throughout worm- and egg-development using a mass spectrometry-based glycomics approach. Our study revealed that during worm development N-glycans with Galβ1-4(Fucα1-3)GlcNAc (LeX) and core-xylose motifs were rapidly lost after cercariae to schistosomula transformation, whereas GalNAcβ1-4GlcNAc (LDN)-motifs gradually became abundant and predominated in adult worms. LeX-motifs were present on glycolipids up to 2 weeks of schistosomula development, whereas glycolipids with mono- and multifucosylated LDN-motifs remained present up to the adult worm stage. In contrast, expression of complex O-glycans diminished to undetectable levels within days after transformation. During egg development, a rich diversity of N-glycans with fucosylated motifs was expressed, but with α3-core fucose and a high degree of multifucosylated antennae only in mature eggs and miracidia. N-glycan antennae were exclusively LDN-based in miracidia. O-glycans in the mature eggs were also diverse and contained LeX- and multifucosylated LDN, but none of these were associated with miracidia in which we detected only the Galβ1-3(Galβ1-6)GalNAc core glycan. Immature eggs also exhibited short O-glycan core structures only, suggesting that complex fucosylated O-glycans of schistosome eggs are derived primarily from glycoproteins produced by the subshell envelope in the developed egg. Lipid glycans with multifucosylated GlcNAc repeats were present throughout egg development, but with the longer highly fucosylated stretches enriched in mature eggs and miracidia. This global analysis of the developing schistosome's glycome provides new insights into how stage-specifically expressed glycans may contribute to different aspects of schistosome-host interactions. PMID: 25883177 [PubMed - indexed for MEDLINE]

Related Articles Metabolic profiling-based data-mining for an effective chemical combination to induce apoptosis of cancer cells. Sci Rep. 2015;5:9474 Authors: Kumazoe M, Fujimura Y, Hidaka S, Kim Y, Murayama K, Takai M, Huang Y, Yamashita S, Murata M, Miura D, Wariishi H, Maeda-Yamamoto M, Tachibana H Abstract Green tea extract (GTE) induces apoptosis of cancer cells without adversely affecting normal cells. Several clinical trials reported that GTE was well tolerated and had potential anti-cancer efficacy. Epigallocatechin-3-O-gallate (EGCG) is the primary compound responsible for the anti-cancer effect of GTE; however, the effect of EGCG alone is limited. To identify GTE compounds capable of potentiating EGCG bioactivity, we performed metabolic profiling of 43 green tea cultivar panels by liquid chromatography-mass spectrometry (LC-MS). Here, we revealed the polyphenol eriodictyol significantly potentiated apoptosis induction by EGCG in vitro and in a mouse tumour model by amplifying EGCG-induced activation of the 67-kDa laminin receptor (67LR)/protein kinase B/endothelial nitric oxide synthase/protein kinase C delta/acid sphingomyelinase signalling pathway. Our results show that metabolic profiling is an effective chemical-mining approach for identifying botanical drugs with therapeutic potential against multiple myeloma. Metabolic profiling-based data mining could be an efficient strategy for screening additional bioactive compounds and identifying effective chemical combinations. PMID: 25824377 [PubMed - indexed for MEDLINE]

Related Articles Altered metabolomic profiles may be associated with sevoflurane-induced neurotoxicity in neonatal rats. Neurochem Res. 2015 Apr;40(4):788-99 Authors: Liu B, Gu Y, Xiao H, Lei X, Liang W, Zhang J Abstract Experimental studies demonstrate that inhaled anesthetics can cause neurodegeneration and neurobehavioral dysfunctions. Evidence suggests changes in cerebral metabolism following inhaled anesthetics treatment can perturb cerebral homeostasis, which may be associated with their induced neurotoxicity. Seven-day-old rat pups were divided into two groups: control group (Group C) and sevoflurane group (Group S, 3 % sevoflurane exposure for 6 h). Gas chromatography-mass spectrometry (GC-MS) was used for analyzed differential metabolites of cerebral cortex in both groups, Also western blot, flow cytometry, enzymatic methods and electron microscopy were performed in various biochemical and anatomical assays. Sevoflurane exposure significantly elevated caspase-3 activation and ROS levels, decreased mitochondrial cardiolipin contents, and changed cellular ultrastructure in the cerebral cortex. Correspondingly, these results corroborated the GC-MS findings which showed altered metabolic pathways of glucose, amino acids, and lipids, as well as intracellular antioxidants and osmolyte systems in neonatal brain following prolonged exposure to high sevoflurane concentration. Our data indicate that sevoflurane anesthesia causes significant oxidative stress, neuroapoptosis, and cellular ultrastructure damage which is associated with altered brain metabotype in the neonatal rat. Our study also confirmed that GC-MS is a strategic and complementary platform for the metabolomic characterization of sevoflurane-induced neurotoxicity in the developing brain. PMID: 25663300 [PubMed - indexed for MEDLINE]

Related Articles Dietary Nucleotides Supplementation and Liver Injury in Alcohol-Treated Rats: A Metabolomics Investigation. Molecules. 2016;21(4) Authors: Cai X, Bao L, Wang N, Xu M, Mao R, Li Y Abstract BACKGROUND: Previous studies suggested that nucleotides were beneficial for liver function, lipid metabolism and so on. The present study aimed to investigate the metabolic response of dietary nucleotides supplementation in alcohol-induced liver injury rats. METHODS: Five groups of male Wistar rats were used: normal control group (basal diet, equivalent distilled water), alcohol control group (basal diet, 50% alcohol (v/v)), dextrose control group (basal diet, isocaloric amount of dextrose), and 0.04% and 0.16% nucleotides groups (basal diet supplemented with 0.4 g and 1.6 g nucleotides kg(-1) respectively, 50% alcohol (v/v)). The liver injury was measured through traditional liver enzymes, expression of oxidative stress markers and histopathological examination. Ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to identify liver metabolite profiles. RESULTS: Nucleotides supplementation prevented the progression of hepatocyte steatosis. The levels of total proteins, globulin, alanine aminotransferase, aspartate aminotransferase, total cholesterol triglyceride, as well as the oxidative stress markers altered by alcohol, were improved by nucleotides supplementation. Elevated levels of liver bile acids (glycocholic acid, chenodeoxyglycocholic acid, and taurodeoxycholic acid), as well as lipids (stearic acid, palmitic acid, oleic acid, phosphatidylcholine, and lysophosphatidylethanolamine) in alcohol-treated rats were reversed by nucleotides supplementation. In addition, supplementation with nucleotides could increase the levels of amino acids, including valyl-Leucine, l-leucine, alanyl-leucine and l-phenylalanine. CONCLUSION: These data indicate potential biomarkers and confirm the benefit of dietary nucleotides on alcoholic liver injury. PMID: 27043516 [PubMed - as supplied by publisher]

Related Articles Emerging aspects of molecular biomarkers for diagnosis, prognosis and treatment response in rheumatoid arthritis. Expert Rev Mol Diagn. 2016 Apr 4; Authors: Márquez A, Martín J, Carmona FD Abstract Important advances have occurred during the last decade in the understanding of the pathogenesis of rheumatoid arthritis (RA). However, we are still far from having a clear picture of the molecular network that predisposes an individual to develop the disease, to worsen the symptoms after that, or to successfully respond to a specific treatment. In this sense, different -omics fields (including transcriptomics, proteomics, metabolomics, genomics and epigenomics) have recently produced promising insights that could definitively help us to sharpen such picture if integrated trough a systems biology approach. In this review we will summarise and discuss the recent progress achieved in those fields and its possible impact on the discovery of suitable biomarkers for RA diagnosis, prognosis and treatment response. PMID: 27043155 [PubMed - as supplied by publisher]