Дисертації: "Metabolomics (LC-MS)"

1

Hellmuth, Christian. "LC-MS/MS applications in Targeted Clinical Metabolomics." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168254.

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2

Elmsjö, Albert. "Selectivity in NMR and LC-MS Metabolomics : The Importance of Sample Preparation and Separation, and how to Measure Selectivity in LC-MS Metabolomics." Doctoral thesis, Uppsala universitet, Avdelningen för analytisk farmaceutisk kemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-318296.

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Until now, most metabolomics protocols have been optimized towards high sample throughput and high metabolite coverage, parameters considered to be highly important for identifying influenced biological pathways and to generate as many potential biomarkers as possible. From an analytical point of view this can be troubling, as neither sample throughput nor the number of signals relates to actual quality of the detected signals/metabolites. However, a method’s selectivity for a specific signal/metabolite is often closely associated to the quality of that signal, yet this is a parameter often neglected in metabolomics. This thesis demonstrates the importance of considering selectivity when developing NMR and LC-MS metabolomics methods, and introduces a novel approach for measuring chromatographic and signal selectivity in LC-MS metabolomics. Selectivity for various sample preparations and HILIC stationary phases was compared. The choice of sample preparation affected the selectivity in both NMR and LC-MS. For the stationary phases, selectivity differences related primarily to retention differences of unwanted matrix components, e.g. inorganic salts or glycerophospholipids. Metabolites co-eluting with these matrix components often showed an incorrect quantitative signal, due to an influenced ionization efficiency and/or adduct formation. A novel approach for measuring selectivity in LC-MS metabolomics has been introduced. By dividing the intensity of each feature (a unique mass at a specific retention time) with the total intensity of the co-eluting features, a ratio representing the combined chromatographic (amount of co-elution) and signal (e.g. in-source fragmentation) selectivity is acquired. The calculated co-feature ratios have successfully been used to compare the selectivity of sample preparations and HILIC stationary phases. In conclusion, standard approaches in metabolomics research might be unwise, as each metabolomics investigation is often unique. The methods used should be adapted for the research question at hand, primarily based on any key metabolites, as well as the type of sample to be analyzed. Increased selectivity, through proper choice of analytical methods, may reduce the risks of matrix-associated effects and thereby reduce the false positive and false negative discovery rate of any metabolomics investigation.

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3

Gipson, Geoffrey T. Sokhansanj Bahrad. "Discovery Of discriminative LC-MS and 1H NMR metabolomics markers /." Philadelphia, Pa. : Drexel University, 2008. http://hdl.handle.net/1860/2766.

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4

Zhou, Bin. "Computational Analysis of LC-MS/MS Data for Metabolite Identification." Thesis, Virginia Tech, 2011. http://hdl.handle.net/10919/36109.

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Metabolomics aims at the detection and quantitation of metabolites within a biological system. As the most direct representation of phenotypic changes, metabolomics is an important component in system biology research. Recent development on high-resolution, high-accuracy mass spectrometers enables the simultaneous study of hundreds or even thousands of metabolites in one experiment. Liquid chromatography-mass spectrometry (LC-MS) is a commonly used instrument for metabolomic studies due to its high sensitivity and broad coverage of metabolome. However, the identification of metabolites remains a bottle-neck for current metabolomic studies. This thesis focuses on utilizing computational approaches to improve the accuracy and efficiency for metabolite identification in LC-MS/MS-based metabolomic studies. First, an outlier screening approach is developed to identify those LC-MS runs with low analytical quality, so they will not adversely affect the identification of metabolites. The approach is computationally simple but effective, and does not depend on any preprocessing approach. Second, an integrated computational framework is proposed and implemented to improve the accuracy of metabolite identification and prioritize the multiple putative identifications of one peak in LC-MS data. Through the framework, peaks are likely to have the m/z values that can give appropriate putative identifications. And important guidance for the metabolite verification is provided by prioritizing the putative identifications. Third, an MS/MS spectral matching algorithm is proposed based on support vector machine classification. The approach provides an improved retrieval performance in spectral matching, especially in the presence of data heterogeneity due to different instruments or experimental settings used during the MS/MS spectra acquisition.
Master of Science

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5

Ebshiana, Amera Abugiala A. "Brain metabolomics : a new comprehensive metabolic profiling approach to Alzheimer's disease pathology using LC-MS and GC-MS." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/brain-metabolomics(3abd12c5-da78-4fce-b122-bfaa48b2bb09).html.

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Alzheimer’s disease (AD) is the most common form of dementia characterized by memory loss and other cognitive abilities that worsen overtime to interfere with daily life. AD’s incidence and financial burden is rapidly increasing worldwide. Considering brain disease pathology starts 20 years before symptoms become noticeable, detecting molecules capable of precise diagnosis of disease before development of symptoms is a priority. This thesis investigates the possibility of using metabolomics to detect AD associated metabolites and to measure the abundance of a range of small molecule metabolites in human brain to examine how these metabolites are associated with severity of AD pathology and expression of symptoms. A project plan was designed to investigate brain metabolic profiling of AD samples. Initially rat brain samples were used to develop a method capable of the coverage of a wide range of metabolites using Liquid chromatography quadrupole time of flight mass spectrometry (LC- Q-TOF-MS) combining two separation techniques reversed phase (RP) and Hydrophilic liquid chromatography (HILIC). After this, gas chromatography mass spectrometry (GC-MS) analysis was employed with the aim of developing untargeted analysis and expanding the metabolome, thus identifying new and novel AD predictor metabolites to help elucidate and understand brain metabolism. Later, a brain invial dual extraction (IVDE) method was tested and applied to plasma of control and AD groups using a multimodal strategy that combines both LC-MS and GC-MS data. Finally, human brain samples from control, asymptomatic and AD patients were analysed using the developed untargeted LC&GC-MS brain IVDE method. Results revealed unsaturated fatty acids and sphingolipid metabolism to be significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.

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6

D'Urso, Gilda. "Integrated metabolomics approaches for berry fruit used in nutraceutical formulations." Doctoral thesis, Universita degli studi di Salerno, 2016. http://hdl.handle.net/10556/2225.

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2014 - 2015
The species under investigation during these three years of PhD course were: Fragaria ananassa, Fragaria vesca, Morus alba, Morus nigra and Myrtus communis. All these species are characterized by the production of small fruits, and all of them are plant species that can be used for the formulation of plant food supplements, in fact they are reported into the official list of Italian legislation (DM 9 luglio 2012- G.U. 21-7-2012, serie generale n. 169, and update on March 27, 2014). Some of them are recognized as traditional food products of Italian region, like Fragaria vesca, that is typical of Campania region and Myrtus communis, that is typical of Sardinia... [edited by author]
XIV n.s.

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7

Rhönnstad, Sofie. "Biotinylation and high affinity avidin capture as a strategy for LC-MS based metabolomics." Thesis, Linköping University, Department of Physics, Chemistry and Biology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-56771.

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Metabolites, small endogenous molecules existing in every living cell, tissue or organism, play a vital role for maintaining life. The collective group of all metabolites, the metabolome, is a consequence of the biochemistry and biochemical pathways that a cell or tissue uses to promote survival. Analysis of the metabolome can be done to reveal changes of specific metabolites which can be a manifestation, a reason or a consequence of for example a disease. The physical chemical diversity amongst these components is tremendous and it poses a large analytical challenge to measure and quantify all of them. Targeting sub groups of the metabolome such as specific functional classes has shown potential for increasing metabolite coverage. Group selective labeling with biotin-tags followed by high affinity avidin capture is a well established purification strategy for protein purification.

The purpose with this project is to explore if it is possible to transfer the avidin biotin approach to metabolomics and use this method for small molecules purification. Specifically, this investigation aims to see if it is achievable to make a biotinylation of specific functional groups, to increase the sensitivity through reduction of sample complexity in liquid chromatography mass spectrometry metabolomics analyses after high affinity avidin capture. By purifying the analyte of interest and thereby reducing the sample complexity there will be a reduction in ion suppression. The aim is to increase the analytical sensitivity through a reduction in ion suppression during liquid chromatography mass spectrometry analysis.

Delimitations have been done to only investigate the possibility to obtain a biotinylation of primary amines and amides. As model compounds phenylalanine, spermidine, histamine and nicotinamide have been selected.

The result from this study indicates that it is possible to increase metabolite coverage through biotin labeling followed by high affinity avidin capture. It is a gain in analytical sensitivity of selected model compounds when comparing biotinylation strategy with a control nonbiotinylation approach in a complex sample. A broader study of additional model compounds and a method development of this strategy are necessary to optimize a potential future method.

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8

Scherling, Christian. "Environmental Metabolomics - Metabolomische Studien zu Biodiversität, phänotypischer Plastizität und biotischen Wechselwirkungen von Pflanzen." Phd thesis, Universität Potsdam, 2009. http://opus.kobv.de/ubp/volltexte/2009/3241/.

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Ein genereller Ansatz zur Charakterisierung von biologischen Systemen bietet die Untersuchung des Metaboloms, dessen Analyse als „Metabolomics“ bezeichnet wird. “Omics”- Technologien haben das Ziel, ohne Selektionskriterien möglichst alle Bestandteile einer biologischen Probe zu detektieren (identifizieren und quantifizieren), um daraus Rückschlüsse auf nicht vorhersehbare und somit neuartige Korrelationen in biologischen Systemen zu ziehen. Ein zentrales Dogma in der Biologie besteht in der Kausalität zwischen Gen – Enzym – Metabolite. Perturbationen auf einer Ebene rufen systemische Antworten hervor, die in einem veränderten Phänotyp münden können. Metabolite sind die Endprodukte von zellulären regulatorischen Prozessen, deren Abundanz durch die Resonanz auf genetische Modifikationen oder Umwelteinflüsse zurückzuführen ist. Zudem repräsentieren Metabolite ultimativ den Phänotyp eines Organismus und haben die Fähigkeit als Biomarker zu fungieren. Die integrale Analyse verschiedenster Stoffwechselwegen wie Krebszyklus, Pentosephosphatzyklus oder Calvinzyklus offeriert die Identifikation von metabolischen Mustern. In dieser Arbeit wurden sowohl das targeted Profiling via GC-TOF-MS als auch das untargeted Profiling via GC-TOF-MS und LC-FT-MS als analytische Strategien genutzt, um biologische Systeme anhand ihrer Metabolite zu charakterisieren und um physiologische Muster als Resonanz auf endogene oder exogene Stimuli zu erkennen. Dabei standen die metabolische, phänotypische und genotypische Plastizität von Pflanzen im Fokus der Untersuchungen. Metabolische Varianzen eines Phänotyps reflektieren die genotyp-abhängige Resonanz des Organismus auf umweltbedingte Parameter (abiotischer und biotischer Stress, Entwicklung) und können mit sensitiven Metabolite Profiling Methoden determiniert werden. Diese Anwendungen haben unter anderem auch zum Begriff des „Environmental Metabolomics“ geführt. In Kapitel 2 wurde der Einfluss biotischer Interaktionen von endophytischen Bakterien auf den Metabolismus von Pappelklonen untersucht; Kapitel 3 betrachtet die metabolische Plastizität von Pflanzen im Freiland auf veränderte biotische Interaktionsmuster (Konkurrenz/Diversität/Artenzusammensetzung); Abschließend wurde in Kapitel 4 der Einfluss von spezifischen genetischen Modifikationen an Peroxisomen und den daraus resultierenden veränderten metabolischen Fluss der Photorespiration dargestellt. Aufgrund der sensitiven Analyse- Technik konnten metabolische Phänotypen, die nicht zwingend in einen morphologischen Phänotyp mündeten, in drei biologischen Systemen identifiziert und in einen stoffwechselphysiologischen Kontext gestellt werden. Die drei untersuchten biologischen Systeme – in vitro- Pappeln, Grünland- Arten (Arrhenatherion-Gesellschaft) und der Modellorganismus (Arabidopsis) – belegten anschaulich die Plastizität des Metabolismus der Arten, welche durch endogene oder exogene Faktoren erzeugt wurden.
A general approach to characterise biological systems offers the analysis of the metabolome, named “metabolomics”. “Omics”- technologies are untargeted approaches without any selection criteria which aim to detect every potential analyte in a sample in order to draw conclusions about new correlations in biological systems. A central dogma in biology is the causality between gene – enzyme – metabolite. Perturbations on one level are reflected in systemic response, which possibly result in a changed phenotype. Metabolites are end products of its gene expression and metabolism, whose abundance is determined as a resonance of genetic modifications or environmental disturbance. Furthermore metabolites represent the ultimate phenotype of an organism and are able to act as a biomarker. The integral analysis of distinct metabolic pathways like TCA, Pentose phosphate and Calvin cycle consequently leads to the identification of metabolic patterns. In this work targeted profiling via GC-TOF-MS as well as untargeted profiling via GC-TOF-MS and LC-FT-MS were used as analytical strategies to characterise biological systems on the basis of their metabolites and to identify physiological patterns as resonance of endogenic or exogenic stimuli. The focus of the investigations concentrates on the metabolic, phenotypic and genotypic plasticity of plants. Metabolic variance of a phenotype is reflected in the genotypic dependence response of an organism on environmental parameters which may be detected via sensitive metabolic profiling methods. In chapter 2 the influence of biotic interaction of endophytic bacteria on the metabolism of their poplar host was analyzed; chapter 3 explores the metabolic plasticity of field-grown grassland species as a consequence of biotic interaction pattern (competition / diversity / species composition); In conclusion, chapter 4 illustrates the influence of specific genetic modifications on peroxisomes and the consequent changed metabolic flux in the photorespiration pathway. Due to the sensitive analytic methods, metabolic phenotypes in all three biological systems could be identified and classified in a physiological context. The three biological systems – in vitro poplar plants, field-grown grassland species and the model organism Arabidopsis – demonstrate the plasticity of the metabolism of species in response to stimuli.

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9

Parmar, D. S. "High resolution mass spectrometry based quantification in metabolomics." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2018. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/4562.

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10

Ghezal, Salma. "Etude métabolomique par LC-MS/MS chez Plasmodium Falciparum, parasite responsable du Paludisme." Thesis, Montpellier 2, 2014. http://www.theses.fr/2014MON20179.

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La forme la plus sévère de paludisme est causée par le parasite unicellulaire P. falciparum. Lors de la phase intra-érythrocytaire de son développement, P. falciparum met en place des fonctions métaboliques nécessaires à son développement dans l'érythrocyte, à sa multiplication et enfin à sa dissémination vers d'autres érythrocytes. Comprendre et élucider les structures et les dynamiques du réseau métabolique chez le parasite, permettent de découvrir de nouvelles voies métaboliques et des étapes clefs qui peuvent jouer un rôle important dans le développement du parasite. Elles permettent également de déterminer le mécanisme d'action des agents antipaludiques et de mieux comprendre les résistances associées aux traitements existants. Dans cet objectif, une approche métabolomique ciblée, utilisant la chromatographie liquide couplée à la spectrométrie de masse en tandem (LC-MS/MS) a été utilisée. Cette approche consiste en une quantification absolue de métabolites impliqués dans les voies de biosynthèse des phospholipides membranaires du parasite mais également d'autres métabolites qui reflètent son statut métabolique. Nous avons dans un premier temps, déterminé les distributions et les quantités absolues des métabolites présents dans un érythrocyte infecté par P. falciparum en comparaison avec un érythrocyte sain. Nous avons également mis en évidence les perturbations causées par cette infection sur le métabolisme de l'érythrocyte humain ainsi que les différents échanges qu'entretien le parasite avec sa cellule hôte mais également avec le milieu extracellulaire. Le métabolisme phospholipidique de Plasmodium est complexe car il possède plusieurs voies de synthèses opérant à partir de précurseurs initiaux distincts et conduisant à la synthèse d'un même produit final. Dans l'objectif d'étudier la contribution relative des différentes voies métaboliques dans la biosynthèse des phospholipides majoritaires chez P. falciparum (PC et PE), nous avons développé une approche qui consiste à incuber les érythrocytes infectés en présence de précurseurs marqués
The most severe form of malaria is caused by the single-celled parasite P. falciparum. During the intra-erythrocytic stage of its development, P. falciparum implements several metabolic functions necessary for its development in the erythrocyte, its multiplication and finally to its spread to other erythrocytes. Understand and elucidate the structures and the dynamics of the parasite's metabolic network is useful to discover new metabolic pathways and key steps that may play an important role in the development of the parasite. They also help determine the mechanism of action of antimalarial agents and better understand the resistances associated with available treatments. For this purpose, a targeted metabolomics approach, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used. This approach consists of an absolute quantitation of metabolites involved in the biosynthesis of membrane phospholipids of the parasite but also other metabolites that reflect its metabolic status. We initially determined the distributions and the absolute amounts of metabolites in infected erythrocytes in comparison with healthy erythrocytes. We also highlighted the disruption caused by this infection on the metabolism of the human erythrocyte and the various interactions between the parasite and its host cell as well as the extracellular medium. The phospholipids metabolism of Plasmodium is complex because it has several synthetic pathways operating from separate initial precursor and leading to the synthesis of a single end product. With the aim to study the relative contribution of these different metabolics pathways in the biosynthesis of the most important phospholipids in P. falciparum (PC and PE), we have developed an approach that involves incubation of infected erythrocytes in the presence of labeled precursors

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11

Cain, Nicolas [Verfasser], and Markus [Akademischer Betreuer] Fischer. "Entwicklung von LC-MS-basierten Metabolomics-Applikationen für den Kakaoschalennachweis / Nicolas Cain ; Betreuer: Markus Fischer." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/1214811914/34.

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12

Kouloura, Eirini. "Phytochemical investigation of Acronychia species using NMR and LC-MS based dereplication and metabolomics approaches." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P636/document.

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Les plantes médicinales constituent une source inexhaustible de composés (des produits naturels - PN) utilisé en médecine pour la prévention et le traitement de diverses maladies. L'introduction de nouvelles technologies et méthodes dans le domaine de la chimie des produits naturels a permis le développement de méthodes ‘high throughput’ pour la détermination de la composition chimique des extraits de plantes, l'évaluation de leurs propriétés et l'exploration de leur potentiel en tant que candidats médicaments. Dernièrement, la métabolomique, une approche intégrée incorporant les avantages des technologies d'analyse moderne et la puissance de la bioinformatique s’est révélé un outil efficace dans la biologie des systèmes. En particulier, l'application de la métabolomique pour la découverte de nouveaux composés bioactifs constitue un domaine émergent dans la chimie des produits naturels. Dans ce contexte, le genre Acronychia de la famille des Rutaceae a été choisi sur la base de son usage en médecine traditionnelle pour ses propriétés antimicrobienne, antipyrétique, antispasmodique et anti-inflammatoire. Nombre de méthodes chromatographiques modernes, spectrométriques et spectroscopiques sont utilisées pour l'exploration de leur contenu en métabolites suivant trois axes principaux constituant les trois chapitres de cette thèse. En bref, le premier chapitre décrit l’étude phytochimique d’Acronychia pedunculata, l’identification des métabolites secondaires contenus dans cette espèce et l'évaluation de leurs propriétés biologiques. Le deuxième chapitre vise au développement de méthodes analytiques pour l'identification des dimères d’acétophénones (marqueurs chimiotaxonomiques du genre) et aux stratégies utilisées pour la déréplication de ces différents extraits et la caractérisation chimique des composés par UHPLC-HRMSn. Le troisième chapitre se concentre sur l'application de méthodologies métabolomique (RMN et LC-MS) pour l'analyse comparative (entre les différentes espèces, origines, organes), pour des études chimiotaxonomiques (entre les espèces) et pour la corrélation des composés contenus avec une activité pharmacologique
Medicinal plants constitute an unfailing source of compounds (natural products – NPs) utilised in medicine for the prevention and treatment of various deceases. The introduction of new technologies and methods in the field of natural products chemistry enabled the development of high throughput methodologies for the chemical composition determination of plant extracts, evaluation of their properties and the exploration of their potentials as drug candidates. Lately, metabolomics, an integrated approach incorporating the advantages of modern analytical technologies and the power of bioinformatics has been proven an efficient tool in systems biology. In particular, the application of metabolomics for the discovery of new bioactive compounds constitutes an emerging field in natural products chemistry. In this context, Acronychia genus of Rutaceae family was selected based on its well-known traditional use as antimicrobial, antipyretic, antispasmodic and anti-inflammatory therapeutic agent. Modern chromatographic, spectrometric and spectroscopic methods were utilised for the exploration of their metabolite content following three basic axes constituting the three chapters of this thesis. Briefly, the first chapter describes the phytochemical investigation of Acronychia pedunculata, the identification of secondary metabolites contained in this species and evaluation of their biological properties. The second chapter refers to the development of analytical methods for the identification of acetophenones (chemotaxonomic markers of the genus) and to the dereplication strategies for the chemical characterisation of extracts by UHPLC-HRMSn. The third chapter focuses on the application of metabolomic methodologies (LC-MS & NMR) for comparative analysis (between different species, origins, organs), chemotaxonomic studies (between species) and compound-activity correlations

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13

Näsström, Elin. "Diagnosis of acute and chronic enteric fever using metabolomics." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-140188.

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Enteric (or typhoid) fever is a systemic infection mainly caused by Salmonella Typhi and Salmonella Paratyphi A. The disease is common in areas with poor water quality and insufficient sanitation. Humans are the only reservoir for transmission of the disease. The presence of asymptomatic chronic carriers is a complicating factor for the transmission. There are major limitations regarding the current diagnostic methods both for acute infection and chronic carriage. Metabolomics is a methodology studying metabolites in biological systems under influence of environmental or physiological perturbations. It has been applied to study several infectious diseases, with the goal of detecting diagnostic biomarkers. In this thesis, a mass spectrometry-based metabolomics approach, including chemometric bioinformatics techniques for data analysis, has been used to evaluate the potential of metabolite biomarker patterns for diagnosis of enteric fever at different stages of the disease. In Paper I, metabolite patterns related to acute enteric fever were investigated. Human plasma samples from patients in Nepal with culture-confirmed S. Typhi or S. Paratyphi A infection were compared to afebrile controls. A metabolite pattern discriminating between acute enteric fever and afebrile controls, as well as between the two causative agents of enteric fever was detected. The strength of using a panel of metabolites instead of single metabolites as biomarkers was also highlighted. In Paper II, metabolite patterns for acute enteric fever, this time focusing only on S. Typhi infections, were investigated. Human plasma from patients in Bangladesh with culture-positive or -negative but clinically suspected S. Typhi infection were compared to febrile controls. Differences were found in metabolite patterns between the culture-positive S. Typhi group and the febrile controls with a heterogeneity among the suspected S. Typhi samples. Consistencies in metabolite patterns were found to the results from Paper I. In addition, a validation cohort with culture-positive S. Typhi samples and a control group including patients with malaria and infections caused by other pathogens was analysed. Differences in metabolite patterns were detected between S. Typhi samples and all controls as well as between S. Typhi and malaria. Consistencies in metabolite patterns were found to the primary Bangladeshi cohort and the Nepali cohort from Paper I. Paper III focused on chronic Salmonella carriers. Human plasma samples from patients in Nepal undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage were compared to non-carriage controls. The Salmonella carriage samples were distinguished from the non-carriage controls and differential signatures were also found between the S. Typhi and S. Paratyphi A carriage samples. Comparing metabolites found during chronic carriage and acute enteric fever (in Paper I) resulted in a panel of metabolites significant only during chronic carriage. This work has contributed to highlight the potential of using metabolomics as a tool to find diagnostic biomarker patterns associated with different stages of enteric fever.

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14

Rodrigues, Karina Trevisan. "Investigação do refluxo vésico-ureteral por abordagens metabolômicas alvo e global em urina utilizando como plataformas analíticas CE-MS, CESI-MS, RPLC-MS e HILIC-MS." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/46/46136/tde-14122017-133339/.

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O refluxo vésico-ureteral (RVU) é uma das condições urológicas comumente diagnosticada entre crianças. Altos graus dessa condição podem causar cicatrização renal, insuficiência renal e hipertensão arterial. A uretrocistografia miccional é o método mais comumente utilizado para o diagnóstico, no entanto, esse procedimento envolve sedação, cateterismo vesical e expõe a criança a uma quantidade significativa de radiação. A investigação metabolômica pode fornecer novos entendimentos sobre a doença e visa a descoberta de metabólitos específicos associados a ela. Assim, existe um potencial considerável para a implementação de perfil metabólico em análises clínicas. Dessa forma, buscou-se estabelecer uma alternativa não invasiva para identificar crianças com o RVU através da metabolômica. Para a investigação metabolômica alvo um método por eletroforese capilar acoplada ao espectrômetro de massas (CE-MS) com analisador to tipo ion trap foi desenvolvido e validado para a determinação de 27 aminoácidos em urina. Os parâmetros experimentais relacionados às configurações da interface CE-MS, eletrólito (BGE) e espectrômetro de de massas (MS) foram otimizados, proporcionando uma boa separação dos 27 aminoácidos, incluindo os isômeros L-leucina, L-isoleucina e L-alloisoleucina, em menos de 30 min. O líquido auxiliar (SHL) foi composto de 0,5% (v/v) ácido fórmico em 60% (v/v) água/metanol à uma vazão de 5 µL min-1. O BGE consistiu de 0,80 mol L-1 de ácido fórmico e 15% (v/v) de metanol. Um procedimento de stacking por pH foi implementado para aumentar a detectabilidade (uma solução de NH4OH a 12,5% (v/v) foi injetada a 0,5 psi/9 s antes das amostras). O método foi validado de acordo com os protocolos FDA e ICH, exibindo parâmetros aceitáveis. A quantificação bem sucedida dos aminoácidos em amostras de urina de um estudo piloto do RVU foi alcançada. A avaliação estatística dos resultados mostrou que alguns dos aminoácidos avaliados podem carregar informações que possibilitam discriminar as amostras de urina entre os grupos teste e controle. Para a análise metabolômica global urinária, métodos por RPLC-MS e HILIC-MS foram otimizados. Cinco colunas com diferentes propriedades foram investigadas para RPLC e quatro colunas para HILIC; adicionalmente, foram investigados a influência dos aditivos e pH da fase móvel. As condições ótimas foram determinadas avaliando o formato de pico, a relação sinal-ruído, o tempo de retenção, o número de molecular features detectados e sua distribuição durante o gradiente de eluição. A melhor condição obtida para RPLC utiliza a coluna CSH C18 e fase móvel composta por 0,1% (v/v) ácido fórmico em água (A) e 0,1% (v/v) ácido fórmico em acetonitrila (B). Para HILIC, o melhor desempenho foi obtido com a coluna zwitteriônica ZIC-HILIC e fase móvel composta por 10 mmol L-1 acetato de amônio pH 6,8 (B) e 95% (v/v) acetonitrila e 5% 200 mmol L-1 acetato de amônio pH 6,8 (A). As amostras de urina dos grupos controle e teste foram submetidas à análise metabolômica global por RPLC-MS usando o método otimizado e por CESI-MS. Os resultados indicaram que diversas rotas metabólicas podem ter sido alteradas pelo RVU. Alteração dos níveis de carnitinas e acilcarnitinas, aminoácidos e derivados, purinas e outros foi observada. Ainda, a presença de acilcarnitinas na urina podem indicar danos mitocondriais e a diminuição de triptofano e aumento do ácido quinurênico indicam uma alteração no metabolismo do triptofano.
Vesicoureteral reflux (VUR) is one of the most commonly urologic conditions diagnosed among children. A high degree of this condition can cause kidney scarring, kidney failure and high blood pressure. Voiding cystourethrography is the standard method for diagnosis; however, this procedure involves sedation, bladder catheterization and exposes the child to a significant amount of radiation. Metabolomics has provided new insights about the disease and aims to discover specific metabolites associated with it. Thus, there is a considerable potential for the implementation of metabolic profile in clinical analyses. Thus, we attempted to establish a noninvasive alternative to identify children with VUR through metabolomics approach. For target metabolomics, a CE-MS method was developed and validated for the separation and quantitative analysis of 27 amino acids in urine. Experimental parameters related to the CE-MS interface (based on co-axial sheath liquid, SHL), background electrolyte (BGE) and mass spectrometer (MS) settings were optimized providing a good separation of 27 amino acids, including the isomers L-leucine, L-isoleucine and L-alloisoleucine, in less than 30 min. The SHL was composed of 0.50% (v/v) formic acid in 60% (v/v) methanol-water delivered at a flow rate of 5 µL min-1. The BGE consisted of 0.80 mol L-1 formic acid and 15% (v/v) methanol. A pH stacking procedure was implemented to enhance sensitivity (a 12.5% (v/v) NH4OH solution was injected at 0.5 psi/9 s prior to samples). The proposed method was thoroughly validated according to FDA and ICH protocols exhibiting acceptable parameters. A successful quantification of amino acids in urine samples from the VUR cohort was achieved. The statistical evaluation of the results showed that some of the amino acids may carry information for the discrimination of the urine samples between the test and control groups. For untargeted metabolomics analysis, methods by RPLC-MS and HILIC-MS were optimized. Five columns with different properties were investigated for RPLC and four columns for HILIC; additionally, the influence of additives and pH of the mobile phase were investigated. The optimum conditions were determined assessing the peak shape, signal-to-noise ratio, retention time, number of molecular features detected and their distribution during the elution gradient. The best condition obtained for RPLC uses CSH C18 column and mobile phase composed by 0.1% (v/v) formic acid in water (A) and 0.1% (v/v) formic acid in acetonitrile (B). For HILIC, the best performance was obtained with the zwitterionic ZIC-HILIC column and mobile phase composed by 10 mmol L-1 ammonium acetate pH 6.8 (B) and 95% (v/v) acetonitrile and 5% (v/v) 200 mmol L-1 ammonium acetate pH 6.8 (A). Urine samples from the control and test groups were submitted to global metabolomics analysis by RPLC-MS using the optimized method and by CESI-MS. The results indicated that several metabolic pathways may have been altered by VUR. Changes of carnitine and acylcarnitine levels, amino acids and derivatives, purines and others was observed. Furthermore, the presence of acylcarnitines in the urine may indicate mitochondrial damage and the decrease of tryptophan and increase of the kynurenic acid indicate a change in the metabolism of tryptophan.

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15

Knee, Jose. "Determining the metabolic profiles in Drosophila melanogaster: Development and application of a novel ion-pairing liquid chromatography-mass spectrometry protocol." Thesis, Laurentian University of Sudbury, 2014. https://zone.biblio.laurentian.ca/dspace/handle/10219/2138.

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Genetic perturbations and foreign chemicals can result in a multitude of changes across a wide range of biochemical processes in a biological system. These perturbations may affect the metabolome, the small molecule metabolites in an organism. Recently, liquid-chromatography coupled to mass spectrometry (LC-MS) technology has been used to quantify large proportions of the metabolome, however standardized protocols are not yet available for use with Drosophila melanogaster. Here, I developed an ion-pairing LC-MS protocol for the metabolomic characterization of D. melanogaster and demonstrated its implementation in establishing the metabolomic profile of flies under oxidative stress and in the metabolic profiles of four different Drosophila species. I demonstrated that this new method allows for the detection of otherwise difficult metabolites and that it is repeatable and sensitive with acceptable levels of ionsuppression, matrix effects, limits of detection and quantification. I then used this method to determine and quantify the metabolomic fingerprints of loss of Superoxide dismutase activity and paraquat-induced stress. Comparing and contrasting the effects of these two sources of oxidative stress, I document both similarities and stressor-specific effects.

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16

Kölfeldt, Niklas. "Development and evaluation of sample preparation procedure for human plasma samples in LC/MS-based metabolomics." Thesis, Uppsala universitet, Avdelningen för analytisk farmaceutisk kemi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-242982.

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The aim of this master thesis project was to develop methods for sample preparation and analysis by LC-MS suitable for global metabolomics of human plasma samples. In this thesis six different methods was tested, based on precipitation, solid phase extraction (SPE), and ultrafiltration. The methods differ in their mechanisms of action, but the end goal is the same, to remove the proteins and other high molecular weight compounds from the samples and to retain as many metabolites as possible in a reproducible manner. The LC-MS analysis were performed on a C18 and a HILIC type column using electrospray ionization (ESI) with both positive and negative ionization to cover as much of the metabolome as possible. The MarkerLynx software was then used to extract features from the chromatograms. The coefficient of variation (CV) was calculated and the features with CV > 30 % were removed. The features were then used to compare the methods with each other in order to see whether any of the methods yielded the same capture of features. The largest amount of features was detected for precipitation with MeOH when using a C18 type column. For HILIC type columns precipitation with MeOH with a small addition of H3PO4 resulted in most unique features detected. The ionization mode was found to be less important, compared whit the choice of column, but more features was detected using positive mode than negative mode.

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17

Ohtani, Yuta. "Molecular breeding of functional spinaches rich in folate and betacyanin based on metabolome analysis." Kyoto University, 2020. http://hdl.handle.net/2433/253323.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第22487号
農博第2391号
新制||農||1076(附属図書館)
学位論文||R2||N5267(農学部図書室)
京都大学大学院農学研究科応用生命科学専攻
(主査)教授植田充美, 教授梅澤俊明, 教授栗原達夫
学位規則第4条第1項該当

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18

Anlind, Alice. "Improvments and evaluation of data processing in LC-MS metabolomics : for application in in vitro systems pharmacology." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-329971.

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The resistance of established medicines is rapidly increasing while the rate of discovery of new drugs and treatments have not increases during the last decades (Spiro et al. 2008). Systems pharmacology can be used to find new combinations or concentrations of established drugs to find new treatments faster (Borisy et al. 2003). A recent study aimed to use high resolution Liquid chromatography–mass spectrometry (LC-MS) for in vitro systems pharmacology, but encountered problems with unwanted variability and batch effects(Herman et al. 2017). This thesis builds on this work by improving the pipeline and comparing alternative methods and evaluating used methods. The evaluation of methods indicated that the data quality was often not improved substantially by complex methods and pipelines. Instead simpler methods such as binning for feature extraction performed best. In-fact many of the preprocessing method commonly used proved to have negative or neglect-able effects on resulting data quality. Finally the recently introduced Optimal Orthonormal System for Discriminant Analysis (OOS-DA) for batch removal was found to be a good alternative to the more complex Combat method.

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19

Kameda, Masahiro. "Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility." Kyoto University, 2020. http://hdl.handle.net/2433/259000.

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20

Trammell, Samuel A. J. "Novel NAD+ metabolomic technologies and their applications to Nicotinamide Riboside interventions." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3203.

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Nicotinamide adenine dinucleotide (NAD+) is a cofactor in hydride transfer reactions and consumed substrate of several classes of glycohydrolyitc enzymes, including sirtuins. NAD+, its biosynthetic intermediates, breakdown products, and related nucleotides (the NAD metabolome) is altered in many metabolic disorders, such as aging and obesity. Supplementation with the novel NAD+ precursor, nicotinamide riboside (NR), ameliorates these alterations and opposes systemic metabolic dysfunctions in rodent models. Based on the hypothesis that perturbations of the NAD metabolome are both a symptom and cause of metabolic disease, accurate assessment of the abundance of these metabolites is expected to provide insight into the biology of diseases and the mechanism of action of NR in promoting metabolic health. Current quantitative methods, such as HPLC, lack specificity and sensitivity to detect distinct alterations to the NAD metabolome. In this thesis, I developed novel sensitive, accurate, robust liquid chromatography mass spectrometry methodologies to quantify the NAD metabolome and applied these methods to determine the effects of disease states and NR supplementation on NAD+ metabolism. My investigations indicate that NR robustly increases the NAD metabolome, especially NAD+ in a manner kinetically different than any other NAD+ precursor. I provide the first evidence of effective NAD+ supplementation from NR in a healthy, 52 year old human male, suggesting the metabolic promoting qualities of NR uncovered in rodent studies are translatable to humans. During my investigation of NR supplementation, my work establishes an unexpected robust, dramatic increase in deamino–NAD+, NAAD, directly from NR, which I argue could serve as an accessible biomarker for efficacious NAD+ supplementation and the effect of disease upon the NAD metabolome. Lastly, I further establish NR as a general therapeutic against metabolic disorder by detailing its ability to oppose aspects of chronic alcoholism and diabetes mellitus.

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21

Olivon, Florent. "Nouvelle stratégie de priorisation pour l’étude des produits naturels par l’approche des réseaux moléculaires multi-informatifs." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS383.

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Cette thèse initie et développe un programme ayant pour but de définir une stratégie de priorisation efficace pour accélérer la découverte de molécules bioactives au sein d’extraits végétaux. Dans le cadre de ce projet, plusieurs criblages biologiques ont été menés sur une collection de 292 extraits d'Euphorbiaceae.Afin d’identifier et cibler au sein de ces mélanges complexes les structures d’intérêt biologique tout en écartant les molécules connues ou présentant un intérêt structural limité, les profils métabolomiques des extraits ont été acquis par spectrométrie de masse tandem. Pour exploiter au mieux la quantité d'information générée par ces analyses, les spectres MS2 ont ensuite été organisés sous forme de réseaux moléculaires. Ces réseaux permettent de lier les ions détectés en fonction de la similarité de leurs voies de fragmentation et donc de leur proximité structurale. Les informations taxonomiques et d’activités biologiques ont été croisées avec les données spectrales au sein de cette carte moléculaire multi-informative, offrant ainsi une approche nouvelle pour accélérer la découverte de nouveaux ligands des cibles biologiques étudiées et pour une sélection plus pertinente des extraits à forte diversité structurale.Si l’outil des réseaux moléculaires représente une méthode innovante et particulièrement instructive pour le phytochimiste, il présente cependant quelques défauts qui limitent son spectre d'utilisation et ses capacités en métabolomique. Une deuxième partie de cette thèse a donc été consacrée à l’implémentation d’une étape de prétraitement pour améliorer la fiabilité des réseaux et au développement de MetGem, un logiciel dédié à la génération de réseaux moléculaires permettant d’optimiser la gestion et l’analyse des matrices de scores de similarité spectrale
This thesis initiates and develops a program seeking to accelerate the discovery of new therapeutic molecules using an efficient prioritization strategy. As part of this project, a collection of 292 Euphorbiaceae extracts was screened over several biological targets.To focus on unknown bioactive chemicals and to avoid the isolation of known or inactive molecules, the acquisition of high resolution tandem mass spectrometry profiles of these extracts was performed. To highlight relevant information within these data, MS2 spectra were organized as molecular networks. It consists in visualizing tandem mass spectrometry data by detecting related MS2 spectra and representing them in a same spectral space. Taxonomical details and bioassay screening results were merged with the network visualization to generate a comprehensive multi-informative molecular map, which offers a radically novel outlook to target novel bioactive scaffolds and select extracts with high structural diversity. Although very instructive for the phytochemist, the molecular networking tool has some imperfections that limit its potential in metabolomics. Therefore, the second part of this thesis was dedicated to the introduction of a data preprocessing step to enhance the networks reliability and to the development of MetGem, a software dedicated to the generation of molecular networks to improve the way matrices of similarity scores are managed and analyzed

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22

Karimpour, Masoumeh. "Multi-platform metabolomics assays to study the responsiveness of the human plasma and lung lavage metabolome." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-120591.

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Metabolomics as a field has been used to track changes and perturbations in the human body by investigating metabolite profiles indicating the change of metabolite levels over time and in response to different challenges. In this thesis work, the main focus was on applying multiplatform-metabolomics to study the human metabolome following exposure to perturbations, such as diet (in the form of a challenge meal) and exhaust emissions (air pollution exposure in a controlled setting). The cutting-edge analytical platforms used for this purpose were nuclear magnetic resonance (NMR), as well as gas chromatography (GC) and liquid chromatography (LC) coupled to mass spectrometry (MS). Each platform offered unique characterization features, allowing detection and identification of a specific range of metabolites. The use of multiplatform-metabolomics was found to enhance the metabolome coverage and to provide complementary findings that enabled a better understanding of the biochemical processes reflected by the metabolite profiles. Using non-targeted analysis, a wide range of unknown metabolites in plasma were identified during the postprandial stage after a well-defined challenge meal (in Paper I). In addition, a considerable number of metabolites were detected and identified in lung lavage fluid after biodiesel exhaust exposure compared to filtered air exposure (in Paper II). In parallel, using targeted analysis, both lung lavage and plasma fatty acid metabolites were detected and quantified in response to filtered air and biodiesel exhaust exposure (in Paper III and IV). Data processing of raw data followed by data analysis, using both univariate and multivariate methods, enabled changes occurring in metabolites levels to be screened and investigated. For the initial pilot postprandial study, the aim was to investigate the plasma metabolome response after a well-defined meal during the postprandial stage for two types of diet. It was found that independent of the background diet type, levels of metabolites returned to their baseline levels after three hours. This finding was taken into consideration for the biodiesel exhaust exposures studies, designed to limit the impact of dietary effects. Both targeted and non-targeted approaches resulted in important findings. For instance, different metabolite profiles were detected in bronchial wash (BW) compared to bronchoalveolar lavage (BAL) fluid with mainly NMR and LC-MS. Furthermore, biodiesel exhaust exposure resulted in different metabolite profiles as observed by GC-MS, especially in BAL. In addition, fatty acid metabolites in BW, BAL, and plasma were shown to be responsive to biodiesel exhaust exposure, as measured by a targeted LC-MS/MS protocol. In summary, the new analytical methods developed to investigate the responsiveness of the human plasma and lung lavage metabolome proved to be useful in an analytical perspective, and provided important biological findings. However, further studies are needed to validate these results.
Metabolomik har använts för att spåra förändringar och störningar i kroppens funktioner genom undersökning av metabolit-profiler. I detta avhandlingasarbete har huvudfokus varit på tillämpning av flera olika analytiska plattformar för metabolomikstudier av det mänskliga metabolomet efter exponering för olika kost och avgasutsläpp från biodieselbränsle. De sofistikerade analytiska plattformarna som användes för detta ändamål var kärnmagnetisk resonans (NMR), samt gaskromatografi (GC) och vätskekromatografi (LC) kopplat till masspektrometri (MS). Varje plattform erbjöd unika karakteriseringsmöjligheter med detektion och identifiering av specifika grupper av metaboliter. Användningen av multipattformmetabolomik förbättrade täckningen av metabolomet och genererade kompletterande resultat som möjliggjorde en bättre förståelse av de biokemiska processer som reflekteras av metabolitprofilerna. Med hjälp av breda analyser har ett stort antal okända metaboliter i plasma identifierats under den postprandial fasen efter en väldefinerad måltid (i Paper I). Dessutom har ett stort antal metaboliter påvisats och identifierats i lungsköljvätska efter exponering av biodieselavgaser jämfört med kontollexponering med filtrerad luft (i Paper II). Parallellt med dessa breda analyser har också riktade analyser genomförts av både lungsköljvätska och plasma. Därigenom har bioaktiva lipider detekterats och kvantifieras efter avgasexponering och resultaten har jämförts med filtrerad luft som kontrollexponering (Paper III och IV). Processning av rådata följt av dataanalys, med både univariata och multivariata metoder möjliggjorde screening och fördjupad undersökning av förändringen i metabolitnivåer. I den första pilotstudien av postprandiala nivåer var syftet att undersöka responsen i plasmametabolomet efter en väldefinierad måltid under den postprandiala fasen vid två olika typer av kost. Resultaten visade att oberoende av kosten, så återvände metabolitnivåerna till sina baslinjenivåer tre timmar efter måltiden. Detta togs i beaktande vid exponeringsstudierna för biodieselavgaser, som designades så att dietens inverkan minimerades. Både breda och riktade analyser resulterade i viktiga resultat. Exempelvis så detekterades olika metabolitprofiler i bronkiell sköljvätska (BW) jämfört med bronkoalveolär sköljvätska (BAL), speciellt med NMR och LC-MS. Dessutom resulterade avgasexponering i förändrade metabolitprofiler, observerade med GC-MS, särskilt i BAL. Dessutom uppvisade fettsyrametaboliter i BW, BAL och plasma förändrade halter efter avgasexponering, uppmätt genom en riktad LC-MS/MS-analys. Sammanfattningsvis så visade sig de nya metoderna som utvecklats för att undersöka förändringar i metabolithalterna i plasma och lungsköljvätska fungera väl ur ett analytiskt perspektiv och resulterade i viktiga biologiska fynd. Fördjupade studier behövs dock för att validera resultaten.

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Godinho, Camila Capel. "Análise metabolômica da bioatividade em vias COX e LOX-dependentes de plantas da subtribo Lychnophorinae." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-03102016-143050/.

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Muitas substâncias das espécies de Lychnophorinae (Asteraceae) são relatadas como inibidoras da síntese de mediadores da cascata do processo inflamatório. Nesse processo, duas enzimas são essenciais e atuam no metabolismo do ácido araquidônico, formado em processos inflamatórios: ciclooxigenase (COX) e lipoxigenase (LOX). A análise de impressões digitais metabólicas é um método capaz de fornecer informações sobre o objeto de estudo através da utilização de ferramentas estatísticas, além de possibilitar a correlação desses dados com outros utilizando métodos in silico. O objetivo deste estudo foi analisar 26 espécies da subtribo Lychnophorinae quanto à atividade inibitória in vitro das vias COX- e LOX-dependentes e identificar as substâncias responsáveis por essa atividade através de análises in silico de correlação entre bioatividade e impressão digital metabólica. As impressões digitais metabólicas dos extratos hidrometanólicos das espécies de Lychnophorinae foram obtidas utilizando UHPLC-UV-(DAD)-MS (OrbitrapTM). Os ensaios de triagem de inibição das vias COX-1 e 5-LOX-dependentes revelaram que 20 espécies possuem atividade inibitória dupla para ambas as vias com valores de IC50 menores que 100 ?g.mL-1. Dentre essas, 11 espécies apresentaram valores de IC50 menores que 40 ?g.mL-1, e cinco apresentaram valores de IC50 menores que 10 ?g.mL-1. Utilizando-se as impressões digitais metabólicas e os resultados de inibição enzimática foram realizadas análises estatísticas multivariadas supervisionadas e não supervisionadas (PCA, PLS e OPLS) visando à identificação de substâncias discriminantes (ativas). Através das análises de correlação, obtiveram-se as prováveis substâncias que detém o potencial inibitório. As cinco substâncias com maior potencial discriminante foram identificadas por técnicas de desreplicação e são: a lactona sesquiterpênica (4,5-diidro-15-desoxigoyazensolido), dois flavonóides glicosilados (3-O-(acetil-hexosídeo)-quercetina e 7-O-(cumaroil-hexosídeo)-apigenina), e um hidroxinerolidol. Assim, este estudo revelou o ótimo potencial inibidor das enzimas COX-1 e 5-LOX dos extratos hidrometanólicos das espécies de Lychnophorinae. Além disso, indicou as substâncias mais discriminantes responsáveis por essa atividade, sendo as substâncias acima mencionadas as propostas como as principais responsáveis pela atividade inibidora das enzimas COX e LOX
Several compounds from Lychnophorinae species (Asteraceae) are reported as inhibitors of cascade mediators that elicits the inflammatory process. During this process, two enzymes are essential in the metabolism of the arachidonic acid: cyclooxygenase (COX) and lipoxygenase (LOX). The analysis of metabolic fingerprinting is a method that provides information about the object of study by using statistical tools, and enables the correlation of these data with others using in silico methods. This work therefore aimed to analyze 26 species of the Lychnophorinae subtribe for in vitro inhibition of COX-1 and 5-LOX and (to) identify the bioactive compounds responsible for this activity by in silico correlation analysis between bioactivity and metabolic fingerprint. The metabolomic analysis was carried out using UHPLC-DAD-ESI-Orbitrap and a metabolic fingerprint for each extract was obtained. The in vitro inhibition screening assays of COX-1 and 5-LOX revealed that 20 extracts presented dual inhibitory activity on both enzymes with IC50 values lower than 100 ?g.mL-1. Among them, 11 species showed IC50 values lower than 40 ?g.mL-1 and five lower than 10 ?g.mL-1. In order to identify discriminant substances (active), supervised and non-supervised multivariate statistical analysis (PCA, PLS e OPLS) were performed using the metabolic fingerprints and the results of enzyme inhibition. Through correlation analysis, it was possible to locate the substances most likely to be responsible for the pharmacological activity in both enzymes simultaneously; among them, five were chosen as the most likely. The substances were identified by dereplication as: a sesquiterpene lactone (4,5-dihydro-15-desoxygoyazensolide), two flavonoids (3-O-(acetil-hexoside)-quercetin and 7-O-(cumaroil-hexoside)-apigenine), and a hidroxynerolidol. In summary, in this work it was possible to reveal crude extracts with outstanding inhibitory potential of both, COX-1 and 5-LOX, enzymes as well as to propose the most probable compounds responsible for this action, and the compounds mentioned above were proposed as the main responsible for the inhibitory activity.

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Klockmann, Sven [Verfasser], and Markus [Akademischer Betreuer] Fischer. "Entwicklung von LC-MS-basierten Metabolomics-Applikationen zur Bestimmung der geographischen Herkunft von Haselnüssen (Corylus avellana) / Sven Klockmann ; Betreuer: Markus Fischer." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://d-nb.info/1150401540/34.

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Klockmann, Sven Verfasser], and Markus [Akademischer Betreuer] [Fischer. "Entwicklung von LC-MS-basierten Metabolomics-Applikationen zur Bestimmung der geographischen Herkunft von Haselnüssen (Corylus avellana) / Sven Klockmann ; Betreuer: Markus Fischer." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2018. http://nbn-resolving.de/urn:nbn:de:gbv:18-89011.

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Browder, Andrew Blake Austin. "Quantitated Effects of Nutritional Supplementation on Exercise Induced Sweat." Wright State University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=wright1616769068342984.

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Martucci, Maria Elvira Poleti. "Metabolômica e screening de interações ecoquímicas de plantas da subtribo Lychnophorinae (Asteraceae)." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-02052016-114731/.

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A subtribo Lychnophorinae ocorre na região do Cerrado do Brasil e contém cerca de 120 espécies. Recentemente, a filogenia da subtribo Lychnophorinae, baseada em sequências de DNA e dados morfológicos foi capaz de fornecer novas informações sobre a subtribo e seus gêneros. Além disso, o Cerrado brasileiro possivelmente abriga uma parcela considerável da entomofauna neotropical. Os objetivos gerais deste projeto de pesquisa são obter perfis metabólicos de plantas da subtribo Lychnophorinae e utilizá-los como ferramenta quimiotaxonômica para auxiliar na resolução da classificação taxonômica dessa subtribo e ainda, obter perfis metabólicos de insetos que se alimentem dessas plantas, visando a identificação de possíveis interações inseto-planta. Foram analisadas 78 espécies de plantas por GC-MS e UHPLC-UV(DAD)-MS(ESI-Orbitrap) nos modos positivo e negativo de ionização. As coletas de insetos foram feitas em intervalos trimestrais e, em seguida, esses insetos foram analisados utilizando a mesma metodologia analítica das plantas. As \"impressões digitais\" metabólicas das plantas e dos insetos foram precessadas no MetAlignTM e no MSClust, e as matrizes geradas foram submetidas a análises multivariadas no SIMCA. As plantas foram submetidas a análise de componentes principais (PCA), análise de cluster hierárquico (HCA) e análise discriminante ortogonal por mínimos quadrados parciais (OPLS-DA), entretanto os insetos, juntamente com suas plantas hospedeiras, foram analisados por PCA com o intuito de determinar a correlação entre seus metabólitos secundários. Os resultados das análises metabolômicas apresentaram proximidade com a filogenia principalmente para os dois maiors gêneros, Eremanthus e Lychnophora, analisados separadamente. Portanto, os resultados sugerem que os dados gerados a partir das análises metabolômicas podem ser utilizados em estudos quimiotaxonômicos da subtribo Lychnophorinae, sobretudo como dados primários para a reconstrução filogenética de gêneros. No que diz respeito às análises de possíveis interações inseto-planta, foi possível observar que alguns espécimens apresentaram correlação significativa com as plantas hospedeiras, evidenciando que a abordagem metabolômica pode ser utilizada como ferramenta na investigação de interações inseto-planta. Nestas amostras, pôde-se observar a presença de triterpenos, flavonoides e lactonas sesquiterpênicas adquiridas nas plantas por meio da herbivoria.
The subtribe Lychnophorinae occurs in the Cerrado domain of the Brazilian Central Plateau. The relationships among its recognized genera, as well as the relationships between Lychnophorinae and other subtribes belonging in tribe Vernonieae have been recently investigated upon a phylogeny based on molecular and morphological data. In addition, a preliminar overview of insect diversity in Brazilian Cerrado suggests that it may harbor a considerable fraction of the neotropical. We here report the use of a comprehensive untargeted metabolomics approach, combining LC-MS and GC-MS data together, followed by multivariate analyses aiming to assess the congruence between metabolomics data and the phylogenetic hypothesis, as well as its potential as a chemotaxonomic tool. Also we report the use of untargeted metabolomics approach aiming to assess insect-plant interactions. We analyzed 78 species by GC-MS and LC-MS in both positive and negative ionization modes. The metabolic profiles obtained for these species were treated in MetAlign and in MSClust and the matrices generated were combined and used in SIMCA for hierarchical cluster analyses (HCA), principal component analyses (PCA) and orthogonal partial least square discriminant analysis (OPLS-DA). The insects were collected quarterly and analyzed by the same analytical methods as plants. Results show that metabolomics analyses are mostly congruent with the phylogenetic hypothesis especially at lower taxonomic levels. Therefore, our results suggest that data generated by metabolomics approaches provide valuable evidence for chemotaxonomical studies of Lychnophorinae subtribe, in particular as primary data for phylogenetic reconstruction of lineages as genera. Regarding to insects, it was possible to observe significative correlations between some insects and their host plants. In these samples, were able to identify triterpenes, flavonoids and sesquiterpene lactones.

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Hellmuth, Christian [Verfasser], and Berthold [Akademischer Betreuer] Koletzko. "LC-MS/MS applications in Targeted Clinical Metabolomics : method development and validation with focus on sulphur-containing amino acids and nonesterified fatty acids / Christian Hellmuth. Betreuer: Berthold Koletzko." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1049891201/34.

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29

Héral, Bénédicte. "Approche métabolomique pour l’étude du dépérissement de la lavande : application aux composés non-volatils." Thesis, Université Côte d'Azur, 2021. http://www.theses.fr/2021COAZ4009.

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La lavande et le lavandin sont des plantes à parfums très appréciées des industries cosmétiques et de la parfumerie, et sont un des symboles de la Provence. Seulement, les lavanderaies françaises subissent un fort déclin depuis une quinzaine d’années lié à des épisodes de sécheresse et à une maladie communément appelée « le dépérissement de la lavande ». Cette maladie est provoquée par une bactérie sans paroi le phytoplasme du Stolbur (Candidatus Phytoplasma solani) et véhiculée par un insecte la cicadelle (Hyalestes obsoletus). Cette thèse se propose d’étudier les interactions tripartites entre l’insecte, la plante et la bactérie à travers les modifications induites sur les composés organiques non volatiles (COnVs).Pour répondre à cette problématique, une approche métabolomique non ciblée a été développée et réalisée sur quatre variétés de lavande (7713, maillette) et de lavandin (abrial, grosso). Pour ce faire, une campagne d’échantillonnage a été menée en champs et a conduit au prélèvement de 480 échantillons. Des triplicats d’extraction ont ensuite été réalisés par extraction solide-liquide assistée par ultra-sons avec un mélange eau-éthanol (50:50, v/v). Les analyses ont été conduites sur une UPLC-HRMS (XevoG2 QTOF, Waters). Le traitement des données a été effectué sur la plateforme W4M-Galaxy pour l’extraction des données spectrales, et sur MetaboAnalyst pour les corrections et les tests statistiques (ACP et PLS-DA). Les résultats obtenus ont mis en évidence des différences significatives entre des variétés sensibles et tolérantes au phytoplasme du Stolbur pour chaque organe étudié (parties chlorophylliennes / inflorescences). Des signatures chimiques distinctes en fonction de l’état symptomatique des plants (symptomatique/asymptomatique) ont également pu être révélées pour plusieurs variétés et parties de la plante. En fonction des organes, des composés discriminants du caractère symptomatique communs à plusieurs variétés ont été détectés. Plusieurs dérivées de chlorophylles et des caroténoïdes ont été trouvés comme probables marqueurs de l’état sanitaires des plantes
Fine lavender and lavandin are historic and emblematic crops of Provence (South-East France). They are cultivated for their aromatic and perfume properties. They represented an important economic value in France. Nevertheless, over the last decades, lavender’s field decline because of the lack of rain fall and a disease name “yellow disease”. This infection lead to phloem-limited bacterial pathogen (Candidatus Phytoplasma solani) and transmitted by a planthopper (Hyalesthes obsoletus). The purpose of this PhD is to study induced chemical defences (i.e. non-volatile organic compounds) in order to better understand interaction between insect, plant and bacteria. To answer this issue, an untargeted metabolomic approach was developed. Four varieties chosen for their sensibility or tolerance against phytoplasma, were used: two lavender (7713, maillette) and two lavandin (abrial, grosso), and 480 samples were collected. Compound extraction was performed by a solid-liquid extraction assisted by ultrasounds with an ethanol-water mixture (50:50, v/v). Afterwards, 1429 extracts were analysed by an UPLC-HRMS (XevoG2 QTOF, Waters). Spectral data was first handle using W4M-Galaxy to obtain a peak table fitting by statistical tools. Next, MetaboAnalyst was conducted to correct data and performed multivariate analyses. PCA was used to visualize trends and outliers. PLS-DA was applied to highlight biological differences between subgroups, to discover the most relevant factors and detected biomarkers. The most discriminant compounds specific to sensitivity/tolerant species as well as to plant symptomatic status (asymptomatic/symptomatic) were annotated. Chlorophyll derivatives, under-expressed in symptomatic plants, are probably health plant status biomarkers

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Kim, Dong Hyun. "Investigation of HIV anti-viral drug effect on HPV16 E6 expressing cervical carcinoma cells using advanced metabolomics methods." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/investigation-of-hiv-antiviral-drug-effect-on-hpv16-e6-expressing-cervical-carcinoma-cells-using-advanced-metabolomics-methods(d52b3b66-2a7b-4577-a334-b74bc12b27cc).html.

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Metabolomics approaches have recently been used to understand the complex molecular interactions of biological systems. One popular area in which these methods are being developed is to understand the biochemical changes during abiotic and biotic stresses; for example, how a cell may respond to a drug. Since metabolites are the end products of gene expression, these can be used to indicate the result of the activities and interaction of the cell or organism with its environment. The investigation of the level and compositional changes of metabolites against metabolic stresses such as chemotherapeutic treatment (drug exposure) are required to understand more fully abiotic perturbation to biological systems. The aim of this project was to understand the metabolic effect that the anti-viral drugs indinavir and lopinavir (currently used by HIV patients) have on HPV-related cervical cancer cell lines by measuring changes in metabolism using a wide range of analytical techniques; including Fourier transform infrared (FT-IR) and Raman spectroscopies, and gas and liquid chromatography-mass spectrometry (GC and LC-MS). The analyses and interpretation of the large volumes of complex multidimensional data generated by metabolomics approaches were performed with a combination of multivariate data analysis techniques such as principal components analysis (PCA) and canonical variates analysis (CVA), as well as univariate approaches such as N-Way analysis of variance (ANOVA). By combining biochemical imaging, metabolite fingerprinting and footprinting, and metabolite profiling, with multi- and uni-variate analyses, the actions and effects of the anti-viral drugs were investigated. FT-IR spectroscopy was initially used to generate global biochemical finger- and foot-prints, and Raman spectroscopy was employed to investigate intracellular distribution of metabolites, and other cellular species, as well as the localisation of drug molecules within cells. FT-IR spectroscopy ascertained that the intra- and extra-cellular metabolomes were being directly influenced in a fashion that correlated with increasing anti-viral dosing; these effects were phenotypic rather than measurements of the drug level. Raman imaging spectroscopy indicated that the indinavir but not lopinavir was being compartmentalised within the cell nucleus, but only in HPV early protein 6 (E6) expressing cells. This observation was further confirmed by fractionation of cell samples into nuclear and cytoplasmic fractions and assessing the indinavir concentrations via LC-MS. Finally, LC-MS and GC-MS metabolite profiling were employed to investigate changes in the intracellular metabolome in response to the anti-viral compounds across a range of physiologically relevant concentrations and in the presence and absence of the E6 oncoprotein. General effects of both anti-viral compounds included the regulation of metabolites such as glutathione, octenedionoic and octadecenoic acids, which may be involved in stress related responses, reduced levels of sugars and sugar-phosphates indicating a potential arrest of glycolysis, and reduced levels of malic acid indicating potential decreased flux into the TCA cycle; all indicating that central metabolism was being reduced. Finally, LC-MS based quantification indicated that in the presence of E6, lopinavir was actively removed from the cell, whereas the indinavir intracellular concentration increased concomitantly with the level of dosing. These investigations have revealed that metabolomics approaches are an apt tool for the study of anti-viral effects within cell cultures, but improvements need to be made with respect to the major limitation of metabolite identification.

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31

Paudel, Liladhar. "High Field ¹H Nuclear Magnetic Resonance (NMR) Spectroscopy Based Metabolomics and Complex Mixture Analysis by Multidimensional NMR and Liquid Chromatography-Mass Spectrometry (LC-MS)." University of Akron / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=akron1343403647.

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32

Jonsson, Pär. "Multivariate processing and modelling of hyphenated metabolite data." Doctoral thesis, Umeå universitet, Kemi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-663.

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One trend in the ‘omics’ sciences is the generation of increasing amounts of data, describing complex biological samples. To cope with this and facilitate progress towards reliable diagnostic tools, it is crucial to develop methods for extracting representative and predictive information. In global metabolite analysis (metabolomics and metabonomics) NMR, GC/MS and LC/MS are the main platforms for data generation. Multivariate projection methods (e.g. PCA, PLS and O-PLS) have been recognized as efficient tools for data analysis within subjects such as biology and chemistry due to their ability to provide interpretable models based on many, correlated variables. In global metabolite analysis, these methods have been successfully applied in areas such as toxicology, disease diagnosis and plant functional genomics. This thesis describes the development of processing methods for the unbiased extraction of representative and predictive information from metabolic GC/MS and LC/MS data characterizing biofluids, e.g. plant extracts, urine and blood plasma. In order to allow the multivariate projections to detect and highlight differences between samples, one requirement of the processing methods is that they must extract a common set of descriptors from all samples and still retain the metabolically relevant information in the data. In Papers I and II this was done by applying a hierarchical multivariate compression approach to both GC/MS and LC/MS data. In the study described in Paper III a hierarchical multivariate curve resolution strategy (H-MCR) was developed for simultaneously resolving multiple GC/MS samples into pure profiles. In Paper IV the H-MCR method was applied to a drug toxicity study in rats, where the method’s potential for biomarker detection and identification was exemplified. Finally, the H-MCR method was extended, as described in Paper V, allowing independent samples to be processed and predicted using a model based on an existing set of representative samples. The fact that these processing methods proved to be valid for predicting the properties of new independent samples indicates that it is now possible for global metabolite analysis to be extended beyond isolated studies. In addition, the results facilitate high through-put analysis, because predicting the nature of samples is rapid compared to the actual processing. In summary this research highlights the possibilities for using global metabolite analysis in diagnosis.

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Zamani, Leila. "Methods for structural studies of an antibody, screening metabolites in rat urine and analysis of spent cell cultivation media using LC/ESI-MS and chemometrics." Doctoral thesis, Stockholms universitet, Institutionen för analytisk kemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-28921.

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This thesis describes bioanalytical methods for generating fingerprints of biological systems for extracting relevant information with (protein) drugs in focus. Similarities and differences between samples can reveal the hidden relevant information, which can be used to optimize the production and facilitate the quality control of such protein drugs during their development and manufacture. Metabolic fingerprinting and multivariate data analysis (MVDA) can also facilitate early diagnosis of diseases and the effects and toxicity of drugs. Currently, several protein drugs are available on the global market. Nevertheless, despite, the success of such biotherapeutics significant challenges remain to be overcome in maintaining their stability and efficacity throughout their production cycle and long-term storage. The native structure and functional activity of therapeutic proteins is affected by many variables from production to delivery, incl. variables assoc. with conditions in bioreactors, purification, storage and delivery. Thus, part of the work underlying this thesis focused on structural analysis of a protein drug using chemical labeling, peptide mapping, and evaluation of the charge state distributions of the whole protein generated by ESI. The other part focuses on non-targeted metabolomics with a view to optimizing the cell cultivation process and assessment of the drug’s toxicity. A combination of appropriate analytical methods and MVDA is needed to find markers that can facilitate optimization of the cultivation system and expression of the target proteins in early stages of process development. Rapid methods for characterizing the protein drugs in different stages of the process are also required for quality control. In order to obtain high quality fingerprints analytical separation techniques with high resolution (such as HPLC or UHPLC) and sensitive analytical detection techniques (such as ESI, quadrupole or TOF MS) have been used, singly or in combination.
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript.

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Pinto, Joana Isabel Monteiro. "Healthy pregnancy and prenatal disorders followed by blood plasma metabolomics." Doctoral thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/14784.

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Doutoramento em Bioquímica
The work presented in this thesis aimed to investigate the impact of healthy pregnancy and selected prenatal disorders on the metabolome and lipidome of maternal blood plasma, in order to define new potential biomarkers for non-invasive prediction and diagnosis. Chapter 1 describes the present status and challenges of the clinically relevant prenatal disorders, along with a presentation of the metabolomics strategy applied and the state of the art of metabolomics in prenatal research. All experimental details are described in Chapter 2, comprising sample metadata, sample collection and preparation, data acquisition protocols and data analysis procedures. The plasma metabolome and lipidome viewed by 1D and 2D NMR experiments are presented in Chapter 3. In this chapter, the use of Multiple Quantum NMR spectroscopy was explored, for the first time, for assignment of complex lipid mixtures. Chapter 4 contributes to filling in some existing gaps regarding human plasma degradability during handling and storage, as well as the importance of fasting conditions at collection. The use of heparin collection tubes resulted in no interference of the polysaccharide and full conservation of spectral information, while EDTA tubes produced a number of interfering signals from free and Ca2+/Mg2+ complexed EDTA, the impact of which on metabolomic analysis is discussed. Regarding temperature stability, large changes in lipoproteins and choline compounds were observed in plasma kept at room temperature for  2.5 hours, whereas short-term storage at -20ºC was found suitable up to 7 days, with storage at -80ºC being recommended, particularly for long-term periods (at least up to 2.5 years). Regarding freeze-thaw cycles, no more than 3 consecutive cycles were found advisable, while the use of non-fasting conditions (instead of fasting) was found acceptable. Chapter 5 presents the first NMR metabolomics study of maternal plasma throughout pregnancy, including correlation between plasma and urine metabolites. Some of the metabolic alterations observed confirmed known metabolic effects, while novel changes were observed, suggesting adjustments in energy and gut microflora metabolisms (citrate, lactate and dimethyl sulfone) and alterations in glomerular filtration rate (creatine and creatinine). Correlations studies unveiled specific lipoprotein/protein metabolic aspects of healthy pregnancy with impact on the excreted metabolome, providing further understanding of pregnancy metabolism. In Chapter 6, the impact of prenatal disorders on maternal plasma metabolome and lipidome is described for fetal chromosomal disorders (CD), including Trisomy 21 (T21). High classification rates were obtained for CD (88-89%) and T21 (85-92%) in 1st and 2nd trimesters, based on variable selection of NMR data. In addition, novel metabolic deviations were found through plasma/urine correlations, namely in low density and very low density lipoproteins (LDL+VLDL), sugar and gut microflora metabolisms. Changes in plasma phospholipid profile, namely in phosphatidylcholines, were further confirmed and characterised by hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-LC/MS). In Chapter 7, metabolic biomarkers of pre- and post-diagnosis GDM were sought by NMR metabolomics of whole maternal plasma and plasma lipid profile in the 2nd trimester. Metabolic alterations found to be predictive of GDM comprised increases in cholesterol, fatty acids, triglycerides and small metabolites changes in glucose, amino acids, betaine, urea, creatine and metabolites related with gut microflora. Post-diagnosis GDM was successfully classified using a 26-resonance plasma biomarker corresponding to 10 metabolites and lipids, advancing the possibility of using a multi-metabolite biomarker as a complementary tool in the clinical management of GDM. Chapter 8 describes the results obtained for prenatal disorders shown to have lower impact on maternal plasma metabolome, namely diagnosed fetal malformations and pre-diagnosis premature rupture of membranes, preterm delivery and preeclampsia. Finally, Chapter 9 describes the general conclusions and future perspectives in the context of this thesis, highlighting how this work contributes with new knowledge on prenatal disease mechanisms and possible biomarkers for prenatal diagnosis and prediction methods.
O trabalho apresentado nesta tese teve como principal objetivo investigar o impacto da gravidez saudável e algumas doenças pré-natais no metaboloma e lipidoma de plasma sanguíneo materno, com vista à definição de novos biomarcadores para a previsão e diagnóstico não invasivos daquelas doenças. O Capítulo 1 descreve a perspectiva atual e os desafios das doenças pré-natais mais relevantes, assim como a estratégia metabolómica e estado da arte na investigação pré-natal. Todos os detalhes experimentais do trabalho realizado estão descritos no Capítulo 2, incluindo as condições de amostragem, recolha e preparação das amostras, bem como os protocolos de aquisição e análise dos dados. No Capítulo 3 descreve-se o metaboloma e lipidoma de plasma detectados por RMN 1D e 2D. Neste capítulo, a utilização de espectroscopia de RMN de quantum-múltiplo foi explorada, pela primeira vez, para caracterização de misturas lipídicas complexas. O Capítulo 4 contribui para colmatar algumas falhas no conhecimento sobre a degradibilidade do plasma humano durante o manuseamento da amostra e armazenamento, e a importância de condições de colheita como o jejum. A utilização de tubos de colheita com heparina não mostrou interferência do polissacarídeo nos espectros conservando-se toda a informação espectral, enquanto que os tubos com EDTA deram origem a sinais interferentes provenientes do EDTA livre e complexado com Ca2+/Mg2+, cujo impacto na análise metabolómica é discutido. Relativamente à estabilidade do plasma à temperatura ambiente, foram observadas alterações nas lipoproteínas e compostos de colina a partir de 2.5 horas, enquanto que o armazenamento a -20ºC mostrou ser adequado até 7 dias, sendo o armazenamento a -80ºC aconselhado, particularmente para períodos de tempo longos (pelo menos até 2.5 anos). Relativamente aos ciclos de congelação-descongelação, não se aconselham mais de 3 ciclos consecutivos, enquanto que o efeito da colheita das amostras em não-jejum (em vez de jejum) foi considerado aceitável. O Capítulo 5 apresenta o primeiro estudo de metabolómica por RMN do plasma materno ao longo da gravidez, incluindo correlação entre plasma e urina. Algumas das alterações metabólicas observadas confirmaram efeitos metabólicos conhecidos, tendo outras sido observadas pela primeira vez sugerindo alterações no metabolismo energético, na microflora bacteriana (citrato, lactato e dimetil sulfona) e na taxa de filtração glomerular (creatina e creatinina). Os estudos de correlação revelaram aspetos metabólicos específicos das lipoproteínas/proteínas com impacto no metaboloma excretado. No Capítulo 6 descreve-se o impacto das doenças cromossómicas (CD), incluindo Trissomia 21 (T21) no metaboloma e lipidoma de plasma materno. Obtiveram-se elevadas taxas de classificação para CD (88-89%) e T21 (85-92%) no 1º e 2º trimestres baseadas na seleção de variáveis dos dados de RMN. A correlação de plasma e urina revelou novos desvios metabólicos, nomeadamente no metabolismo das lipoproteínas de baixa densidade e de muito baixa densidade (LDL+VLDL), dos açúcares e da microflora bacteriana. As alterações observadas no perfil de fosfolípidos do plasma, nomeadamente das fosfatidilcolinas, foram confirmadas e caracterizadas por cromatografia liquida hidrofílica acoplada a espetrometria de massa (HILIC-LC/MS). No Capítulo 7 apresentam-se os resultados obtidos na prospecção de biomarcadores metabólicos de diabetes mellitus gestacional (GDM) pré- e pós-diagnóstico por metabolómica de RMN de plasma materno do 2º trimestre. Observaram-se alterações metabólicas com poder de previsão de GDM, nomeadamente um aumento no colesterol, ácidos gordos, triglicerídeos e pequenas variações metabólicas na glucose, aminoácidos, betaína, ureia, creatina e metabolitos relacionados com a microflora bacteriana. O grupo de GDM pós-diagnóstico foi bem classificado utilizando como biomarcador um conjunto de 26 ressonâncias do espectro de plasma correspondendo a lípidos e 10 metabolitos de baixo peso molecular, sugerindo-se a possibilidade de usar este marcador conjunto na gestão clínica da GDM. O Capítulo 8 descreve os resultados obtidos para as doenças pré-natais que mostraram ter um menor impacto no metaboloma de plasma materno, nomeadamente as malformações fetais (FM), e os estados de pré-diagnóstico da rutura prematura das membranas (PROM), parto pré-termo (PTD) e pré-eclampsia. Finalmente, no Capítulo 9 são descritas as conclusões gerais e perspetivas futuras no contexto desta tese, realçando-se como este trabalho contribui para o novo conhecimento dos mecanismos das doenças pré-natais e possíveis biomarcadores para a sua previsão e diagnóstico.

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Mejait, Anouar. "Evaluation of the environmental fate and impact of organic contaminants using innovative approach coupling high-throughput methods." Electronic Thesis or Diss., Perpignan, 2024. http://www.theses.fr/2024PERP0034.

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Les contaminants organiques sont des substances nocives présentes dans l'environnement qui peuvent affecter la santé humaine et les écosystèmes. Parmi eux, les composés pharmaceutiques et les pesticides sont liés à de nombreuses maladies chez l'homme. Ils peuvent également affecter des espèces non-cibles dans l'environnement. Dans le cas des pesticides, largement utilisés en agriculture, des alternatives sont à l'étude. Les biopesticides, qui sont des substances complexes dérivées de sources naturelles, représentent une alternative aux pesticides. Ils sont présumés moins nocifs ; cependant, les réglementations actuelles ne sont pas bien adaptées à ces substances. Par conséquent, de nouveaux paramètres doivent être développés pour étudier le devenir et l'impact des biopesticides. Au sein de l'unité de recherche CRIOBE, une nouvelle méthode appelée « Environmental Metabolic Footprinting » (EMF) a été développée. Cette méthode repose sur l'utilisation de la métabolomique non-ciblée par LC-MS afin d'étudier le devenir et l'impact environnemental des substances complexes comme les biopesticides, en analysant le méta-métabolome de la matrice environnementale, qui comprend à la fois l'endométabolome (métabolome de la matrice environnementale) et le xénométabolome (composés contaminants organiques et leurs produits de dégradation). L'objectif de ma thèse était d'apporter de nouveaux développements à l'approche EMF afin de mettre en place une approche pour l'évaluation des risques environnementaux (ERA) des contaminants organiques dans les matrices environnementales des sols et des sédiments. De nouveaux paramètres ont été mis en place et des approches supplémentaires -omiques ont été introduites. Dans le premier chapitre, je me concentre sur la détermination de la méthode d'extraction chimique optimale et du kit d'extraction d'ADN optimal pour analyser le devenir et l'impact des contaminants organiques dans les matrices de sédiments. Quatre méthodes d'extraction chimique ont été comparées, et pour l'extraction d'ADN, cinq kits commerciaux ont été testés. En utilisant les résultats de la LC-MS, j'ai identifié la méthode d'extraction chimique optimale et, en analysant les métriques de diversité alpha et bêta, le meilleur kit d'extraction d'ADN a été sélectionné. Le deuxième chapitre se concentre sur le développement d'un flux de travail statistique pour étudier le devenir des contaminants organiques tels que les biopesticides (par exemple, Beloukha). Ce flux de travail inclut le développement d'un nouveau paramètre, le temps de dissipation, qui correspond au temps nécessaire à la dissipation des contaminants organiques. Une expérience cinétique de 57 jours a été menée sur une matrice de sol (microcosme) et le bioherbicide Beloukha. En utilisant un flux de travail ad hoc et des scripts développés, nous avons pu extraire les composés biopesticides du méta-métabolome et déterminer le temps de dissipation de Beloukha. Dans le troisième chapitre, je me concentre sur l'impact de Beloukha sur la biodiversité. Le métabarcoding bactérien et eucaryote a été réalisé. Les résultats montrent que les composés biopesticides ont un impact significatif sur les bactéries et les microeucaryotes, alors qu'aucun effet significatif n'a été observé sur les métazoaires. De plus, nous avons pu identifier les taxons spécifiques impactés et les métabolites responsables. En conclusion, ce travail a permis d'apporter des améliorations significatives à l'approche EMF, la rendant plus intégrative et adaptée à l'étude du devenir et de l'impact des contaminants organiques dans différents types de matrices (sol, sédiment, etc.). L'introduction de l'approche génomique permettra de déterminer plus en détail l'impact des contaminants organiques sur la biodiversité. Les nouveaux développements, contribueront à mettre à jour les réglementations existantes, les rendant plus adaptées aux substances complexes et garantissant l'utilisation sécurisée des biopesticides
Organic contaminants are harmful substances present in the environment that can affect human health and ecosystems. Among them, pharmaceutical compounds and pesticides, are linked to many diseases in humans, such as cancer, respiratory disorders, and neurological disorders. They can also affect non-target species in the environment, including beneficial insects. In the case of pesticides, widely used in agriculture and other fields, alternatives are under consideration. Biopesticides, which are complex substances derived from natural sources such as plants and microorganisms, present a promising alternative to pesticides. They are presumed to be less harmful; however, the existing regulations are not well adapted to these substances, and current parameters, like DT50 and DT90, are not suitable for studying the degradation of biopesticides. Therefore, new parameters need to be developed to study the fate and impact of biopesticides. At CRIOBE research unit, a new method called Environmental Metabolic Footprinting (EMF) has been developed. This method is based on the use of non-target metabolic LC-MS in order to study the environmental fate and impact of organic contaminants and in particularly complex substances like biopesticides by analyzing the environmental matrix meta-metabolome, which includes both the endometabolome (environmental matrix metabolome) and the xenometabolome (organic contaminant compounds and their degradation products). The aim of my PhD was to bring new developments to the EMF approach in order to set up an approach for the Environmental Risk Assessment (ERA) of organic contaminants in soil and sediment environmental matrices. New parameters were set-up and additional -omics approaches were introduced. In the first chapter, I focus on determining the optimal chemical extraction method and the optimal DNA extraction kit for analyzing the fate and impact of organic contaminants in sediment matrices. Four chemical extraction methods were compared, and for DNA extraction, five commercial kits were tested. Using LC-MS results, I identified the optimal chemical extraction method, and by analyzing alpha and beta diversity metrics, the best DNA extraction kit was selected. These findings will make the EMF approach suitable and well-adapted for studying organic contaminants in sediment matrices. The second chapter centers on the development of a statistical workflow to study the fate of organic contaminants such as biopesticides (e.g., Beloukha). This workflow includes the development of a new parameter, dissipation time, which corresponds to the time required for the dissipation of organic contaminants. A 57-day kinetic experiment was conducted on a soil matrix (microcosm) and the bioherbicide Beloukha. Using ad-hoc workflow and develo pedscripts, we were able to extract biopesticide compounds from the meta-metabolome and determine the dissipation time of Beloukha. In the third chapter, I focus on the impact of Beloukha on biodiversity. Bacterial and eukaryotic metabarcoding (16S and 18S Ribosomal ribonucleic acid (rRNA) genes) were performed. The results show that biopesticide compounds significantly impacted bacteria and microeukaryotes, whereas no significant effect was observed on metazoa. Additionally, we were able to identify the specific taxa impacted and the metabolites responsible. In conclusion, this work has led to significant improvements in the EMF approach, making it more integrative and suitable for studying the fate and impact of organic contaminants in different types of matrices (soil, sediment, etc.), the introduction of genomic approach will help to determine in more details the impact of the organic contaminant on biodiversity. The new developments such as dissipation time will help update existing regulations, making them more suitable for complex substances and ensuring the safe use of biopesticides to preserve ecosystem balance

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36

Perera, Munasinhage Venura Lakshitha. "Metabolic profiling of plant disease : from data alignment to pathway predictions." Thesis, University of Exeter, 2011. http://hdl.handle.net/10036/3906.

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Understanding the complex metabolic networks present in organisms, through the use of high throughput liquid chromatography coupled mass spectrometry, will give insight into the physiological changes responding to stress. However the lack of a proper work flow and robust methodology hinders verifiable biological interpretation of mass profiling data. In this study a novel workflow has been developed. A novel Kernel based feature alignment algorithm, which outperformed Agilent’s Mass profiler and showed roughly a 20% increase in alignment accuracy, is presented for the alignment of mass profiling data. Prior to statistical analysis post processing of data is carried out in two stages, noise filtering is applied to consensus features which were aligned at a 50% or higher rate. Followed by missing value imputation a method was developed that outperforms both at model recovery and false positive detection. The use of parametric methods for statistical analysis is inefficient and produces a large number of false positives. In order to tackle this three non-parametric methods were considered. The histogram method for statistical analysis was found to yield the lowest false positive rate. Data is presented which was analysed using these methods to reveal metabolomic changes during plant pathogenesis. A high resolution time series dataset was produced to explore the infection of Arabidopsis thaliana by the (hemi) biotroph Pseudomonas syringe pv tomato DC3000 and its disarmed mutant DC3000hrpA, which is incapable of causing infection. Approximately 2000 features were found to be significant through the time series. It was also found that by 4h the plants basal defence mechanism caused the significant ‘up-regulation’ of roughly 400 features, of which 240 were found to be at a 4-fold change. The identification of these features role in pathogenesis is supported by the fact that of those features found to discriminate between treatments a number of pathways were identified which have previously been documented to be active due to pathogenesis

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37

Bilbrey, Emma A. "Seeding Multi-omic Improvement of Apple." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1594907111820227.

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38

Callagy, Sandra. "An investigation into changes to trace metals and metabolic profiling in the diabetic retina." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/an-investigation-into-changes-to-trace-metals-and-metabolic-profiling-in-the-diabetic-retina(213607b0-2a34-490a-bb17-2e08435eb446).html.

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Diabetes mellitus currently affects over 422 million people globally and over 80% of patients with diabetes will develop diabetic retinopathy. Patients with diabetic retinopathy initially develop background retinopathy, which does not cause significant deterioration of visual function; however, background retinopathy may progress and lead to proliferative diabetic retinopathy and diabetic macular oedema, both of which cause severe visual dysfunction if left untreated. Current therapies for diabetic retinopathy include invasive intravitreal injections and laser photocoagulation; however these treatments only attenuate the progression of proliferative diabetic retinopathy and diabetic macular oedema. Aside from prevention by maintaining good blood glucose and blood pressure control, there are currently no treatments to prevent progression to late-stage diabetic retinopathy and new innovations in the field have not significantly progressed. For this reason, we have used untargeted âomics approaches to identify previously unknown pathological pathways in diabetes. In this thesis, I have analysed a range of trace metals in donor retinas and found that total copper was increased in diabetic retinas compared with non-diabetic. This result was replicated in streptozotocin-induced diabetic rat retinas and further evidenced by upregulation of metallothioneins and caeruloplasmin in diabetic rat retinas compared with non-diabetic. Treatment with the copper chelator triethylenetetramine modulated these changes, the downstream effects of which require further study. This is the first description, to our knowledge, of dysregulated copper homeostasis in the diabetic retina. I have also mapped metabolic changes in streptozotocin-induced diabetic rat retinas and found previously undescribed metabolite changes such as diabetes-induced downregulation of scyllo inositol. This coincided with substantial changes to retinal lipids during diabetes and changes to individual lipids were consistent within their respective class. I have also found a pattern whereby regardless of the extent of change to a lipid class in diabetes, lipids containing docosahexaenoic acid (22:6 carbon chain) were consistently downregulated. This is thought to be the first study to describe this range of metabolite changes in the diabetic retina but also the first study to describe this range of metabolite analysis concomitantly within the same tissue sample. The data from this study provides new insights into metallomic and metabolic dysfunction in diabetic retinopathy and shown that these data are reproducible. We suggest that there is plenty of scope for further research to investigate mechanisms behind copper dysregulation, how this affects pathogenesis of diabetic retinopathy along with new insights into dysregulated metabolic pathways.

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39

Cerutti, Estela Soledad. "LC/MS-based targeted and global metabolomic methodologies and their application to biomarker discovery." [Gainesville, Fla.] : University of Florida, 2009. http://purl.fcla.edu/fcla/etd/UFE0024947.

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40

Laourdakis, Christian Daniel. "Molecular target identification of antimalarial drugs using proteomic and metabolomic approaches." Thesis, Virginia Tech, 2014. http://hdl.handle.net/10919/63987.

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Malaria is a parasitic infectious disease that results in millions of clinical cases per year and accounts for approximately 1 million deaths annually. Because the parasite has developed resistance to all current antimalarials, new therapies are urgently needed. Purine and pyrimidine biosynthesis for DNA and RNA synthesis has been recognized as a source of therapeutic targets. Targeted metabolite profiling has aided in the understanding of several biological processes in the parasite besides drug discovery. Therefore, having a robust analytical platform to quantify the purines and pyrimidines is of a great value. For this purpose an ion pair reversed phase ultra-performance liquid chromatography in tandem with mass spectrometry method was developed and validated. In addition, the apicoplast is an organelle present in the malaria parasite and other apicomplexan parasites. It was demonstrated that the apicoplast is essential for parasite's survival. The supply of isopentenyl diphosphate and dimethylallyl diphosphate for isoprenoid biosynthesis is the sole function of this organelle in the asexual intraerythrocytic stages. Isoprenoid precursors are synthesized through the methylerythritol phosphate (MEP) pathway in the malaria parasite while humans utilize the mevalonate pathway. Therefore, the MEP pathway is a source of drug targets for drug development. Our group has identified MMV008138 as anti-apicoplast inhibitor through phenotypic screening. Preliminary data suggest that the molecular target of MMV008138 may be within the MEP pathway. We used proteomic and metabolomic approaches to identify the molecular target of MMV008138 to aid future medicinal chemistry to improve the efficacy of this inhibitor.
Master of Science

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41

Mori, Shinsuke. "Studies on the global screening of functional food ingredients in tomato using LC-MS and metabolomic analysis." Kyoto University, 2018. http://hdl.handle.net/2433/235095.

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Kyoto University (京都大学)
0048
新制・課程博士
博士(農学)
甲第21375号
農博第2299号
新制||農||1067(附属図書館)
学位論文||H30||N5148(農学部図書室)
京都大学大学院農学研究科食品生物科学専攻
(主査)教授入江一浩, 教授橋本渉, 准教授後藤剛
学位規則第4条第1項該当

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42

Tautenhahn, Ralf [Verfasser], Stefan [Akademischer Betreuer] Posch, and Sebastian [Akademischer Betreuer] Böcker. "Feature-Detektion, Annotation und Alignment von Metabolomik LC-MS Daten / Ralf Tautenhahn. Betreuer: Stefan Posch ; Sebastian Böcker." Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2009. http://d-nb.info/1024859193/34.

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43

Díaz, San Pedro Ramón. "Potential of LC-(Q)TOF MS in target and non-target analyses: wide scope screening of organic contaminants and metabolomic applications." Doctoral thesis, Universitat Jaume I, 2016. http://hdl.handle.net/10803/669026.

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En la presente tesis se ha investigado el potencial de la cromatografía líquida acoplada a la espectrometría de masas de alta resolución en aproximaciones analíticas tanto de tipo target (análisis de compuestos diana) como non-target (análisis no dirigido). Las ventajas que este tipo de instrumentación ofrece, derivadas de la adquisición del espectro completo con alta resolución y medidas de masa exacta, la hacen idónea para el screening de contaminantes orgánicos así como para estudios metabolómicos tanto de denominación de origen de alimentos como de carácter biomédico. El trabajo presentado se ha estructurado en tres grandes bloques. En el primero de ellos se aborda el desarrollo y optimización de un método de screening “universal” de contaminantes orgánicos usando un acoplamiento instrumental LC-QTOF MS. Con este fin, se ha desarrollado una base de datos de compuestos, se ha optimizado la metodología analítica y, finalmente, se ha validado dicha metodología en matrices medioambientales. El segundo bloque muestra el potencial de la técnica para la investigación y diagnosis en exhalados pulmonares, los cuales presentan un bajísima concentración de metabolitos. En el tercer y último bloque, se lleva a cabo la búsqueda de compuestos que puedan utilizarse como marcadores de D.O. en muestras de naranja y vino, centrándose especialmente en aquellas pertenecientes a la Comunidad Valenciana. El primer bloque se inicia con la optimización de los parámetros instrumentales que puedan tener un efecto notorio en la creación de la base de datos y/o en el análisis de las muestras. Para ello, se han investigado los factores que afectan a la sensibilidad instrumental y a la exactitud de masa. Además, se estudia la fragmentación de los compuestos incluidos en la base de datos con el fin de facilitar de forma automática y simultánea la confirmación de la identidad de los compuestos detectados en las muestras. Finalmente se ha evaluado la influencia de la resolución de masa y cromatográfica en la exactitud de masa en el caso de matrices complejas. Posteriormente, se han creado dos bases de datos de contaminantes orgánicos: una teórica, la cual contiene alrededor de 1000 contaminantes orgánicos reportados en la literatura como analizables por LC-MS. Esta base de datos incluye tiempo de retención y fórmula empírica de fragmentos y aductos de aquellos compuestos de los que se dispone de patrones de referencia y que han sido inyectados de acuerdo con los parámetros previamente optimizados. La segunda base de datos se trata de una librería de espectros experimental que contiene los espectros a alta y baja energía de colisión (estos últimos proporcionando información sobre la fragmentación), así como tiempos de retención, de los compuestos con patrón disponible. Finalmente, se ha evaluado la eficacia de la librería en el análisis de muestras reales. En un segundo trabajo se evalúa el potencial de los dos principales procedimientos para la investigación de contaminantes orgánicos mediante métodos de screening: non-target y post-target. Para ello, se lleva a cabo un screening de muestras ambientales, alimentos y muestras de interés toxicológico mediante las dos metodologías y se comparan los resultados obtenidos. La primera aproximación (non-target), basada en la deconvolución del cromatograma para la búsqueda de componentes en la muestra, ha demostrado una notable dependencia de la intensidad del pico cromatográfico debido a la baja eficiencia del algoritmo de deconvolución. En el caso de la aproximación non-target, tras la búsqueda de los componentes, los espectros correspondientes son automáticamente comparados con la librería de espectros experimental creada anteriormente, así como con una librería teórica generada a partir de los compuestos incluidos en la base de datos de contaminantes. En cuanto a la segunda aproximación, tipo post-target, esta se basa en la búsqueda, después de la inyección de las muestras, de compuestos seleccionados (target) incluidos en la base de datos. Como se ha indicado anteriormente, ésta incluye información de fragmentación y tiempo de retención de aquellos compuestos con patrón de referencia disponible, es decir aquellos que están también presentes en la librería experimental de espectros. A la vista de los resultados, se concluye que la aproximación post-target resulta la más ventajosa para abordar un screening “universal” de un elevado número de compuestos. Además, los procesos de revisión de datos y los tiempos de procesamiento se reducen considerablemente. Sin embargo, la metodología non-target presenta una excelente capacidad de confirmación de la identidad de los contaminantes encontrados ya que facilita la comparación de los espectros de fragmentación de patrones con los obtenidos en la muestra. Mediante la aproximación post-target, se encontró un importante número de contaminantes en muestras ambientales y alimentarias, así como drogas de abuso y fármacos en las muestras de orina de voluntarios en tratamientos de desintoxicación. El primer bloque de la tesis finaliza con una validación cualitativa de la metodología desarrollada en muestras de agua subterránea, superficial y el efluente de una planta de tratamiento de aguas residuales. Se han evaluado dos tipos de relleno en la extracción en fase sólida aplicada a las muestras: Oasis HLB y MCX. El primero ha resultado más genérico, perdiéndose únicamente el fármaco Gabapentina en dicho proceso de preconcentración. Para la validación cualitativa, se fortifican 3 muestras independientes de cada tipo de agua analizada a dos niveles de concentración (0.1 y 1 µg/L) y se comprueba la capacidad del método para detectar (típicamente, usando la molécula protonada) e identificar (mediante al menos dos iones: molécula protonada y un fragmento) los contaminantes seleccionados como modelo: 146 compuestos entre los que se incluyen 52 pesticidas, 52 medicamentos (21 antibióticos), 13 drogas de abuso, 11 hormonas, 11 micotoxinas y 7 agentes de protección UV. El método desarrollado permite la detección de la gran mayoría de los compuestos ensayados y la identificación de un buen número de ellos. Posteriormente, se ha aplicado dicha metodología al análisis de muestras reales, identificando varios de los contaminantes seleccionados, incluso a niveles de concentración inferiores al más bajo validado. También ha sido posible la detección e identificación tentativa de varios contaminantes no incluidos en la validación del método, incluso sin patrón de referencia disponible, gracias a la valiosa información suministrada por el analizador QTOF-MS. En el segundo bloque se aprovechan las ventajas que ofrece el acoplamiento LC-MS, y en especial HRMS, para aplicaciones metabolómicas que requieren de una elevada sensibilidad instrumental. Este es el caso de los condensados de exhalados pulmonares, cuyas concentraciones de metabolitos son extremadamente bajas y, por tanto, requieren de técnicas más sensibles como son las LC-HRMS frente al típico análisis mediante NMR. En el trabajo realizado, en colaboración con el Instituto de Estudios Biofuncionales de la Universidad Complutense de Madrid (UCM, Madrid, Spain) y llevado a cabo en el Department of Biomolecular Medicine en Imperial College London (London, UK), se realiza un estudio preliminar sobre las capacidades de LC-HRMS y NMR para abordar la diferenciación de pacientes sanos de aquellos con enfermedades respiratorias, concretamente con obstrucción pulmonar crónica, mediante el análisis no invasivo de condensados de exhalados pulmonares. En base a los resultados obtenidos, se propone el uso de LC-HRMS como aproximación metabolómica estándar para este tipo de análisis. En el tercer y último bloque se investigan los marcadores que permiten la diferenciación de alimentos según su origen, especialmente en productos de interés para la Comunidad Valenciana y cuya calidad está directamente relacionada con su D.O. El primero de los trabajos incluidos en este capítulo se centra en el análisis de las diferencias a nivel químico presentes en naranjas de diferentes orígenes. Para ello, se han seleccionado muestras de la Comunidad Valenciana y de países del hemisferio sur (Sudáfrica y Argentina) de variedades de maduración tardía. Las muestras completas (piel y pulpa) se trituran, homogenizan y extraen con una mezcla agua:metanol, se diluyen con agua y finalmente se analizan mediante UHPLC-HRMS. Posteriormente, se procesan los datos mediante análisis multivariante para encontrar los que permitirían la distinción en función del origen. Finalmente, se ha ampliado el muestreo a la siguiente campaña, incluyendo también muestras de Brasil, con la finalidad de comprobar la validez de los marcadores encontrados y su posible aplicación a otros destinos. Se ha encontrado un marcador idóneo en ambos casos (primer y segundo muestreo) que corresponde a un compuesto de tiempo de retención 4.83 minutos, que finalmente y gracias a la información espectral en masa exacta ofrecida por LC-HRMS se ha identificado como Citrusin D. Finalmente, en el último trabajo presentado se ha realizado un estudio similar al de las naranjas. El vino es un producto muy preciado cuyo valor está extremadamente ligado a su origen, entre otros. En este artículo científico se realiza un comparación interlaboratorio para el estudio metabolómico de muestras de vino procedentes de tres importantes denominaciones de origen en España (Ribera del Duero, Rioja y Penedés). Los resultados de ambas plataformas ofrecen una clasificación óptima de las muestras en base a marcadores definidos en las rutas metabólicas de la vitis vinífera. Además, se discute sobre las ventajas y desventajas de ambas plataformas, no solo en el aspecto instrumental (TOF vs Orbitrap) sino también en el procesamiento de los datos y la selección de los marcadores. Como cabía esperar por ser geográficamente la más diversa, la denomiancion de origen Penedés era separada de las otras dos mediante un simple análisis no-supervisado PCA. Para separar completamente las 3 D.O. se analizaron mediante PLS-DA obteniéndose una clasificación correcta para todas las muestras. Se encontraron diversos marcadores de la familia de los polifenoles como la Catequina, Epicatequina y Galactocatequina, entre otros. Finalmente, los marcadores de cada plataforma fueron cuantificados en un modo target en la otra plataforma. Se demostró que, para ambas plataformas, los diferentes marcadores eran significativos y que por tanto, el tratamiento de datos había filtrado estos marcadores. El modelo estadístico aplicado haciendo uso exclusivamente de los marcadores fue capaz de separar perfectamente las diferentes denominaciones de origen mediante PCA.

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44

Alothaim, Ibrahim. "Applications of LC-MS metabolomic profiling in inflammatory bowel disease and the development of derivatisation methods to enhance selective detection of certain compound classes." Thesis, University of Strathclyde, 2018. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=29531.

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Inflammatory bowel disease (IBD) is a chronic inflammation of all parts of the gastrointestinal tract and is represented by two major variations, ulcerative colitis (UC) and Crohn's disease (CD). It is diagnosed based on the pattern of inflammation. In order to understand the pathology of the disease better urine and saliva samples were collected from patients with IBD, patients in remission and a control group. The metabolomes of the urine and saliva samples were profiled by carrying out chromatography on a ZICpHILIC column in combination with high resolution mass spectrometry. It was possible to separate the different classes of urine samples on the basis of their metabolomic profiles by modelling with data using orthogonal partial least squares analysis (OPLSDA). A number of metabolites were found to vary between the three groups although the models for separation were weak. The OPLSDA models of the saliva data were much stronger and saliva analysis looks promising for diagnostic and prognostic purposes. Nine variables were able to discriminate the control and affected samples and these included four sphingosine bases. The analysis of short chain fatty acids (SCFAs) by LC-MS is a problem since they are too volatile to give good responses. SCFAs are potentially important makers for IBD. A quantitative LC-MS method for acetic, propionic, butyric and lactic acids was developed by carrying out derivatisation of the acids using a carbodimide to activate the acids and then reacting with dimethylaminophenylamine and separating the derivatives using HILIC chromatography. Quantification was carried out by using stable isotope dilution. The method was very sensitive but detection limits were set by the background contamination by the SCFAs rather than by absolute sensitivity. The method was applied to the urine samples and differences in acetate and butyrate were found between the affected and control samples. The microbiome plays a role in IBD and one marker for bacterial activity it the breakdown of dietary fibre in sugar monomers. Thus urine and saliva samples from controls and IBD samples were profiled using a reductive amination method previously developed. It was found that there were significant differences in the pattern of hexoses, pentoses and deoxy hexoses in the urine and saliva samples.

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45

De, Marchi Fabiola. "Studio dei metaboliti chimici dell'uva finalizzato a valutare le potenzialità enologiche, nutraceutiche ed industriali di alcune varietà di vite e nuovi approcci di metabolomica." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423516.

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Grape, wine and oenology by-products are rich in polyphenols and in particular flavonoids: flavonols, anthocyanins, flavanols and proanthocyanidins. Those molecules are plants secondary metabolites and may also contribute to the bitterness and astringency of grapes and wines. In recent years, epidemiological studies have revealed the great potential of polyphenols and flavonoids in human diet on protection against cancers, infections, their role in anti-aging and also against the development of several chronic diseases such as cardiovascular diseases (CVDs) or diabetes. Their role for human health is attributed mainly to their antioxidant, anti-inflammatory, antimicrobial activities. Therefore these bio-compounds could find promising applications in pharmaceutical, nutraceutical and food industries as active ingredients in supplements with antioxidant activity, value-added ingredients in fortified foods or as natural dyes and preservatives. The aim of this research is to investigate the contents of chemical metabolites in several unique Vitis vinifera varieties and hybrids, and to examine their potential for oenological, nutraceutical and industrial applications. Modern spectrophotometry, chromatography and mass spectrometry (MALDI/MS, LC/MS, GC/MS) analytical techniques were applied in order to achieve the aims of the research. Nine Vitis vinifera italian native grape varieties from Friuli Venezia Giulia and Veneto regions, were investigated for their enological potential, by studying the main classes of polyphenols and aroma compounds of grapes and their organoleptic wine characteristics. In addition 32 hybrid varieties (21 red, 11 white) that belong to the CRA-VIT Grapevine Germplasm Collection located in Conegliano (TV) were studied to evaluate their nutraceutical and industrial potential. The study of anthocyanins of red hybrids showed that some varieties (e.g. Seibel 8357) have rich content of pigments and are therefore attractive for the production of natural dyes that are used in the food and pharmaceutical industry. Moreover, some varieties (Bacò 1 and Seibel 10878) were also found interesting for their triglycerides content in grape seed oil with high linoleic acid content (up to 70%), which is essential fatty acid effective in reducing LDL cholesterol. The nutraceutical potential of hybrid varieties was investigated by studying grape seed proanthocyanidins. Oligomeric and polymeric proanthocyanidins with different degree of galloylation were determined in grape seed extracts suggesting potential application of the extracts as antioxidants in nutraceutical products and also as oenological tannins. Eventually, a new methodology was established for grape metabolome study based on High-Resolution Mass Spectrometry (HR-MS) analysis and the “suspect screening analysis” approach. This method was proved to be very effective due to the ability to identify hundreds of compounds in one single run and also individual classes of grape polyphenols
L’uva, il vino ed i sottoprodotti dell’industria enologica sono ricche fonti di polifenoli e flavonoidi, quali flavonoli, antociani, flavanoli e proantocianidine. Questi composti determinano le caratteristiche sensoriali delle uve e dei vini, come il colore, il sapore e l’astringenza. Numerosi studi epidemiologici hanno dimostrato che questi composti esercitano un’azione benefica sulla salute umana e proteggono dall’insorgere di patologie croniche e degenerative soprattutto a carico dell’apparato cardiovascolare, grazie alle loro proprietà antiossidanti, anticancro, antinfiammatorie ed antimicrobiche. Questi biocomponenti, una volta estratti dalle varie parti della pianta, possono trovare importanti applicazioni come principi attivi di supplementi farmaceutici con attività antiossidante, ingredienti a valore aggiunto in alimenti fortificati, coloranti e conservanti naturali per l’industria alimentare. Lo scopo della ricerca è quello di studiare, mediante le moderne tecniche analitiche di spettrofotometria, cromatografia e spettrometria di massa (MALDI/MS, LC/MS, GC/MS), i metaboliti nelle uve di alcune varietà di Vitis vinifera e di viti ibride ad oggi poco conosciute al fine di individuarne le potenzialità enologiche, nutraceutiche ed industriali. Sono state valutate le potenzialità enologiche di nove varietà di V. vinifera appartenenti a vitigni autoctoni del Friuli Venezia Giulia e del Veneto, attraverso lo studio delle principali classi di polifenoli e aromi delle uve e dei principali parametri chimici e profili organolettici dei vini. Inoltre, sono state studiate le uve di 32 varietà di viti ibride (21 rosse e 11 bianche) presenti nella collezione del Germoplasma viticolo del CRA-VIT al fine di valutarne le potenzialità per i loro impieghi industriali e nella nutraceutica. Lo studio degli antociani delle varietà ibride rosse ha evidenzato alcune varietà particolarmente ricche di pigmenti (es. il Seibel 8357) e quindi interessanti per la produzione di coloranti naturali che vengono impiegati in particolare nell’industria alimentare e farmaceutica. Lo studio dei trigliceridi dell’olio di vinaccioli delle uve ibride ha evidenziato che in generale queste varietà hanno un elevato contenuto di acido linoleico (superiore al 70%), un acido grasso essenziale avente la proprietà di diminuire i livelli di colesterolo LDL, ed alcune varietà particolarmente interessanti per la loro produttività (Bacò 1 e Seibel 10878). Le potenzialità nutraceutiche di queste varietà sono state investigate anche studiando le proantocianidine negli estratti di vinaccioli. Sono state determinate numerose proantocianidine oligomere e polimere aventi diversi gradi di galloilazione, utilizzabili, oltre che come preparati antiossidanti, anche come tannini enologici per la chiarifica di mosti e vini. Infine, è stato sviluppato un nuovo metodo per lo studio della metabolomica dell’uva mediante analisi di spettrometria di massa ad alta risoluzione (HR-MS) con un approccio di “suspect screening analysis”. Il metodo è risultato molto efficace, ed ha permesso l’identificazione di centinaia di metaboliti con una singola analisi, incluse diverse classi di polifenoli dell’uva

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46

Koch, Maximilian [Verfasser], Stephan A. [Akademischer Betreuer] Sieber, and Wolfgang [Akademischer Betreuer] Eisenreich. "Functional analysis of selective aldehyde dehydrogenase 1A1 inhibition by cytotoxic duocarmycin analogs and LC-MS-based metabolomic profiling of polar metabolites in bacteria / Maximilian Koch. Betreuer: Stephan A. Sieber. Gutachter: Wolfgang Eisenreich ; Stephan A. Sieber." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1079324054/34.

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47

FRIGERIO, GIANFRANCO. "DEVELOPMENT, VALIDATION, AND APPLICATION OF ANALYTICAL ASSAYS FOR THE HUMAN BIOMONITORING OF VOLATILE AND PERSISTENT ORGANIC COMPOUNDS." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/816457.

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Il monitoraggio biologico è un utile approccio per valutare l'esposizione umana a sostanze inquinanti. Lo scopo di questo progetto è stato quello di sviluppare nuovi metodi analitici per il biomonitoraggio dell'esposizione umana a inquinanti organici volatili e persistenti, oltre alla loro applicazione a determinati gruppi di soggetti e ad un confronto tra diversi approcci (approcci mirati e non-mirati). Un metodo in spettrometria di massa tandem accoppiato con la cromatografia liquida in fase inversa (HPLC-MS/MS) è stato sviluppato per l'analisi di un totale di 17 acidi mercapturici urinari, metaboliti di diversi composti organici volatili. È stata eseguita una completa validazione includendo precisione, accuratezza, linearità, sensibilità, efficienza del processo di preparazione del campione e verifica esterna. Questo metodo è stato applicato a un gruppo di 49 lavoratori di una cokeria e 49 individui non-esposti che vivevano nella stessa area geografica. Il fumo di tabacco è stato un criterio di esclusione per entrambi i gruppi. I livelli urinari dei metaboliti di benzene, stirene, acrilonitrile e 1,3-butadiene erano da 2 a 10 volte più alti nei lavoratori rispetto ai controlli. Il metodo è stato applicato anche a un gruppo di soggetti con diverse abitudini al fumo, in particolare: 38 non-fumatori (NS), 7 utilizzatori di sigarette elettroniche (ECU) e 22 fumatori di sigarette tradizionali (TTS). La maggior parte degli acidi mercapturici misurati era da 2 a 165 volte più alta nei TTS rispetto ai NS. I metaboliti di acrilonitrile e acroleina erano, rispettivamente, 1.8 e 4.9 volte più alti nei ECU rispetto ai NS. Inoltre, confrontando i fumatori con i lavoratori della cokeria non fumatori, i primi sono stati esposti a una maggiore quantità di composti organici volatili. Un approccio di metabolomica non-mirata è stato applicato alla stessa popolazione di soggetti con diverse abitudini al fumo. I campioni sono stati analizzati mediante cromatografia liquida accoppiata a spettrometria di massa a tempo di volo. Tra i composti putativamente annotati vi erano il glucuronide coniugato della 3-idrossicotinina e il coniugato solfato del metossifenolo. Considerando gli acidi mercapturici, la coerenza tra l'approccio mirato e quello non mirato è stata trovata per un numero limitato di sostanze chimiche, tipicamente le più abbondanti. Infine, è stato sviluppato un metodo HPLC-MS/MS per la determinazione di alcune sostanze interferenti con il sistema endocrino. Le molecole analizzate comprendevano bisfenolo A e metaboliti di ftalati, inclusi tereftalati in quanto prodotti sostitutivi emergenti. È stata effettuata una completa validazione e il metodo è stato applicato a 36 adulti non esposti professionalmente.
Biomonitoring is a useful approach to assess the exposure to pollutants in human subjects. The aim of this project was the development of new analytical methods for the biomonitoring of exposure to volatile and persistent organic pollutants, their application to selected groups of subjects, and a comparison between different approaches (untargeted vs targeted approaches). A high-throughput isotope dilution tandem mass spectrometric method coupled with reversed-phase liquid chromatography (HPLC-MS/MS) was developed for the analysis of a total of 17 urinary mercapturic acids, as metabolites of several volatile organic compounds. A complete validation was carried out including precision, accuracy, linearity, sensibility, process efficiency, and external verification. This method was applied to a group of 49 coke-oven workers and 49 individuals living in the same area. Active tobacco smoking was an exclusion criterion for both groups. Urinary levels of the metabolites of benzene, styrene, acrylonitrile, and 1,3-butadiene were 2–10 fold higher in workers than in controls. The method was also applied to a group of subjects with different smoking habits, in particular: 38 non-smokers (NS), 7 electronic cigarette users (ECU), and 22 traditional tobacco smokers (TTS). Most of the measured mercapturic acids were 2 - 165 fold-higher in TTS compared to NS. The metabolites of acrylonitrile and acrolein were 1.8 and 4.9 fold-higher higher in ECU than NS, respectively. Furthermore, comparing smokers to non-smoking coke oven workers, the first were exposed to a greater amount of volatile organic compounds. An untargeted metabolomic approach was applied to the same population of subjects with different smoking habits. Samples were analysed by liquid chromatography/time-of flight mass spectrometry. Among putatively annotated compounds there were the glucuronide conjugated of 3-hydroxycotinine and the sulfate conjugate of methoxyphenol. Considering mercapturic acids, the coherence between the targeted and untargeted approach was found for a limited number of chemicals, typically the most abundant. Finally, an HPLC-MS/MS method for the determination of some endocrine-disrupting persistent chemicals was developed. Targeted molecules were bisphenol A and metabolites of phthalates, including emergent terephthalates. A complete validation was carried out and the method was applied to 36 non-occupationally exposed adults.

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Chang, Chiung-Wen, and 張瓊文. "LC-MS-based metabolomics study Anoectochilus formosanus Hayata under flooding condition." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/4zxp4h.

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碩士
臺北醫學大學
生藥學研究所
102
Anoectochilus formosanus Hayata (Orchidaceae), is a folk medicinal plants in Taiwan. A. formosanus as “the king of medicine” has been used for treating cancer, hypertension, and diabetes mellitus. The major compound kinsenoside, which has shown diversed pharmacological effects, including anti-inflammation and hepatoprotection. In this study, we applied LC-MS technique combinated with principal component analysis (PCA) to study what the soil hydroponics or flooding would affect the kinsenoside content in A. formosanus plant. Our data showed that kinsenoside was not changed but the compounds showed m/z 130.2, 181.1, 273.3 and 331.0 were significant changed, between regular soil condition and flooding, the chemical structures of those responsive compound will be elucidated in future study.

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"Targeted Metabolomics Reveals the Effect of Nitrate Supplementation on Vascular Function." Master's thesis, 2020. http://hdl.handle.net/2286/R.I.62984.

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abstract: In the United States, two-thirds of adults are considered hypertensive orprehypertensive. In addition, chronic illness, such as hypertension, cardiovascular disease, and type II diabetes, results in $3.5 trillion in annual healthcare cost and is the primary cause of disability and death. As a result, many individuals seek cheaper and simpler alternatives to combat their conditions. In this exploratory analysis, a study assessing nitrate intake and its effects on vascular function in 39 young adult males was investigated for underlying metabolic variations through a liquid chromatography – mass spectrometry-based large-scale targeted metabolomics approach. A two-way repeated measures ANOVA was used, and 18 significant metabolites were discovered across the time, treatment, and time & treatment groups, including prostaglandin E2 (p<0.001), stearic acid (p=0.002), caprylic acid (p=0.016), pentadecanoic acid (p=0.027), and heptadecanoic acid (p=0.005). In addition, log-transformed principal component analysis and orthogonal partial least squares – discriminant analysis models demonstrated distinct separation among the treatment, control, and time variables. Moreover, pathway and enrichment analyses validated the effect of nitrate intake on the metabolite sets and its possible function in fatty acid oxidation. This better understanding of altered metabolic pathways may help explicate the benefits of nitrate on vascular function and reveal any unknown mechanisms of its supplementation.
Dissertation/Thesis
Masters Thesis Nutrition 2020

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50

Tsai, Dong-Ming, and 蔡東銘. "HILIC-LC-MS Based Metabolomics- Chemometric Method Development and Analysis of Peritoneal Dialysis Effluent." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/71250291097138501761.

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博士
國立臺灣大學
生醫電子與資訊學研究所
105
Through holistic metabolite profiling and quantitation in biosystems, metabolomics conveys phenotype information and provides understanding difference among living systems and the mechanisms of diseases. Metabolomic datasets come from state-of-art high-throughput chemical analytical instruments such as nuclear magnetic resonance (NMR) or liquid chromatography hyphenated to mass spectrometry. The data size is huge and requires bioinformatic tools to facilitate analysis. We introduced for the study of metabolomics the procedures of data management and pertinent multivariate analysis. Biosamples used in metabolomics study may come from biofluids such as plasma, urine or others, such as peritoneal effluent disposed from peritoneal dialysis. Hydrophilic interaction liquid chromatography (HILIC) hyphenated to mass spectrometry (LC-MS) is widely used in the study of metabolomics, particularly for polar metabolites. However, determining an optimized mobile phase and developing a proper HILIC method tend to be laborious, time-consuming, and experience-dependent tasks. In this study, we developed a chemometric workflow to quickly determine the optimized mobile phase and to objectively construct a HILIC LC-MS reference library database. All chromatograms in the process were baseline corrected, smoothed and noise filtered. A mass chromatographic quality value, an asymmetric factor, and local maxima of the extracted ion chromatogram were calculated to determine the number of peaks and peak retention time. The optimal mobile phase can be quickly determined by selecting the mobile phase that produces the largest number of resolved peaks. Moreover, the workflow enables one to automatically process the repeats and to determine the retention time of large numbers of standards. This method was successfully applied to construct a reference library of 571 metabolites for HILIC LC-MS platform based metabolomics study . We used metabolomic approach to study peritoneal effluent with HILIC LC-MS platform. The function of peritoneal membrane is critical to uremic patients receiving peritoneal dialysis (PD). Clinically, the result of peritoneal equilibration test (PET) defines peritoneal transport status. Metabolite profiles in peritoneal effluents can imply dialytic efficiency of peritoneal dialysis and elucidate differences among peritoneal transport status. We collected peritoneal effluents from 20 PD patients whose PET were evenly distributed among four peritoneal transport status groups (low, low average, high average and high). We analyze metabolomic differences in PD effluents among PET groups of peritoneal transport status. HILIC LC-MS was implemented for metabolite detection. With data processing, PITracer peak detection algorithm and multivariate analysis we successfully recognized metabolite profiling patterns between PET defined high and low transport groups. The difference can be detected at 2 hour and 4 hour dialysate dwell by PCA and PLS-DA. Using variable important projection (VIP) values from PLS-DA, we found several metabolites significantly differentiated between Low and High transport groups, at 2 and/or at 4 hour dwell. Hippurate concentration was higher in High transport groups which had been suspected a risk metabolites in peritoneal effluent for encapsulating peritoneal sclerosis, a severe peritoneal dialysis complication. Prostaglandin E2, a peritoneal cellular reactive substance to high osmolar dialysate was found in higher concentration to Low transport group. A possible response biomarker indicating the higher osmolar gap from related lower flux of dialysate sugar. To find related metabolic pathways distinguished between Low and High transport group. Metabolic pathways related to amino acid, sugar and fatty acid were found. As the prognosis of peritoneal dialysis is deemed poorer in High transporter than in Low transporter. We provided possible biomarkers and involved metabolic pathways from metabolomics study to peritoneal creatinine equilibration defined clinical transport status. In conclusion, metabolomics study for clinically easily feasible peritoneal dialysis effluents provides promising study for peritoneal membrane pathophysiological changes.

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