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Related Articles Mitochondrial mutations and metabolic adaptation in pancreatic cancer. Cancer Metab. 2017;5:2 Authors: Hardie RA, van Dam E, Cowley M, Han TL, Balaban S, Pajic M, Pinese M, Iconomou M, Shearer RF, McKenna J, Miller D, Waddell N, Pearson JV, Grimmond SM, Australian Pancreatic Cancer Genome Initiative, Sazanov L, Biankin AV, Villas-Boas S, Hoy AJ, Turner N, Saunders DN Abstract BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited. METHODS: We deployed an integrated approach combining genomics, metabolomics, and phenotypic analysis on a unique cohort of patient-derived pancreatic cancer cell lines (PDCLs). Genome analysis was performed via targeted sequencing of the mitochondrial genome (mtDNA) and nuclear genes encoding mitochondrial components and metabolic genes. Phenotypic characterization of PDCLs included measurement of cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a Seahorse XF extracellular flux analyser, targeted metabolomics and pathway profiling, and radiolabelled glutamine tracing. RESULTS: We identified 24 somatic mutations in the mtDNA of 12 patient-derived pancreatic cancer cell lines (PDCLs). A further 18 mutations were identified in a targeted study of ~1000 nuclear genes important for mitochondrial function and metabolism. Comparison with reference datasets indicated a strong selection bias for non-synonymous mutants with predicted functional effects. Phenotypic analysis showed metabolic changes consistent with mitochondrial dysfunction, including reduced oxygen consumption and increased glycolysis. Metabolomics and radiolabeled substrate tracing indicated the initiation of reductive glutamine metabolism and lipid synthesis in tumours. CONCLUSIONS: The heterogeneous genomic landscape of pancreatic tumours may converge on a common metabolic phenotype, with individual tumours adapting to increased anabolic demands via different genetic mechanisms. Targeting resulting metabolic phenotypes may be a productive therapeutic strategy. PMID: 28163917 [PubMed]

Related Articles Probing the metabolic phenotype of breast cancer cells by multiple tracer Stable Isotope Resolved Metabolomics. Metab Eng. 2017 Feb 02;: Authors: Lane AN, Tan J, Wang Y, Yan J, Higashi RM, Fan TW Abstract Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using (13)C6-glucose, (13)C-1+2-glucose, (13)C5,(15)N2-Gln, (13)C3-glycerol, and (13)C8-octanoate as tracers. These tracers were designed to probe the central energy producing and anabolic pathways (glycolysis, pentose phosphate pathway, Krebs Cycle, glutaminolysis, nucleotide synthesis and lipid turnover). We found that glycolysis was not associated with the rate of breast cancer cell proliferation, glutaminolysis did not support lipid synthesis in primary breast or breast cancer cells, but was a major contributor to pyrimidine ring synthesis in all cell types; anaplerotic pyruvate carboxylation was activated in breast cancer versus primary cells. We also found that glucose metabolism in individual breast cancer cell lines differed between in vitro cultures and tumor xenografts, but not the metabolic distinctions between cell lines, which may reflect the influence of tumor architecture/microenvironment. PMID: 28163219 [PubMed - as supplied by publisher]

Related Articles Metabolomics analysis of serum from subjects after occupational exposure to acrylamide using UPLC-MS. Mol Cell Endocrinol. 2017 Feb 02;: Authors: Wang SY, Yu CP, Pan YL, Zhou XR, Xin R, Wang Y, Ma WW, Gao R, Wang C, Wu YH Abstract Since occupational exposure to acrylamide (ACR) may cause nerve damage, sensitive biomarkers to evaluate the early effects of ACR on human health are needed. In the present study, we have compared a group of individuals with occupational exposure to ACR (contact group, n = 65) with a group of individuals with no exposure (non-contact group, n = 60). Serum metabolomics analysis of the contact and non-contact groups was carried out using ultra performance liquid chromatograph/time of flight mass spectrometry, combined with multivariate analysis, to identify potential metabolites. Serum biochemical indexes of the contact and non-contact groups were also determined using an automatic biochemistry analyzer. There was a clear separation between the contact group and the non-contact group; receiver operator characteristic curve analysis suggested that phytosphingosine, 4E,15Z-bilirubin IXa and tryptophan were the best metabolites to use as biomarkers. Liver function was also found to be abnormal in the contact group. Important, ACR-related, metabolic changes were seen in the contact group and new biomarkers for assessing the toxicity of ACR on the central nervous system have been proposed. This study will provide a sound basis for exploring the toxic mechanisms and metabolic pathways of ACR. PMID: 28163100 [PubMed - as supplied by publisher]

Related Articles Toxicology of the aqueous extract from the flowers of Butea monosperma Lam. and it's metabolomics in yeast cells. Food Chem Toxicol. 2017 Feb 02;: Authors: Khan W, Gupta S, Ahmad S Abstract Due to lack of scientific evidence for the safety of Butea monosperma (Fabaceae), our study aimed to carry out its toxicological profile and to identify its metabolic pattern in yeast cell. The effect of aqueous extract of B. monosperma flower on glucose uptake in yeast cell was evaluated through optimizing pH, temperature, incubation time, substrate concentration and kinetic parameters. Further, the metabolic pattern of extract as such and in yeast cell were analyzed by gas chromatography-mass spectrometry. Mice were administered aqueous extract up to 6000 and 4000 mg/kg for acute oral and intraperitoneal toxicity, respectively, while up to 4500 mg/kg for sub-acute oral toxicity (30 days). Elongation in the lag and log phase was observed in yeast cells supplemented with extract as compared to control. A maximum of 184.9% glucose uptake was observed whereas kinetic parameters (Km and Vmax) were 1.38 and 41.91 mol/s, respectively. Out of 75 metabolites found in the extract, 14 and 18 metabolites were utilized by yeast cell after 15 and 30 min of incubation, respectively. The LD50 of extract administered through intraperitoneal route was estimated to be 3500 mg/kg. The extract did not elicit any significant difference (P ≥ 0.05) in weight gain, food consumption, water intake, hematological, biochemical parameters and histological changes as compared to the normal control. Results ascertained the safety of B. monosperma flower extract which can be explored as potential candidates for the development of anti-diabetic phytopharmaceuticals. PMID: 28163055 [PubMed - as supplied by publisher]

Related Articles Proteomic analysis of red blood cells and the potential for the clinic: what have we learned so far? Expert Rev Proteomics. 2017 Feb 04;: Authors: D'Alessandro A, Zolla L Abstract INTRODUCTION: Red blood cells (RBC) are the most abundant host cells in the human body. Mature erythrocytes are devoid of nuclei and organelles and have always been regarded as circulating "bags of hemoglobin". The advent of proteomics has challenged this assumption, revealing unanticipated complexity and novel roles for RBCs not just in gas transport, but also in systemic metabolic homeostasis in health and disease. Areas covered: In this review we will summarize the main advancements in the field of discovery mode and redox/quantitative proteomics with respect to RBC biology. We thus focus on translational/clinical applications, such as transfusion medicine, hematology (e.g. hemoglobinopathies) and personalized medicine. Synergy of omics technologies - especially proteomics and metabolomics - are highlighted as a hallmark of clinical metabolomics applications for the foreseeable future. Expert commentary: The introduction of advanced proteomics technologies, especially quantitative and redox proteomics, and the integration of proteomics data with omics information gathered through orthogonal technologies (especially metabolomics) promise to revolutionize many biomedical areas, from hematology and transfusion medicine to personalized medicine and clinical biochemistry. PMID: 28162022 [PubMed - as supplied by publisher]

Related Articles Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression. Tumour Biol. 2016 Oct;37(10):13307-13322 Authors: Sridaran D, Ramamoorthi G, MahaboobKhan R, Kumpati P Abstract During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention. Graphical abstract Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment (TM), and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic cytomorphological variations, alterations in expression patterns of adhesion markers, redox homeostasis, and metabolic reprogramming that supports epithelial to mesenchymal transition and cancer progression. PMID: 27460079 [PubMed - indexed for MEDLINE]

Related Articles Lipid profiles in a large cohort of Italian children with Down syndrome. Eur J Med Genet. 2016 Aug;59(8):392-5 Authors: Buonuomo PS, Bartuli A, Mastrogiorgio G, Vittucci A, Di Camillo C, Bianchi S, Pires Marafon D, Villani A, Valentini D Abstract OBJECTIVES: Results of epidemiological studies of lipid profiles in individuals with Down Syndrome (DS) in different settings showed discordant results but laboratory norms for this population has been lacking. The aim of our study is to evaluate lipid profiles in a large population of Italian children with DS. METHODS: Lipid profiles of 357 patients with diagnosis of DS were recorded. RESULTS: Multiple linear regression was employed to estimate models for each lipid fraction as a function of sex and age in patients with DS. CONCLUSIONS: The main contribution of this paper is to provide data about lipid profile on a large cohort of people with Down syndrome. Long-term surveillance will be crucial to establish if this specific lipid profile may translate into increased morbidity and mortality from cardiovascular diseases (CVD). PMID: 27343989 [PubMed - indexed for MEDLINE]

Related Articles Regulation of the fungal secretome. Curr Genet. 2016 Aug;62(3):533-45 Authors: McCotter SW, Horianopoulos LC, Kronstad JW Abstract The ability of countless representatives of the Kingdom Fungi to adapt to and proliferate in diverse environments is facilitated by regulation of their secretomes to respond to changes in environmental conditions and to mediate interactions with other organisms. Secretome changes often fulfill common functions of nutrient acquisition, facilitation of host/symbiont interactions, cell wall modification, and optimization of the enzyme suite to adapt to new environmental resources. In this review, we expand on our recent work on signaling and the secretome in the pathogenic fungus Cryptococcus neoformans to consider a range of selected examples of regulation of fungal secretomes. These examples include the impact of carbon source and aspects of the response to plant and animal hosts. Additionally, the influence of key protein kinases (e.g., Pka1, Snf1) and transcription factors (e.g., Rim101/PacC) is highlighted to illustrate some underlying regulatory factors influencing the secretome. Although there is a wealth of information about fungal secretomes from both experimentation and genome sequence mining, there are also major gaps in our knowledge about the complete composition of fungal secretomes and mechanisms of dynamic change. For example, a more comprehensive understanding of the composition and regulation of the secretome will require consideration of the emerging roles of unconventional secretion and extracellular vesicles in delivering proteins outside the cell. Overall, changes in the secretome are well documented in diverse fungi and the underlying mechanisms are currently under investigation; however, there remain unknown steps in the regulation of secretory pathways and gaps in understanding the regulation of unconventional secretion, which warrant further research. PMID: 26879194 [PubMed - indexed for MEDLINE]

Related Articles Linking Biomarker and Comparative Omics to Pathogens in Legumes. Curr Issues Mol Biol. 2016;19:137-44 Authors: Diapari M Abstract It is envisioned that a more precise study of the association between the traits and biomarkers will dramatically decrease the time and costs required to bring new improved disease resistance lines to market. The field of omics has an enormous potential to assess diseases more precise, including the identification and understanding of pathogenic mechanisms in legume crops, and have been exemplified by a relatively large number of studies. Recently, molecular genetic studies have accumulated a huge amount of genotypic data, through a more affordable next generation sequencing (NGS) technology, causing the omics approaches to fall behind. In this paper I provide an overview of genomics and proteomics and their use in legume crops, including the use of comparative genomics to identify homologous markers within legume crops. PMID: 26364313 [PubMed - indexed for MEDLINE]

Related Articles The Power of Omics to Identify Plant Susceptibility Factors and to Study Resistance to Root-knot Nematodes. Curr Issues Mol Biol. 2016;19:53-72 Authors: Cabrera J, Barcala M, Fenoll C, Escobar C Abstract Technology has contributed to the advances on the genomic, transcriptomic, metabolomic and proteomic analyses of the plant-root-knot nematode (RKN) interaction. Holistic approaches to obtain expression profiles, such as cDNA libraries, differential display, q-PCR, microarray hybridization, massive sequencing, etc., have increased our knowledge on the molecular aspects of the interaction and have triggered the development of biotechnological tools to control this plague. An important limitation, however, has been the difficulty of cross-comparative analysis of these data. The construction of a database, NEMATIC, compiling microarray data available in Arabidopsis of the interaction with plant endoparasitic nematodes facilitated the in silico analysis, but is not sufficient for the handling of 'omic' information of different plant species. Omics combined with cell isolation techniques have shed some light on the heterogeneous expression signatures of nematode induced gall tissues, i.e., plant defences are specifically inhibited in giant cells within the gall aiding the nematode for a successful establishment. The natural resistance against RKNs varies from an early hypersensitive reaction before the establishment of the nematode, to the arrest of gall growth. The molecular bases of these mechanisms, not fully understood yet, could disclose powerful targets for the development of biotechnology based tools for nematode control. PMID: 26363962 [PubMed - indexed for MEDLINE]

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/02/06PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A Non-Targeted Liquid Chromatographic-Mass Spectrometric Metabolomics Approach for Association with Coronary Artery Disease: An Identification of Biomarkers for Depiction of Underlying Biological Mechanisms. Med Sci Monit. 2017 Feb 02;23:613-622 Authors: Zhang XZ, Zheng SX, Hou YM Abstract BACKGROUND We performed non-targeted metabolomics analysis using liquid chromatography-mass spectrometry coupled technique to explore the biological mechanism of coronary artery disease (CAD) events for improved prediction. MATERIAL AND METHODS We studied the association of CAD events in 4092 individuals and observed the replication of sphingomyelin (28:1), lysophosphatidylcholine (18:2), lysophosphatidylcholine (18:1), and monoglyceride (18:2), which were independent of main CAD risk factors. RESULTS We found that these 4 metabolites were responsible for traditional risk factors and also contributed to the modifications related to reclassification and discrimination. Monoglycerides (MonoGs) were positively associated with C-reactive proteins and body mass index, while lysophosphatidylcholines (LPPCs), which had less evidence of subclinical CAD in an additional 1010 participants, yielded a reverse pattern. An association between monoGs and CAD independence of triglycerides (triGs) were also observed. On the basis of Mendelian randomization analysis, we observed a positive but weak irregular effect (odds ratio per unit increase in standard deviation in monoG=1.11, P-value=0.05) on CAD. CONCLUSIONS Our work establishes the relationship of metabolome with coronary artery disease and explains the biological mechanism of CAD events, as we identified the above-mentioned metabolites along with the evidence supporting their clinical use. PMID: 28151921 [PubMed - in process]

Related Articles Progress in Metabolomics Standardisation and its Significance in Future Clinical Laboratory Medicine. EJIFCC. 2016 Dec;27(4):331-343 Authors: Dias DA, Koal T Abstract Today, the technology of 'targeted' based metabolomics is pivotal in the clinical analysis workflow as it provides information of metabolic phenotyping (metabotypes) by enhancing our understanding of metabolism of complex diseases, biomarker discovery for disease development, progression, treatment, and drug function and assessment. This review is focused on surveying and providing a gap analysis on metabolic phenotyping with a focus on targeted based metabolomics from an instrumental, technical point-of-view discussing the state-of-the-art instrumentation, pre- to post- analytical aspects as well as an overall future necessity for biomarker discovery and future (pre-) clinical routine application. PMID: 28149265 [PubMed - in process]

Related Articles Mixing omics: combining genetics and metabolomics to study rheumatic diseases. Nat Rev Rheumatol. 2017 Feb 02;: Authors: Menni C, Zierer J, Valdes AM, Spector TD Abstract Metabolomics is an exciting field in systems biology that provides a direct readout of the biochemical activities taking place within an individual at a particular point in time. Metabolite levels are influenced by many factors, including disease status, environment, medications, diet and, importantly, genetics. Thanks to their dynamic nature, metabolites are useful for diagnosis and prognosis, as well as for predicting and monitoring the efficacy of treatments. At the same time, the strong links between an individual's metabolic and genetic profiles enable the investigation of pathways that underlie changes in metabolite levels. Thus, for the field of metabolomics to yield its full potential, researchers need to take into account the genetic factors underlying the production of metabolites, and the potential role of these metabolites in disease processes. In this Review, the methodological aspects related to metabolomic profiling and any potential links between metabolomics and the genetics of some of the most common rheumatic diseases are described. Links between metabolomics, genetics and emerging fields such as the gut microbiome and proteomics are also discussed. PMID: 28148918 [PubMed - as supplied by publisher]

Related Articles 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. 2017 Feb 01;9(375): Authors: Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, Bindra RS Abstract 2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability. PMID: 28148839 [PubMed - in process]

Targeted Metabolomics of the Phenylpropanoid Pathway in Arabidopsis thaliana using Reversed Phase Liquid Chromatography Coupled with Tandem Mass Spectrometry. Phytochem Anal. 2017 Feb 01;: Authors: Jaini R, Wang P, Dudareva N, Chapple C, Morgan JA Abstract INTRODUCTION: The phenylpropanoid pathway is a source of a diverse group of compounds derived from phenylalanine, many of which are involved in lignin biosynthesis and serve as precursors for the production of valuable compounds, such as coumarins, flavonoids, and lignans. Consequently, recent efforts have been invested in mechanistically understanding monolignol biosynthesis, making the quantification of these metabolites vital. OBJECTIVE: To develop an improved and comprehensive analytical method for (i) extensively profiling, and (ii) accurately quantifiying intermediates of the monolignol biosynthetic network, using Arabidopsis thaliana as a model system. METHOD: A liquid chromatography-tandem mass spectrometry with electrospray ionization was developed to quantify phenylpropanoid metabolites in Arabidopsis wildtype and cinnamoyl CoA reductase1 (CCR1) deficient lines (ccr1). RESULTS: Vortexing at high temperatures (65°C) enhanced release of phenylpropanoids, specifically the more hydrophobic compounds. A pH of 5.3 and ammonium acetate buffer concentration of 2.5 mM resulted in an optimal analyte response across standards. Ion suppression was estimated using standard spike recovery studies for accurate quantitation. The optimized method was used to profile Arabidopsis wildtype and ccr1 stems. An increase in hydroxycinnamic acid derivatives and a decrease in the hydroxycinnamyl aldehydes and alcohols in ccr1 lines, supports a shift of flux from lignin synthesis to other secondary metabolites and phenylpropanoid derivatives. CONCLUSIONS: Compared to existing targeted profiling techniques, our method is capable of quantifying a wider range of intermediates (15 out of 22 in WT Arabidopsis stems) at low in vivo concentrations (~50 pmol/g-FW for certain compounds), while requiring minimal sample preparation. Copyright © 2017 John Wiley & Sons, Ltd. PMID: 28146307 [PubMed - as supplied by publisher]

Metabolomic Biomarkers in Urine of Cushing's Syndrome Patients. Int J Mol Sci. 2017 Jan 29;18(2): Authors: Kotłowska A, Puzyn T, Sworczak K, Stepnowski P, Szefer P Abstract Cushing's syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS. This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs). Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing's syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals. The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects. The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis. PMID: 28146078 [PubMed - in process]

Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes. Oncotarget. 2017 Jan 27;: Authors: Winnard PT, Zhang C, Vesuna F, Kang JW, Garry J, Dasari RR, Barman I, Raman V Abstract Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities - a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy. PMID: 28145887 [PubMed - as supplied by publisher]

Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung. Sci Rep. 2017 Feb 01;7:40555 Authors: Dautel SE, Kyle JE, Clair G, Sontag RL, Weitz KK, Shukla AK, Nguyen SN, Kim YM, Zink EM, Luders T, Frevert CW, Gharib SA, Laskin J, Carson JP, Metz TO, Corley RA, Ansong C Abstract Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylphosphatidylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murine lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 924 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. This multi-omic view provides a unique resource and deeper insight into normal pulmonary development. PMID: 28145528 [PubMed - in process]

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery. Mol Ther. 2017 Jan 28;: Authors: Fu H, Meadows AS, Ware T, Mohney RP, McCarty DM Abstract Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in α-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-month-old MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies. PMID: 28143737 [PubMed - as supplied by publisher]