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1.
Toxicol Lett ; 316: 136-146, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520701

RESUMO

Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multiple organs in offspring, but its serum metabolic profile changes before and after birth are unclear. Here, we employed a LC-MS-based metabolomic approach to detect serum metabolites of PDE offspring rats in utero and adulthood, and explore its change characteristics and toxicological significances. Meanwhile, the bodyweight, serum index related to hepatic and renal function were detected. As compared to healthy control rats, PDE reduced offspring birthweight but caused postnatal catch-up growth accompanied by adult liver and kidney function injury. In utero, the differential metabolites in response to PDE were mainly manifested as enhanced glycolysis, increased protein breakdown and disordered lipid metabolism, and multiple metabolic pathways were changed, which displayed gender differences. In adulthood, PDE offspring showed fewer and inconsistent types of differential metabolites compared to those in utero, which exhibited significant gender differences. The main differential metabolites induced by PDE included lactic acid, carnitine, cortexolone, bile acid, phosphatidylcholine, uric acid and platelet activating factor, which may participate in dexamethasone multi-organ toxicities and multi-disease susceptibility. In conclusion, PDE could induce a gender-difference and sustainable multi-organ damage in the offspring rats via serum metabolic profile analysis, which will enhance offspring susceptibility to multiple adult diseases.


Assuntos
Dexametasona/toxicidade , Metabolismo Energético/efeitos dos fármacos , Glucocorticoides/toxicidade , Metabolômica/métodos , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Peso ao Nascer/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dexametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Gravidez , Ratos Wistar , Medição de Risco , Fatores Sexuais , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Fatores de Tempo
2.
Cancer Sci ; 110(10): 3328-3339, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31429167

RESUMO

Apatinib, an antiangiogenic agent, shows efficient antitumor activity in a broad range of malignancies. Considering tumor is a type of metabolic disease, we investigated the metabolomics changes in serum and tumor after apatinib treatment and the molecular mechanism of characteristic changes associated with its antitumor efficacy. Molecules in serum and tumor tissue were extracted and analyzed by a gas chromatography-mass spectrometry metabolic platform. Apatinib significantly inhibited e tumor growth and alleviated metabolic rearrangement in both serum and tumor of A549 xenograft mice. Among these endogenous metabolites, 3-hydroxybutyric acid (3-HB) was significantly increased in serum, tumor and liver after apatinib treatment. Interestingly, giving exogenous 3-HB also inhibited tumor growth. Gene expression, dual luciferase reporter gene assay and molecular docking analysis all indicated that apatinib could induce 3-HB production through the dependent activation of peroxisome proliferator-activated receptor α (PPARα) and promotion of fatty acid utilization in the liver. Therefore, increased content of 3-HB induced by PPARα activation in the liver partially contributed to the antitumor effect of apatinib. It may provide clues to another potential mechanism underlying the antitumor effect of apatinib besides its antiangiogenic effect through inhibiting vascular endothelial growth factor receptor 2.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Fígado/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , PPAR alfa/genética , Piridinas/administração & dosagem , Células A549 , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Metabolômica/métodos , Camundongos , Piridinas/farmacologia , Ativação Transcricional , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Sci ; 110(10): 3267-3274, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444836

RESUMO

Although the proteasome inhibitor bortezomib (BTZ) shows excellent efficacy in multiple myeloma (MM), a fraction of patients has a suboptimal or no response to this agent. In addition, BTZ-induced peripheral neuropathy (BiPN), a frequent side-effect of this therapy, limits its use in some patients. This study aimed to explore serum lipid biomarker candidates to predict the response to BTZ and the severity of BiPN. Fifty-nine serum samples were collected from patients with MM prior to receiving BTZ plus low-dose dexamethasone therapy. Serum levels of phospholipids, sphingolipids, neutral lipids, and polyunsaturated fatty acids and their oxidation products were measured by a comprehensive lipidomic study. Overall, 385 lipid metabolites were identified in patients' sera; lower levels of several glycerophospholipids, sphingolipids, and cholesteryl esters were associated with a poor treatment response. Metabolites related to platelet-activating factor biosynthesis and cholesterol metabolism appeared particularly relevant. Furthermore, several lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids were significantly increased or decreased in patients with BiPN grades ranging from G0 to G3. Among these compounds, mediators reportedly inducing myelin breakdown and stimulating inflammatory responses were prominent. Although further study is necessary to validate these biomarker candidates, our results contribute to the development of predictive biomarkers for response to BTZ treatment, or ensuing severe BiPN, in patients with MM.


Assuntos
Bortezomib/administração & dosagem , Lipídeos/sangue , Metabolômica/métodos , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Bortezomib/efeitos adversos , Ésteres do Colesterol/sangue , Feminino , Glicerofosfolipídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/química , Índice de Gravidade de Doença , Esfingolipídeos/sangue , Resultado do Tratamento
4.
Physiol Rev ; 99(4): 1819-1875, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31434538

RESUMO

Metabolomics uses advanced analytical chemistry techniques to enable the high-throughput characterization of metabolites from cells, organs, tissues, or biofluids. The rapid growth in metabolomics is leading to a renewed interest in metabolism and the role that small molecule metabolites play in many biological processes. As a result, traditional views of metabolites as being simply the "bricks and mortar" of cells or just the fuel for cellular energetics are being upended. Indeed, metabolites appear to have much more varied and far more important roles as signaling molecules, immune modulators, endogenous toxins, and environmental sensors. This review explores how metabolomics is yielding important new insights into a number of important biological and physiological processes. In particular, a major focus is on illustrating how metabolomics and discoveries made through metabolomics are improving our understanding of both normal physiology and the pathophysiology of many diseases. These discoveries are yielding new insights into how metabolites influence organ function, immune function, nutrient sensing, and gut physiology. Collectively, this work is leading to a much more unified and system-wide perspective of biology wherein metabolites, proteins, and genes are understood to interact synergistically to modify the actions and functions of organelles, organs, and organisms.


Assuntos
Metabolismo Energético , Metaboloma , Metabolômica/métodos , Animais , Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Humanos , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/fisiopatologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Fluxo de Trabalho
5.
Anal Bioanal Chem ; 411(23): 6189-6202, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414155

RESUMO

It is a challenge to expand the metabolome coverage of liquid chromatography (LC)-electrospray ionization (ESI) mass spectrometry (MS) based untargeted metabolomics analysis. The limited coverage is attributed to the weak signal of hydroxyl and carboxyl groups in ESI-MS and the limited capacity of LC separation for metabolites with a wide range of polarities. Here a new sample preparation procedure is proposed to solve these problems. Mixed-mode (reversed-phase and anion-exchange) solid-phase extraction sorbents were used to separate metabolites into hydrophilic amine, hydrophobic amine/alcohol, and organic acid groups. Then, alcohols and carboxylic acids in separated groups were tagged with pyridine with use of two derivatization systems for signal enhancement. Finally, hydrophilic amines were analyzed by LC-MS with a hydrophilic interaction LC column, and the two hydrophobic compound groups were analyzed by LC-MS with a C18 column. From the results for standard samples, the detection limits of the new method are lower than those of the classic solvent extraction-protein precipitation method by 3.3-70 times for five amino acids and by 65-1141 times for five fatty acids. Moreover, the detection limit of this new method is 125 ng mL-1 for cholesterol, which has no signal with the classic method even at 10 µg mL-1. In seminal plasma samples, 110 more metabolites were identified by this new method than by the traditional solvent extraction-protein precipitation method in positive-mode ESI (new method vs traditional method, 65 vs 22 identified by comparing MS/MS spectra with those of standards, 203 vs 136 identified by searching MS spectra in a published database). Among them, 53 carboxylic acids and 21 alcohols were identified only by the new method, and more hydrophilic amine metabolites, such as amino acids and nucleosides, were identified by the new method than by the classic method. Finally, in application to the study of male infertility, more potential biomarkers of oligoasthenoteratospermic infertility were found with the new method (46 potential biomarkers) than with the classic method (19 potential biomarkers) and previously reported methods (10-30 potential biomarkers). Thus, it is demonstrated that this new sample preparation method expands the detection coverage of LC-MS-based untargeted metabolomics methods and has application potential in biological research.


Assuntos
Infertilidade Masculina/metabolismo , Metaboloma , Metabolômica/métodos , Sêmen/metabolismo , Biomarcadores/metabolismo , Humanos , Masculino , Sêmen/química , Extração em Fase Sólida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos
6.
J Agric Food Chem ; 67(34): 9667-9682, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31415166

RESUMO

This study assessed the feasibility of an NMR metabolomics approach coupled to multivariate data analysis to monitor the naturally present or stresses-elicited metabolites from a long-term (>170 days) culture of the dinoflagellate marine microalgae Amphidinium carterae grown in a fiberglass paddlewheel-driven raceway photobioreactor. Metabolic contents, in particular, in two members of the amphidinol family, amphidinol A and its 7-sulfate derivative amphidinol B (referred as APDs), and other compounds of interest (fatty acids, carotenoids, oxylipins, etc.) were evaluated by altering concentration levels of the f/2 medium nutrients and daily mean irradiance. Operating with a 24 h sinusoidal light cycle allowed a 3-fold increase in APD production, which was also detected by an increase in hemolytic activity of the methanolic extract of A. carterae biomass. The presence of APDs was consistent with the antitumoral activity measured in the methanolic extracts of the biomass. Increased daily irradiance was accompanied by a general decrease in pigments and an increase in SFAs (saturated fatty acids), MUFAs (monounsaturated fatty acids), and DHA (docosahexaenoic acid), while increased nutrient availability lead to an increase in sugar, amino acid, and PUFA ω-3 contents and pigments and a decrease in SFAs and MUFAs. NMR-based metabolomics is shown to be a fast and suitable method to accompany the production of APD and bioactive compounds without the need of tedious isolation methods and bioassays. The two APD compounds were chemically identified by spectroscopic NMR and spectrometric ESI-IT MS (electrospray ionization ion trap mass spectrometry) and ESI-TOF MS (ESI time-of-flight mass spectrometry) methods.


Assuntos
Dinoflagelados/metabolismo , Macrolídeos/química , Espectroscopia de Ressonância Magnética/métodos , Metabolômica/métodos , Microalgas/metabolismo , Carotenoides/química , Carotenoides/metabolismo , Dinoflagelados/química , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Macrolídeos/metabolismo , Microalgas/química , Análise Multivariada
7.
Food Chem ; 298: 125063, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31260979

RESUMO

Dioscorea opposita Thunb. cv. Tiegun (DTT), a type of homologous medicinal plant, is commonly used as food in daily life. However, there has always been confusion regarding removal of the peel, as the nutrient metabolite composition of the peel is unclear. Here, a nuclear magnetic resonance (NMR)-based metabolomics approach was used to determine the metabolite distribution in DTT exclude-peel and peel. Thirteen characteristic metabolites with statistical significance were identified and compared using multivariate, univariate and cluster analyses. The results demonstrated that the peel contained the higher levels of α-glucose, batatasin IV, batatasin I, asparagine, ß-glucose, protodioscin, threonine, protogracillin, dioscin, and ß-sitosteryl acetate, and the samples without the peel had the higher levels of leucine, glutamine and alanine. This study provided scientific data for understanding the distribution characteristics of metabolites in DTT samples, promoting reasonable consumption of DTT.


Assuntos
Dioscorea/metabolismo , Metabolômica/métodos , Análise por Conglomerados , Diosgenina/análogos & derivados , Diosgenina/química , Diosgenina/metabolismo , Leucina/metabolismo , Espectroscopia de Ressonância Magnética , Exsudatos de Plantas/metabolismo , Plantas Medicinais/metabolismo , Análise de Componente Principal , Saponinas/química , Saponinas/metabolismo
8.
Food Chem ; 300: 125169, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31336273

RESUMO

Red drupelet is a postharvest disorder of blackberries with several drupelets turning back to red. This affects visual quality and thus marketability and consumers' acceptance. However, the cause of this disorder as well as metabolite changes during color reversion have not been fully understood. Anthocyanins, cyanidin 3-glucoside, cyanidin 3-malonylglucoside, cyanidin 3-dioxalylglucoside, and total anthocyanin, were significantly lower in red drupelets than in black drupelets after 7 days of storage. Sugars and organic acids, lipids, and free amino acids also changed with storage and by color reversion. The untargeted metabolomics analyses indicated that red drupelets were generally differentiated from berries at harvest or black drupelets at metabolite level. The results of this study help better understand the red drupelet disorder. To our knowledge, this is the first study investigating red drupelet disorder by comparing black and red drupelets at metabolite level.


Assuntos
Metabolômica/métodos , Rubus/metabolismo , Aminoácidos/análise , Aminoácidos/metabolismo , Antocianinas/análise , Antocianinas/metabolismo , Cor , Qualidade dos Alimentos , Armazenamento de Alimentos , Frutas/química , Glucosídeos/análise , Glucosídeos/metabolismo , Lipídeos/análise , Rubus/química
9.
Ecotoxicol Environ Saf ; 182: 109427, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31302334

RESUMO

Polybrominated diphenyl ethers (PBDEs) as potential neurotoxicants in environment may possess hazards to human health. Previous studies have reported that PBDEs exposure could induce oxidative stress and disturb mitochondrial functions in mammalian cells. However, the toxicological mechanism remains to be clarified. In this work, the neurotoxic effect and underlying mechanism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was investigated by using human neuroblastoma SK-N-SH cells as an effective model. A liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach combined with cell viability assay was applied to elucidate the metabolic perturbations and relevant toxicological pathways upon BDE-47 exposure. Our results shown that the SK-N-SH cell viability decreased in a dose-dependent manner after exposure to BDE-47 at 24 h within the concentration range of 5-250 µM, and an IC50 value of 88.8 µM was obtained. Based on the dose-response curve and cell morphological observation, the 5 and 10 µM BDE-47 doses (equal to IC5 and IC10, respectively) were used for metabolomics study to capture the sensitive metabolic response following BDE-47 exposure. After BDE-47 treatment, nine metabolites were identified as potential biomarkers, and the most disturbed metabolic pathways were mainly involved in alanine, aspartate and glutamate metabolism, glutathione metabolism, tyrosine and phenylalanine metabolism, and pyrimidine metabolism, which imply that metabolic changes related to neurotransmitters, oxidative stress, and nucleotide-mediated signal transduction systems were the sensitive pathways mostly influenced. Our findings reported here may provide potential neurotoxic effect biomarkers and prompt deep understanding of the molecular and metabolic mechanisms triggered by BDE-47 exposure.


Assuntos
Ácido Glutâmico/metabolismo , Éteres Difenil Halogenados/toxicidade , Pirimidinas/metabolismo , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Metabolômica/métodos , Mitocôndrias/metabolismo , Neuroblastoma , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Testes de Toxicidade
10.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1760-1766, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342699

RESUMO

Lipids have been documented to play comprehensive and significant role in many biological processes. As a branch of metabolomics,lipidomics research mainly involves the analysis of the variation of lipid metabolism profiles under different physiologic,pathologic conditions or drug intervention,the discovery of key lipid biomarkers of a disease in lipid metabolic networks,and the study of the mechanism of action of lipid metabolic regulation during disease onset and progression,and drug treatment. Traditional Chinese medicines( TCMs)are characterized with integrated effects by multi-components,multi-targets and integrated effects. It is urgent to develop methods suitable for the study of complex TCMs to reveal the active constituents and integrated mechanism of action. Systems biology such as lipidomics provides valuable strategy and approach to illustrate the complex mechanisms of TCMs. In this paper,in order to provide technical references for TCMs,we have reviewed the analytical techniques applied in lipidomics and the applications of lipidomics in TCMs researches.


Assuntos
Metabolismo dos Lipídeos , Medicina Tradicional Chinesa , Metabolômica/métodos , Biomarcadores
11.
BMC Bioinformatics ; 20(1): 376, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277571

RESUMO

BACKGROUND: Molecule identification is a crucial step in metabolomics and environmental sciences. Besides in silico fragmentation, as performed by MetFrag, also machine learning and statistical methods evolved, showing an improvement in molecule annotation based on MS/MS data. In this work we present a new statistical scoring method where annotations of m/z fragment peaks to fragment-structures are learned in a training step. Based on a Bayesian model, two additional scoring terms are integrated into the new MetFrag2.4.5 and evaluated on the test data set of the CASMI 2016 contest. RESULTS: The results on the 87 MS/MS spectra from positive and negative mode show a substantial improvement of the results compared to submissions made by the former MetFrag approach. Top1 rankings increased from 5 to 21 and Top10 rankings from 39 to 55 both showing higher values than for CSI:IOKR, the winner of the CASMI 2016 contest. For the negative mode spectra, MetFrag's statistical scoring outperforms all other participants which submitted results for this type of spectra. CONCLUSIONS: This study shows how statistical learning can improve molecular structure identification based on MS/MS data compared on the same method using combinatorial in silico fragmentation only. MetFrag2.4.5 shows especially in negative mode a better performance compared to the other participating approaches.


Assuntos
Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Teorema de Bayes , Simulação por Computador , Estrutura Molecular
12.
J Sci Food Agric ; 99(14): 6455-6461, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31294826

RESUMO

BACKGROUND: The illegal undeclared addition of reconstituted milk powder to ultra-heat treated (UHT) milk to lower production costs is an example of economically motivated adulteration. This activity not only defrauds consumers but also places honest traders at a disadvantage, which could damage the reputation of milk producers and reduce the integrity of the markets. In this research, a non-targeted analytical strategy that combines proton (1 H) nuclear magnetic resonance (NMR) spectroscopy with a chemometrics data mining tool was developed for the authentication of bovine UHT milk. RESULTS: Unsupervised principal component analysis was used to distinguish UHT and tap-water-reconstituted powdered milk. Partial least squares-discriminant analysis (PLS-DA) with R2 (Y) and Q2 equal to 0.859 and 0.748, respectively, was used to differentiate UHT and reconstituted milk samples. Three compounds were selected as biomarkers to distinguish UHT and reconstituted milk and identified according to the standard NMR-spectra database. Finally, a PLS-DA model was established, according to the characteristic spectral bands, to identify UHT milk and reconstituted milk. CONCLUSION: This procedure demonstrated the feasibility of using non-targeted NMR profiling combined with chemometric analysis to combat mislabeling and fraudulent practices in milk production. © 2019 Society of Chemical Industry.


Assuntos
Biomarcadores/análise , Contaminação de Alimentos/análise , Metabolômica/métodos , Leite/química , Espectroscopia de Prótons por Ressonância Magnética/métodos , Animais , Bovinos , Análise Discriminante , Análise de Componente Principal
13.
Aquat Toxicol ; 213: 105215, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31200330

RESUMO

Coral reefs are in significant decline globally due to climate change and environmental pollution. The ocean is becoming more acidic due to rising atmospheric pCO2, and ocean acidification is considered a major threat to coral reefs. However, little is known about the exact mechanism by which acidification impacts coral symbiosis. As an important component of the symbiotic association, to explore the responses of symbionts could greatly enhance our understanding of this issue. The present work aimed to identify metabolomic changes of Breviolum minutum in acidification (low pH) condition, and investigate the underlying mechanisms responsible. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine metabolite profiles after exposure to ambient and acidic conditions. We analysed the resulting metabolite data, and acidification appeared to have little effect on photosynthetic parameters, but it inhibited growth. Marked alterations in metabolite pools were observed in response to acidification that may be important in acclimation to climate change. Acidification may affect the biosynthesis of amino acids and proteins, and thereby inhibit the growth of B. minutum. Metabolites identified using this approach provide targets for future analyses aimed at understanding the responses of Symbiodiniaceae to environmental disturbance.


Assuntos
Ácidos/metabolismo , Antozoários/metabolismo , Metabolômica/métodos , Animais , Análise por Conglomerados , Recifes de Corais , Metaboloma , Fotossíntese , Poluentes Químicos da Água/toxicidade
14.
Analyst ; 144(13): 3988-3998, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31169288

RESUMO

Methylation of components involved in one-carbon metabolism is extremely important in cancer; comprehensive studies on methylation are essential and may provide us with a better understanding of tumorigenesis, and lead to the discovery of potential biomarkers. Here, we present an improved methodology for methylated metabolite profiling and its relative quantification in breast cancer cell lines by isotope dilution mass spectrometry based on 13CD3-methionine metabolic labeling using ultra-high-performance liquid chromatography coupled with high-resolution tandem mass spectrometry (UPLC-HRMS/MS). First, all the methylated metabolites related to methionine were first screened and profiled by introducing 13CD3-methionine as the only medium into breast cancer cell growth cultures for both cellular polar metabolites and lipids. In total, we successfully found 20 labeled methylated metabolites and most of them were identified, some of which have not been reported before. We also developed a relative quantification method for all identified methylated metabolites based on isotope dilution mass spectrometry assays. Finally, the developed method was used for different breast cancer cells and mammary epithelial cells. Most methylated metabolites were disrupted in cancer cells. 1-Methyl-nicotinamide was decreased significantly, while trimethylglycine-glutamic acid-lysine and trimethyl-lysine were increased more than five times. This method offers a new insight into the methylation process, with several key pathways and important new metabolites being identified. Further investigation with biological assays should help to reveal the overall methylation metabolic network.


Assuntos
Metaboloma , Metabolômica/métodos , Metionina/metabolismo , Isótopos de Carbono/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Deutério/química , Humanos , Marcação por Isótopo , Metionina/química , Metilação , Espectrometria de Massas em Tandem
15.
Vasc Health Risk Manag ; 15: 123-135, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190850

RESUMO

Purpose: Disturbed metabolism of cholesterol and triacylglycerols (TGs) carries increased risk for coronary artery calcification (CAC). However, the exact relationship between individual lipid species and CAC remains unclear. The aim of this study was to identify disturbances in lipid profiles involved in the calcification process, in an attempt to propose potential biomarker candidates. Patients and methods: We studied 70 patients at intermediate risk for coronary artery disease who had undergone coronary calcification assessment using computed tomography and Agatston coronary artery calcium score (CACS). Patients were divided into three groups: with no coronary calcification (NCC; CACS: 0; n=26), mild coronary calcification (MCC; CACS: 1-250; n=27), or severe coronary calcification (SCC; CACS: >250; n=17). Patients' serum samples were analyzed using liquid chromatography-mass spectrometry in an untargeted lipidomics approach. Results: We identified 103 lipids within the glycerolipid, glycerophospholipid, sphingolipid, and sterol lipid classes. After false discovery rate correction, phosphatidylcholine (PC)(16:0/20:4) in higher levels and PC(18:2/18:2), PC(36:3), and phosphatidylethanolamine(20:0/18:2) in lower levels were identified as correlates with SCC compared to NCC. There were no significant differences in the levels of individual TGs between the three groups; however, clustering the lipid profiles showed a trend for higher levels of saturated and monounsaturated TGs in SCC compared to NCC. There was also a trend for lower TG(49:2), TG(51:1), TG(54:5), and TG(56:8) levels in SCC compared to MCC. Conclusion: In this study we investigated the lipidome of patients with coronary calcification. Our results suggest that the calcification process may be associated with dysfunction in autophagy. The lipidomic biomarkers revealed in this study may aid in better assessment of patients with subclinical coronary artery disease.


Assuntos
Doença da Artéria Coronariana/sangue , Dislipidemias/sangue , Metabolômica/métodos , Fosfolipídeos/sangue , Calcificação Vascular/sangue , Idoso , Doenças Assintomáticas , Autofagia , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Dislipidemias/diagnóstico , Dislipidemias/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Espectrometria de Massas por Ionização por Electrospray , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/patologia
16.
Nat Commun ; 10(1): 2701, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221965

RESUMO

One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Mutação com Ganho de Função , Perfilação da Expressão Gênica/métodos , Glicólise/efeitos dos fármacos , Glicólise/genética , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica/métodos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Serina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Chem Commun (Camb) ; 55(60): 8868-8871, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31240288

RESUMO

New evidence on the role of H2S as a gasotransmitter suggests that the true signalling effectors are polysulfides. Both oxidized polysulfides and hydropolysulfides were synthesized and their presence in S. cerevisiae was observed for the first time. A single gene-deletant approach allowed observation of the modulation of polysulfide species and levels.


Assuntos
Gasotransmissores/análise , Saccharomyces cerevisiae/química , Sulfetos/análise , Proteínas de Transporte/genética , Cistationina beta-Sintase/genética , Cistationina gama-Liase/genética , Gasotransmissores/síntese química , Gasotransmissores/metabolismo , Deleção de Genes , Metabolômica/métodos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Sulfetos/síntese química , Sulfetos/metabolismo
18.
BMC Bioinformatics ; 20(1): 334, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200644

RESUMO

BACKGROUND: Untargeted metabolomics datasets contain large proportions of uninformative features that can impede subsequent statistical analysis such as biomarker discovery and metabolic pathway analysis. Thus, there is a need for versatile and data-adaptive methods for filtering data prior to investigating the underlying biological phenomena. Here, we propose a data-adaptive pipeline for filtering metabolomics data that are generated by liquid chromatography-mass spectrometry (LC-MS) platforms. Our data-adaptive pipeline includes novel methods for filtering features based on blank samples, proportions of missing values, and estimated intra-class correlation coefficients. RESULTS: Using metabolomics datasets that were generated in our laboratory from samples of human blood, as well as two public LC-MS datasets, we compared our data-adaptive filtering method with traditional methods that rely on non-method specific thresholds. The data-adaptive approach outperformed traditional approaches in terms of removing noisy features and retaining high quality, biologically informative ones. The R code for running the data-adaptive filtering method is provided at https://github.com/courtneyschiffman/Metabolomics-Filtering . CONCLUSIONS: Our proposed data-adaptive filtering pipeline is intuitive and effectively removes uninformative features from untargeted metabolomics datasets. It is particularly relevant for interrogation of biological phenomena in data derived from complex matrices associated with biospecimens.


Assuntos
Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Neoplasias Colorretais/metabolismo , Bases de Dados como Assunto , Humanos , Redes e Vias Metabólicas
19.
Food Chem ; 295: 368-376, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31174771

RESUMO

In liquid chromatography-mass spectrometry (LC-MS) metabolomics, data matrices with up to thousands of variables for each ion peak are subjected to multivariate analysis (MVA) to assess the homogeneity between samples. The large dimensions of LC/MS datasets hinder the identification of the discriminant or the metabolic markers. In the present study, the molecular network (MN) approach and two in silico annotation tools, network annotation propagation (NAP) and the hierarchical chemical classification method, ClassyFire, were used to annotate the metabolites of three Zanthoxylum species, Z. bungeanum, Z. schinifolium and Z. piperitum. The in silico annotation results of the MN nodes and the MVA variables were combined and visualized in loading plots. This approach helped intuitive detection of the variables that greatly contributed to the separation of the samples in the score plot as discriminant or metabolic markers, thereby allowing rapid annotation of two flavanone derivatives.


Assuntos
Biomarcadores/análise , Espectrometria de Massas/métodos , Metabolômica/métodos , Zanthoxylum/química , Zanthoxylum/metabolismo , Biomarcadores/metabolismo , Cromatografia Líquida , Simulação por Computador , Software
20.
Food Chem ; 296: 132-141, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31202297

RESUMO

Spontaneous fermentation is a critical step in the processing of high-quality fish sauce. In this study, a comparative UHPLC-Q/TOF-MS-based metabolomics approach combining equivalent-quantification and the taste activity value (TAV) was used, for the first time, to evaluate the taste qualities and characterize metabolite profiles in Chinese fish sauce during fermentation. A total of 22,816 metabolite ion features were extracted from fish sauce samples. Forty-six metabolites, including amino acids, small peptides, organic acids, amines, carbohydrates, and nucleic acids, were identified as key chemical components of fish sauce. In addition, absolute quantification and TAV showed that aspartic acid and glutamic acid exert an important influence on the umami taste of fish sauce. Specific metabolites were primarily associated with amino acid metabolism, particularly alterations in arginine and proline metabolism. This study identifies chemical components and provides novel insights into the taste quality of fish sauce due to fermentation.


Assuntos
Alimentos Fermentados/análise , Peixes/metabolismo , Metabolômica/métodos , Paladar , Aminoácidos/análise , Animais , China , Cromatografia Líquida de Alta Pressão , Análise Discriminante , Análise dos Mínimos Quadrados , Espectrometria de Massas , Análise de Componente Principal
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