PubMed
Paucimannosidic glycoepitopes are functionally involved in proliferation of neural progenitor cells in the subventricular zone.
Paucimannosidic glycoepitopes are functionally involved in proliferation of neural progenitor cells in the subventricular zone.
Glycobiology. 2015 Apr 28;
Authors: Dahmen AC, Fergen MT, Laurini C, Schmitz B, Loke I, Thaysen-Andersen M, Diestel S
Abstract
Protein glycosylation has received much attention due to its multiple functional roles in physiological and pathophysiological conditions. Paucimannose is a common mannosidic N-glycoepitope in invertebrates and plants but has only recently been detected in vertebrates. Herein, we demonstrate the presence of paucimannosidic epitopes specifically in early postnatal neural progenitor cells between postnatal day 0 and 7 in mouse brain suggesting a possible role in the development of neural progenitor cells. Paucimannosidic epitopes were also detected in human glioblastoma cells and human macrophages by immunofluorescence and mass spectrometric analysis. Its expression was significantly increased after proliferation arrest indicating its importance in regulation of cell proliferation. This hypothesis was further strengthened by reduced cell proliferation after application of paucimannose-reactive Mannitou antibody into culture medium of growing cells. Most interestingly, this reduction of cell proliferation upon administration of Mannitou antibody could also be observed in vivo in the subventricular zone of early postnatal mouse brain. Taken together, these observations demonstrate that paucimannosylation directly influences cell proliferation in various vertebrate cell types including early postnatal neural stem cells.
PMID: 25922361 [PubMed - as supplied by publisher]
Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome.
Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome.
J Physiol. 2015 Apr 29;
Authors: Pereira TJ, Fonseca MA, Campbell KE, Moyce BL, Cole LK, Hatch GM, Doucette CA, Klein J, Aliani M, Dolinsky VW
Abstract
Maternal obesity is associated with a high risk for gestational diabetes mellitus (GDM), which is a common complication of pregnancy. The influence of maternal obesity and GDM on the metabolic health of the offspring is poorly understood. We hypothesize that GDM associated with maternal obesity will cause obesity, insulin resistance and hepatic steatosis in the offspring. Female Sprague-Dawley rats were fed a high-fat (45%) and sucrose (HFS) diet to cause maternal obesity and GDM. Lean control pregnant rats received low-fat (LF; 10%) diets. To investigate the interaction between the prenatal environment and postnatal diets, rat offspring were assigned to LF or HFS diets for 12 weeks and insulin sensitivity and hepatic steatosis were evaluated. Pregnant GDM dams exhibited excessive gestational weight gain, hyperinsulinemia and hyperglycemia. Offspring of GDM dams gained more weight than the offspring of lean dams due to excess adiposity. The offspring of GDM dams also developed hepatic steatosis and insulin resistance. The postnatal consumption of a LF diet did not protect offspring of GDM dams against these metabolic disorders. Analysis of the hepatic metabolome revealed increased diacylglycerol and reduced phosphatidylethanolamine in the offspring of GDM dams compared to offspring of lean dams. Consistent with altered lipid metabolism, the expression of CTP:phosphoethanolamine cytidylyltransferase, and peroxisomal proliferator activated receptor-α mRNA was reduced in the livers of GDM offspring. GDM exposure programs gene expression and hepatic metabolite levels and drives the development of hepatic steatosis and insulin resistance in young adult rat offspring. This article is protected by copyright. All rights reserved.
PMID: 25922055 [PubMed - as supplied by publisher]
The 'prime-ome': towards a holistic approach to priming.
The 'prime-ome': towards a holistic approach to priming.
Trends Plant Sci. 2015 Apr 25;
Authors: Balmer A, Pastor V, Gamir J, Flors V, Mauch-Mani B
Abstract
Plants can be primed to respond faster and more strongly to stress and multiple pathways, specific for the encountered challenge, are involved in priming. This adaptability of priming makes it difficult to pinpoint an exact mechanism: the same phenotypic observation might be the consequence of unrelated underlying events. Recently, details of the molecular aspects of establishing a primed state and its transfer to offspring have come to light. Advances in techniques for detection and quantification of elements spanning the fields of transcriptomics, proteomics, and metabolomics, together with adequate bioinformatics tools, will soon allow us to take a holistic approach to plant defence. This review highlights the state of the art of new strategies to study defence priming in plants and provides perspectives towards 'prime-omics'.
PMID: 25921921 [PubMed - as supplied by publisher]
Dynamic phosphoproteomics reveals TORC1-dependent regulation of yeast nucleotide and amino acid biosynthesis.
Dynamic phosphoproteomics reveals TORC1-dependent regulation of yeast nucleotide and amino acid biosynthesis.
Sci Signal. 2015;8(374):rs4
Authors: Oliveira AP, Ludwig C, Zampieri M, Weisser H, Aebersold R, Sauer U
Abstract
Phosphoproteomics studies have unraveled the extent of protein phosphorylation as a key cellular regulation mechanism, but assigning functionality to specific phosphorylation events remains a major challenge. TORC1 (target of rapamycin complex 1) is a kinase-containing protein complex that transduces changes in nutrient availability into phosphorylation signaling events that alter cell growth and proliferation. To resolve the temporal sequence of phosphorylation responses to nutritionally and chemically induced changes in TORC1 signaling and to identify previously unknown kinase-substrate relationships in Saccharomyces cerevisiae, we performed quantitative mass spectrometry-based phosphoproteomic analyses after shifts in nitrogen sources and rapamycin treatment. From early phosphorylation events that were consistent over at least two experimental perturbations, we identified 51 candidate and 10 known proximal targets of TORC1 that were direct substrates of TORC1 or of one of its kinase or phosphatase substrates. By correlating these phosphoproteomics data with dynamic metabolomics data, we inferred the functional role of phosphorylation on the metabolic activity of 12 enzymes, including three candidate TORC1-proximal targets: Amd1, which is involved in nucleotide metabolism; Hom3, which is involved in amino acid metabolism; and Tsl1, which mediates carbohydrate storage. Finally, we identified the TORC1 substrates Sch9 and Atg1 as candidate kinases that phosphorylate Amd1 and Hom3, respectively.
PMID: 25921291 [PubMed - in process]
Deoxycytidine-kinase (dCK) knock-down as a novel myeloprotective strategy in the context of fludarabine, cytarabine, or cladribine therapy.
Deoxycytidine-kinase (dCK) knock-down as a novel myeloprotective strategy in the context of fludarabine, cytarabine, or cladribine therapy.
Leukemia. 2015 Apr 29;
Authors: Lachmann N, Czarnecki K, Brennig S, Phaltane R, Heise M, Heinz N, Kempf H, Dilloo D, Kaever V, Schambach A, Heuser M, Moritz T
PMID: 25921248 [PubMed - as supplied by publisher]
Technical brief funrich: An open access standalone functional enrichment and interaction network analysis tool.
Technical brief funrich: An open access standalone functional enrichment and interaction network analysis tool.
Proteomics. 2015 Apr 29;
Authors: Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, Mouradov D, Sieber OM, Simpson RJ, Salim A, Bacic A, Hill A, Stroud DA, Ryan MT, Agbinya JI, Mariadasson JM, Burgess AW, Mathivanan S
Abstract
As high-throughput techniques including proteomics become more accessible to individual laboratories, there is an urgent need for a user-friendly bioinformatics analysis system. Here, we describe FunRich, an open access, standalone functional enrichment and network analysis tool. FunRich is designed to be used by biologists with minimal or no support from computational and database experts. Using FunRich, users can perform functional enrichment analysis on background databases that are integrated from heterogeneous genomic and proteomic resources (>1.5 million annotations). Besides default human specific FunRich database, users can download data from the UniProt database which currently supports 20 different taxonomies against which enrichment analysis can be performed. Moreover, the users can build their own custom databases and perform the enrichment analysis irrespective of organism. In addition to proteomics datasets, the custom database allows for the tool to be used for genomics, lipidomics and metabolomics datasets. Thus FunRich allows for complete database customization and thereby permits for the tool to be exploited as a skeleton for enrichment analysis irrespective of the data type or organism used. FunRich is user-friendly and provides graphical representation (Venn, pie charts, bar graphs, column, heatmap and doughnuts) of the data with customizable font, scale and color (publication quality) This article is protected by copyright. All rights reserved.
PMID: 25921073 [PubMed - as supplied by publisher]
[Analysis of metabolic profile of Chlamydomonas reinhardtii cultivated under autotrophic conditions].
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[Analysis of metabolic profile of Chlamydomonas reinhardtii cultivated under autotrophic conditions].
Prikl Biokhim Mikrobiol. 2015 Jan-Feb;51(1):73-85
Authors: Puzanskiĭ RK, Shavarda AL, Tarakhovskaia ER, Shishova MF
Abstract
This study presents a metabolite profile analysis of unicellular green alga Chlamydomonas reinhardtii grown under autotrophic conditions at late stages of culture development. Metabolites were identified by gas chromatography coupled to mass spectrometry. Approximately 400 peaks corresponding to individual compounds were distinguished, of which approximately 100 compounds (including saccharides, fatty acids, aromatic compounds, amino acids, alcohols, etc.) were identified. A local database of mass spectra of unidentified compounds was created using MassBank software. Mapping of the metabolomic data with the use of the ChlamyCyc service showed that the identified compounds are involved in various energetic, synthetic, and signaling pathways in Chlamydomonas. The mapping of metabolites by their chemical structure with the use of Cytoscape software, combined with quantitative interpretation, showed that the majority of organic matter was concentrated primarily in the carbon backbones of fatty acids and terpenes, as well as saccharides and structurally similar compounds.
PMID: 25842907 [PubMed - indexed for MEDLINE]
[Reactivating factor of Luteococcus japonicus subsp. casei: isolation and characterization].
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[Reactivating factor of Luteococcus japonicus subsp. casei: isolation and characterization].
Prikl Biokhim Mikrobiol. 2015 Jan-Feb;51(1):37-45
Authors: Vorob'eva LI, Rogozhin EA, Khodzhaev EIu, Nikolaev IV, Turova TP
Abstract
It has been shown that a producer strain of reactivating factor (RF) is identical to a typical strain of Luteococcus japonicus DSM 10546 from the Propionibacteriaceae family according to the physiological and biochemical properties and the sequencing of 16S rRNA fragments. A number of phenotypical differences from the model strain allowed the producer strain to be considered a subspecies of Luteococcus japonicus, and it was named Luteococcus japonicus subsp. casei. At cultivation of the producer, RF is secreted into the medium and plays the role of a signaling molecule. RF antioxidant activities towards various organic radicals may be a possible mechanism of its protective and reactivating effects. Metabolites secreted by the L. casei producer strain into the culture medium were separated by a combination of liquid chromatographies. Four components possessing biological activities were found. The most active one was studied by MALDI-TOF mass spectrometry, which revealed that it is a polypeptide. Primary identification of some amino acid residues was performed. Sugar residues were found in the structure.
PMID: 25842902 [PubMed - indexed for MEDLINE]
Metabolonote: a wiki-based database for managing hierarchical metadata of metabolome analyses.
Metabolonote: a wiki-based database for managing hierarchical metadata of metabolome analyses.
Front Bioeng Biotechnol. 2015;3:38
Authors: Ara T, Enomoto M, Arita M, Ikeda C, Kera K, Yamada M, Nishioka T, Ikeda T, Nihei Y, Shibata D, Kanaya S, Sakurai N
Abstract
Metabolomics - technology for comprehensive detection of small molecules in an organism - lags behind the other "omics" in terms of publication and dissemination of experimental data. Among the reasons for this are difficulty precisely recording information about complicated analytical experiments (metadata), existence of various databases with their own metadata descriptions, and low reusability of the published data, resulting in submitters (the researchers who generate the data) being insufficiently motivated. To tackle these issues, we developed Metabolonote, a Semantic MediaWiki-based database designed specifically for managing metabolomic metadata. We also defined a metadata and data description format, called "Togo Metabolome Data" (TogoMD), with an ID system that is required for unique access to each level of the tree-structured metadata such as study purpose, sample, analytical method, and data analysis. Separation of the management of metadata from that of data and permission to attach related information to the metadata provide advantages for submitters, readers, and database developers. The metadata are enriched with information such as links to comparable data, thereby functioning as a hub of related data resources. They also enhance not only readers' understanding and use of data but also submitters' motivation to publish the data. The metadata are computationally shared among other systems via APIs, which facilitate the construction of novel databases by database developers. A permission system that allows publication of immature metadata and feedback from readers also helps submitters to improve their metadata. Hence, this aspect of Metabolonote, as a metadata preparation tool, is complementary to high-quality and persistent data repositories such as MetaboLights. A total of 808 metadata for analyzed data obtained from 35 biological species are published currently. Metabolonote and related tools are available free of cost at http://metabolonote.kazusa.or.jp/.
PMID: 25905099 [PubMed]
Maternal hair metabolome analysis identifies a potential marker of lipid peroxidation in gestational diabetes mellitus.
Maternal hair metabolome analysis identifies a potential marker of lipid peroxidation in gestational diabetes mellitus.
Acta Diabetol. 2015 Apr 24;
Authors: He X, de Seymour JV, Sulek K, Qi H, Zhang H, Han TL, Villas-Bôas SG, Baker PN
PMID: 25904507 [PubMed - as supplied by publisher]
Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocopherol, beta-carotene cancer prevention study.
Metabolomic analysis of prostate cancer risk in a prospective cohort: The alpha-tocopherol, beta-carotene cancer prevention study.
Int J Cancer. 2015 Apr 22;
Authors: Mondul AM, Moore SC, Weinstein SJ, Karoly ED, Sampson JN, Albanes D
Abstract
Despite decades of concerted epidemiological research, relatively little is known about the etiology of prostate cancer. As genome-wide association studies have identified numerous genetic variants, so metabolomic profiling of blood and other tissues represents an agnostic, "broad-spectrum" approach for examining potential metabolic biomarkers of prostate cancer risk. To this end, we conducted a prospective analysis of prostate cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort based on 200 cases (100 advanced) and 200 controls (age- and blood collection date-matched) with fasting serum collected up to 20 years prior to case diagnoses. Ultrahigh performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy identified 626 compounds detected in >95% of the men, and the odds ratio per 1-standard deviation increase in log-metabolite levels and risk were estimated using conditional logistic regression. We observed strong inverse associations between energy and lipid metabolites and aggressive cancer (p=0.018 and p=0.041, respectively, for chemical class over-representation). Inositol-1-phosphate showed the strongest association (OR=0.56, 95% CI=0.39-0.81, p=0.002), and glycerophospholipids and fatty acids were heavily represented; e.g., oleoyl-linoleoyl-glycerophosphoinositol (OR=0.64, p=0.004), 1-stearoylglycerophosphoglycerol (OR=0.65, p=0.025), stearate (OR=0.65, p=0.010), and docosadienoate (OR=0.66, p=0.014). Both alpha-ketoglutarate and citrate were associated with aggressive disease risk (OR=0.69, 95% CI=0.51-0.94, p=0.02; OR=0.69, 95% CI=0.50-0.95, p=0.02), as were elevated thyroxine and trimethylamine oxide (TMAO) (OR=1.65, 95% CI=1.08-2.54, p=0.021; and, OR=1.36, 95% CI=1.02-1.81, p=0.039). Serum PSA adjustment did not alter the findings. Our data reveal several metabolomic leads that may have pathophysiological relevance to prostate carcinogenesis and should be examined through additional research. This article is protected by copyright. All rights reserved.
PMID: 25904191 [PubMed - as supplied by publisher]
[Serum metabolomics analysis on benign prostate hyperplasia in mice based on liquid chromatography-mass spectrometry].
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[Serum metabolomics analysis on benign prostate hyperplasia in mice based on liquid chromatography-mass spectrometry].
Se Pu. 2014 Dec;32(12):1301-5
Authors: Geng Y, Sun F, Ma Y, Deng L, Lü J, Li T, Wang C
Abstract
Benign prostatic hyperplasia (BPH) increasingly becomes a common factor affecting the quality of life of aging men. Its pathogenesis has not yet been fully elucidated. Ultra-high pressure liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was employed to detect the changes of serum metabolites in normal mice, benign prostatic hyperplasia model mice and BPH model mice with finasteride intervention. The serum metabolite profiles of the three groups of mice were analyzed. Partial least squares-discriminant analysis (PLS-DA) was used for group differentiation and biomarker selection. The results showed good distinction among the three groups of mice serum metabolite spectra. Three potential biomarkers, 1-hexadecanoyl-SN-glycero-3-phosphocholine, 1-O-hexadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine and (Z)-13-docosenamide, were discovered and identified. They all indicated the occurrence of benign prostatic hypertrophy is closely related to the disorders of lipid metabolism. Coinpared with the control group, the contents of the first two substances were significantly increased in the serum of BPH model mice, and significantly decreased after intervened by finasteride. The contents of (Z)-13-docosenamide decreased significantly in the serum of model group, and increased after intervened by finasteride. Compared with the control group, the contents of three biomarkers in finasteride group did not recover completely and had significant differences. This study is conductive to open new avenues of diagnosis and medical treatment for BPH.
PMID: 25902635 [PubMed - in process]
Metabolomics in nutrition research: biomarkers predicting mortality in children with severe acute malnutrition.
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Metabolomics in nutrition research: biomarkers predicting mortality in children with severe acute malnutrition.
Food Nutr Bull. 2015 Mar;36(1 Suppl):S88-92
Authors: Freemark M
Abstract
BACKGROUND: Millions of the world's children suffer from malnutrition, which predisposes to death from diarrhea and a variety of infectious diseases. Mortality rates among infants and toddlers remain staggeringly high, in part because the pathogenesis of acute malnutrition and its complications remains poorly understood.
OBJECTIVE: We used metabolomic analysis to characterize the metabolic status of Ugandan children with severe acute malnutrition (SAM) and to delineate changes in hormones, metabolites, growth factors, and cytokines during nutritional therapy. We hypothesized that hormonal and metabolic factors measured at presentation would associate with, or predict, subsequent mortality during treatment.
METHODS: This was a prospective cohort study of 75 severely malnourished children 6 months to 5 years of age treated as inpatients with F-75 and F-100 and supplemental micronutrients; after discharge, they received ready-to-use therapeutic food (RUTF). This increased the mean weight-for-height z-score (WHZ) from -4.27 to -1.75 SD. Blood samples were obtained at presentation, after 2 weeks of inpatient therapy, and after 4 to 10 weeks of RUTF. Plasma samples were analyzed by tandem mass spectrometry and microassays.
RESULTS: At presentation there were high levels of nonesterified fatty acids (NEFA), ketones, and even-chain acylcarnitines, indicating active lipolysis and fatty acid oxidation. In contrast, albumin, amino acids, and C3 carnitine, a by-product of branched-chain amino acids, were low. Levels of insulin, insulin-like growth factor 1 (IGF-1), adiponectin, and leptin were low, while levels of ghrelin, growth hormone, cortisol, interleukin 6 (IL-6), peptide YY (PYY), and glucagon-like peptide 1 (GLP-1) were high. The metabolic and hormonal changes were reversed by formula feeding and RUTF. Biomarkers associated with mortality included HIV, WHZ, and mid-upper-arm circumference (MUAC); the biochemical factor associated most strongly with mortality was low leptin, a marker of adipose reserve and modulator of immune function.
CONCLUSIONS: Low leptin predicts mortality in edematous and nonedematous-patients with SAM. Leptin assays might be used to identify malnourished children at highest risk for death.
PMID: 25902620 [PubMed - in process]
Omics as a window to view embryo viability.
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Omics as a window to view embryo viability.
Fertil Steril. 2015 Feb;103(2):333-41
Authors: Krisher RL, Schoolcraft WB, Katz-Jaffe MG
Abstract
The advent of advanced omics technologies and the application of these techniques to the analysis of extremely limited material have opened the door to the investigation of embryo physiology in a focused, in-depth approach never before possible. The application of noninvasive metabolomic and proteomic platforms to understanding embryo viability permits the characterization of individual embryos in culture. Initial clinical data have highlighted the promise of these technologies for the development of noninvasive embryo selection criteria. In this way, a complex view of embryo function can be compiled and related to embryo development, quality, and outcome. Application of knowledge gained from omics will transform both our understanding of embryo physiology as well as our ability to select viable embryos for transfer in assisted reproductive technology.
PMID: 25639968 [PubMed - indexed for MEDLINE]
Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health.
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Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health.
Fertil Steril. 2015 Feb;103(2):303-16
Authors: Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB
Abstract
Bidirectional somatic cell-oocyte signaling is essential to create a changing intrafollicular microenvironment that controls primordial follicle growth into a cohort of growing follicles, from which one antral follicle is selected to ovulate a healthy oocyte. Such intercellular communications allow the oocyte to determine its own fate by influencing the intrafollicular microenvironment, which in turn provides the necessary cellular functions for oocyte developmental competence, which is defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. These coordinated somatic cell-oocyte interactions attempt to balance cellular metabolism with energy requirements during folliculogenesis, including changing energy utilization during meiotic resumption. If these cellular mechanisms are perturbed by metabolic disease and/or maternal aging, molecular damage of the oocyte can alter macromolecules, induce mitochondrial mutations, and reduce adenosine triphosphate production, all of which can harm the oocyte. Recent technologies are now exploring transcriptional, translational, and post-translational events within the human follicle with the goal of identifying biomarkers that reliably predict oocyte quality in the clinical setting.
PMID: 25497448 [PubMed - indexed for MEDLINE]
Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective.
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Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective.
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16526-31
Authors: Abdulnour RE, Dalli J, Colby JK, Krishnamoorthy N, Timmons JY, Tan SH, Colas RA, Petasis NA, Serhan CN, Levy BD
Abstract
Unregulated acute inflammation can lead to collateral tissue injury in vital organs, such as the lung during the acute respiratory distress syndrome. In response to tissue injury, circulating platelet-neutrophil aggregates form to augment neutrophil tissue entry. These early cellular events in acute inflammation are pivotal to timely resolution by mechanisms that remain to be elucidated. Here, we identified a previously undescribed biosynthetic route during human platelet-neutrophil interactions for the proresolving mediator maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid). Docosahexaenoic acid was converted by platelet 12-lipoxygenase to 13S,14S-epoxy-maresin, which was further transformed by neutrophils to MaR1. In a murine model of acute respiratory distress syndrome, lipid mediator metabololipidomics uncovered MaR1 generation in vivo in a temporally regulated manner. Early MaR1 production was dependent on platelet-neutrophil interactions, and intravascular MaR1 was organ-protective, leading to decreased lung neutrophils, edema, tissue hypoxia, and prophlogistic mediators. Together, these findings identify a transcellular route for intravascular maresin 1 biosynthesis via platelet-neutrophil interactions that regulates the extent of lung inflammation.
PMID: 25369934 [PubMed - indexed for MEDLINE]
Global metabolomic analysis of human saliva and plasma from healthy and diabetic subjects, with and without periodontal disease.
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Global metabolomic analysis of human saliva and plasma from healthy and diabetic subjects, with and without periodontal disease.
PLoS One. 2014;9(8):e105181
Authors: Barnes VM, Kennedy AD, Panagakos F, Devizio W, Trivedi HM, Jönsson T, Guo L, Cervi S, Scannapieco FA
Abstract
Recent studies suggest that periodontal disease and type 2 diabetes mellitus are bi-directionally associated. Identification of a molecular signature for periodontitis using unbiased metabolic profiling could allow identification of biomarkers to assist in the diagnosis and monitoring of both diabetes and periodontal disease. This cross-sectional study identified plasma and salivary metabolic products associated with periodontitis and/or diabetes in order to discover biomarkers that may differentiate or demonstrate an interaction of these diseases. Saliva and plasma samples were analyzed from 161 diabetic and non-diabetic human subjects with a healthy periodontium, gingivitis and periodontitis. Metabolite profiling was performed using Metabolon's platform technology. A total of 772 metabolites were found in plasma and 475 in saliva. Diabetics had significantly higher levels of glucose and α-hydroxybutyrate, the established markers of diabetes, for all periodontal groups of subjects. Comparison of healthy, gingivitis and periodontitis saliva samples within the non-diabetic group confirmed findings from previous studies that included increased levels of markers of cellular energetic stress, increased purine degradation and glutathione metabolism through increased levels of oxidized glutathione and cysteine-glutathione disulfide, markers of oxidative stress, including increased purine degradation metabolites (e.g. guanosine and inosine), increased amino acid levels suggesting protein degradation, and increased ω-3 (docosapentaenoate) and ω-6 fatty acid (linoleate and arachidonate) signatures. Differences in saliva between diabetic and non-diabetic cohorts showed altered signatures of carbohydrate, lipid and oxidative stress exist in the diabetic samples. Global untargeted metabolic profiling of human saliva in diabetics replicated the metabolite signature of periodontal disease progression in non-diabetic patients and revealed unique metabolic signatures associated with periodontal disease in diabetics. The metabolites identified in this study that discriminated the periodontal groups may be useful for developing diagnostics and therapeutics tailored to the diabetic population.
PMID: 25133529 [PubMed - indexed for MEDLINE]
Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.
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Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.
PLoS One. 2014;9(8):e104157
Authors: Schechter MA, Hsieh MK, Njoroge LW, Thompson JW, Soderblom EJ, Feger BJ, Troupes CD, Hershberger KA, Ilkayeva OR, Nagel WL, Landinez GP, Shah KM, Burns VA, Santacruz L, Hirschey MD, Foster MW, Milano CA, Moseley MA, Piacentino V, Bowles DE
Abstract
The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared. Proteins extracted from left ventricular sections were proteolyzed and phosphopeptides were enriched using titanium dioxide resin. Gel- and label-free nanoscale capillary liquid chromatography coupled to high resolution accuracy mass tandem mass spectrometry allowed for the quantification of 4,436 peptides (corresponding to 450 proteins) and 823 phosphopeptides (corresponding to 400 proteins) from the unenriched and phospho-enriched fractions, respectively. Protein abundance did not distinguish NIF from IF. In contrast, 37 peptides (corresponding to 26 proteins) exhibited a ≥ 2-fold alteration in phosphorylation state (p<0.05) when comparing IF and NIF. The degree of protein phosphorylation at these 37 sites was specifically dependent upon the heart failure etiology examined. Proteins exhibiting phosphorylation alterations were grouped into functional categories: transcriptional activation/RNA processing; cytoskeleton structure/function; molecular chaperones; cell adhesion/signaling; apoptosis; and energetic/metabolism. Phosphoproteomic analysis demonstrated profound post-translational differences in proteins that are involved in multiple cellular processes between different heart failure phenotypes. Understanding the roles these phosphorylation alterations play in the development of NIF and IF has the potential to generate etiology-specific heart failure therapeutics, which could be more effective than current therapeutics in addressing the growing concern of heart failure.
PMID: 25117565 [PubMed - indexed for MEDLINE]
Dimethyl α-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy.
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Dimethyl α-ketoglutarate inhibits maladaptive autophagy in pressure overload-induced cardiomyopathy.
Autophagy. 2014 May;10(5):930-2
Authors: Mariño G, Pietrocola F, Kong Y, Eisenberg T, Hill JA, Madeo F, Kroemer G
Abstract
It has been a longstanding problem to identify specific and efficient pharmacological modulators of autophagy. Recently, we found that depletion of acetyl-coenzyme A (AcCoA) induced autophagic flux, while manipulations designed to increase cytosolic AcCoA efficiently inhibited autophagy. Thus, the cell permeant ester dimethyl α-ketoglutarate (DMKG) increased the cytosolic concentration of α-ketoglutarate, which was converted into AcCoA through a pathway relying on either of the 2 isocitrate dehydrogenase isoforms (IDH1 or IDH2), as well as on ACLY (ATP citrate lyase). DMKG inhibited autophagy in an IDH1-, IDH2- and ACLY-dependent fashion in vitro, in cultured human cells. Moreover, DMKG efficiently prevented autophagy induced by starvation in vivo, in mice. Autophagy plays a maladaptive role in the dilated cardiomyopathy induced by pressure overload, meaning that genetic inhibition of autophagy by heterozygous knockout of Becn1 suppresses the pathological remodeling of heart muscle responding to hemodynamic stress. Repeated administration of DMKG prevents autophagy in heart muscle responding to thoracic aortic constriction (TAC) and simultaneously abolishes all pathological and functional correlates of dilated cardiomyopathy: hypertrophy of cardiomyocytes, fibrosis, dilation of the left ventricle, and reduced contractile performance. These findings indicate that DMKG may be used for therapeutic autophagy inhibition.
PMID: 24675140 [PubMed - indexed for MEDLINE]
Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation.
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Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation.
Autophagy. 2014 May;10(5):750-65
Authors: Matarrese P, Garofalo T, Manganelli V, Gambardella L, Marconi M, Grasso M, Tinari A, Misasi R, Malorni W, Sorice M
Abstract
Sphingolipids are structural lipid components of cell membranes, including membrane of organelles, such as mitochondria or endoplasmic reticulum, playing a role in signal transduction as well as in the transport and intermixing of cell membranes. Sphingolipid microdomains, also called lipid rafts, participate in several metabolic and catabolic cell processes, including apoptosis. However, the defined role of lipid rafts in the autophagic flux is still unknown. In the present study we analyzed the role of gangliosides, a class of sphingolipids, in autolysosome morphogenesis in human and murine primary fibroblasts by means of biochemical and analytical cytology methods. Upon induction of autophagy, by using amino acid deprivation as well as tunicamycin, we found that GD3 ganglioside, considered as a paradigmatic raft constituent, actively contributed to the biogenesis and maturation of autophagic vacuoles. In particular, fluorescence resonance energy transfer (FRET) and coimmunoprecipitation analyses revealed that this ganglioside interacts with phosphatidylinositol 3-phosphate and can be detected in immature autophagosomes in association with LC3-II as well as in autolysosomes associated with LAMP1. Hence, it appears as a structural component of autophagic flux. Accordingly, we found that autophagy was significantly impaired by knocking down ST8SIA1/GD3 synthase (ST8 α-N-acetyl-neuraminide α-2,8-sialyltransferase 1) or by altering sphingolipid metabolism with fumonisin B1. Interestingly, exogenous administration of GD3 ganglioside was capable of reactivating the autophagic process inhibited by fumonisin B1. Altogether, these results suggest that gangliosides, via their molecular interaction with autophagy-associated molecules, could be recruited to autophagosome and contribute to morphogenic remodeling, e.g., to changes of membrane curvature and fluidity, finally leading to mature autolysosome formation.
PMID: 24589479 [PubMed - indexed for MEDLINE]