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1.
Mol Cell ; 81(18): 3775-3785, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34547238

RESUMO

With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.


Assuntos
Redes e Vias Metabólicas/fisiologia , Metabolismo/fisiologia , Metaboloma/fisiologia , Animais , Humanos , Complexos Multienzimáticos/metabolismo , Mapas de Interação de Proteínas/fisiologia , Purinas/metabolismo
2.
Invest Ophthalmol Vis Sci ; 62(10): 4, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347011

RESUMO

Purpose: Diabetic retinopathy (DR), a common microvascular complication of diabetes, is the leading cause of acquired blindness in the working-age population. Individuals with diabetes still develop DR despite appropriate glycemic and blood pressure control, highlighting the pressing need to identify useful biomarkers for risk stratification. The purpose of this review is to systematically summarize potential metabolic biomarkers and pathways of DR, which could facilitate developing an understanding of the disease mechanisms, as well as new therapeutic measures. Methods: We searched PubMed and Web of Science for relevant metabolomics studies on humans published before September 30, 2020. Information regarding authors, title, publication date, study subjects, analytical platforms, methods of statistical analysis, biological samples, directions of change of potential metabolic biomarkers, and predictive values of metabolic biomarker panels was extracted, and the quality of the studies was assessed. Pathway analysis, including enrichment analysis and topology analysis, was derived from integrating differential metabolites using MetaboAnalyst 3.0, based on the Kyoto Encyclopedia of Genes and Genomes and Human Metabolome Database. Results: We found nine studies focused on the identification of potential biomarkers. Repeatedly identified metabolites including l-glutamine, l-lactic acid, pyruvic acid, acetic acid, l-glutamic acid, d-glucose, l-alanine, l-threonine, citrulline, l-lysine, and succinic acid were found to be potential biomarkers of DR. It was observed that l-glutamine and citrulline changed in all biological samples. Dysregulation of metabolic pathways involved amino acid and energy metabolism. Conclusions: This review summarizes potential biomarkers and metabolic pathways, providing insights into new pathogenic pathways for this microvascular complication of diabetes.


Assuntos
Retinopatia Diabética/metabolismo , Metaboloma/fisiologia , Metabolômica/métodos , Biomarcadores/metabolismo , Humanos , Redes e Vias Metabólicas
3.
Curr Top Med Chem ; 21(11): 985-994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34355684

RESUMO

BACKGROUND: Although Autism Spectrum Disorder (ASD) is considered a heterogeneous neurological disease in childhood, a growing body of evidence associates it with mitochondrial dysfunction explaining the observed comorbidities. INTRODUCTION: The aim of this study is to identify variations in cellular bioenergetics and metabolism dependent on mitochondrial function in ASD patients and healthy controls using Peripheral Blood Mononuclear Cells (PBMCs). We hypothesized that PBMCs may reveal the cellular pathology and provide evidence of bioenergetic and metabolic changes accompanying the disease. METHODS: PBMC from children with ASD and a control group of the same age and gender were isolated. All patients underwent an in-depth clinical evaluation. A well-characterized cohort of Bulgarian children is selected. Bioenergetic and metabolic studies of isolated PBMCs are performed with a Seahorse XFp analyzer. RESULTS: Our data show that PBMCs from patients with ASD have increased respiratory reserve capacity (by 27.5%), increased maximal respiration (by 67%) and altered adaptive response to oxidative stress induced by DMNQ. In addition, we demonstrate а strong dependence on fatty acids and impaired ability to reprogram cell metabolism. The listed characteristics are not observed in the control group. These results can contribute to a better understanding of the underlying causes of ASD, which is crucial for selecting a successful treatment. CONCLUSION: The current study, for the first time, provides a functional analysis of cell bioenergetics and metabolic changes in a group of Bulgarian patients with ASD. It reveals physiological abnormalities that do not allow mitochondria to adapt and meet the increased energetic requirements of the cell. The link between mitochondria and ASD is not yet fully understood, but this may lead to the discovery of new approaches for nutrition and therapy.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Metabolismo Energético/fisiologia , Leucócitos Mononucleares/metabolismo , Metaboloma/fisiologia , Mitocôndrias/metabolismo , Criança , Pré-Escolar , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Mitocôndrias/ultraestrutura , Estresse Oxidativo , Respiração
4.
Nutrients ; 13(8)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34444997

RESUMO

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 (n = 59) and 32 (n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.


Assuntos
Quimiocina CCL17/sangue , Sangue Fetal/química , Microbioma Gastrointestinal/fisiologia , Metaboloma/fisiologia , Adulto , Biomarcadores/sangue , Ácidos Graxos Voláteis/análise , Fezes/microbiologia , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez
5.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299495

RESUMO

Bicuspid aortic valve (BAV) is the most common congenital heart defect responsible for valvular and aortic complications in affected patients. Causes and mechanisms of this pathology are still elusive and thus the lack of early detection biomarkers leads to challenges in its diagnosis and prevention of associated cardiovascular anomalies. The aim of this study was to explore the potential use of urine Nuclear Magnetic Resonance (NMR) metabolomics to evaluate a molecular fingerprint of BAV. Both multivariate and univariate statistical analyses were performed to compare the urinary metabolome of 20 patients with BAV with that of 24 matched controls. Orthogonal partial least squared discriminant analysis (OPLS-DA) showed statistically significant discrimination between cases and controls, suggesting seven metabolites (3-hydroxybutyrate, alanine, betaine, creatine, glycine, hippurate, and taurine) as potential biomarkers. Among these, glycine, hippurate and taurine individually displayed medium sensitivity and specificity by receiver operating characteristic (ROC) analysis. Pathway analysis indicated two metabolic pathways likely perturbed in BAV subjects. Possible contributions of gut microbiota activity and energy imbalance are also discussed. These results constitute encouraging preliminary findings in favor of the use of urine-based metabolomics for early diagnosis of BAV.


Assuntos
Doença da Válvula Aórtica Bicúspide/metabolismo , Doença da Válvula Aórtica Bicúspide/urina , Biomarcadores/urina , Metaboloma/fisiologia , Adolescente , Adulto , Idoso , Análise Discriminante , Feminino , Humanos , Análise dos Mínimos Quadrados , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Redes e Vias Metabólicas/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
6.
Molecules ; 26(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34299442

RESUMO

A new strategy that takes advantage of the synergism between NMR and UHPLC-HRMS yields accurate concentrations of a high number of compounds in biofluids to delineate a personalized metabolic profile (SYNHMET). Metabolite identification and quantification by this method result in a higher accuracy compared to the use of the two techniques separately, even in urine, one of the most challenging biofluids to characterize due to its complexity and variability. We quantified a total of 165 metabolites in the urine of healthy subjects, patients with chronic cystitis, and patients with bladder cancer, with a minimum number of missing values. This result was achieved without the use of analytical standards and calibration curves. A patient's personalized profile can be mapped out from the final dataset's concentrations by comparing them with known normal ranges. This detailed picture has potential applications in clinical practice to monitor a patient's health status and disease progression.


Assuntos
Metabolômica/métodos , Medicina de Precisão/métodos , Urina/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão/métodos , Cistite/metabolismo , Cistite/urina , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Metaboloma/fisiologia , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodos , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/urina
7.
PLoS One ; 16(6): e0252378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086721

RESUMO

Diagnosis of microbial disease etiology in community-acquired pneumonia (CAP) remains challenging. We undertook a large-scale metabolomics study of serum samples in hospitalized CAP patients to determine if host-response associated metabolites can enable diagnosis of microbial etiology, with a specific focus on discrimination between the major CAP pathogen groups S. pneumoniae, atypical bacteria, and respiratory viruses. Targeted metabolomic profiling of serum samples was performed for three groups of hospitalized CAP patients with confirmed microbial etiologies: S. pneumoniae (n = 48), atypical bacteria (n = 47), or viral infections (n = 30). A wide range of 347 metabolites was targeted, including amines, acylcarnitines, organic acids, and lipids. Single discriminating metabolites were selected using Student's T-test and their predictive performance was analyzed using logistic regression. Elastic net regression models were employed to discover metabolite signatures with predictive value for discrimination between pathogen groups. Metabolites to discriminate S. pneumoniae or viral pathogens from the other groups showed poor predictive capability, whereas discrimination of atypical pathogens from the other groups was found to be possible. Classification of atypical pathogens using elastic net regression models was associated with a predictive performance of 61% sensitivity, 86% specificity, and an AUC of 0.81. Targeted profiling of the host metabolic response revealed metabolites that can support diagnosis of microbial etiology in CAP patients with atypical bacterial pathogens compared to patients with S. pneumoniae or viral infections.


Assuntos
Infecções Comunitárias Adquiridas/metabolismo , Metaboloma/fisiologia , Idoso , Bactérias/patogenicidade , Doenças Transmissíveis/metabolismo , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/virologia , Feminino , Hospitalização , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Infecções Pneumocócicas/metabolismo , Infecções Pneumocócicas/microbiologia , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/microbiologia , Streptococcus pneumoniae/patogenicidade , Vírus/patogenicidade
8.
Adv Sci (Weinh) ; 8(17): e2101222, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34180141

RESUMO

COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+ ) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.


Assuntos
COVID-19/metabolismo , Adulto , Idoso , Antioxidantes/metabolismo , COVID-19/sangue , Método Duplo-Cego , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Metaboloma/fisiologia , Pessoa de Meia-Idade , Proteínas/metabolismo , Proteoma/metabolismo , Adulto Jovem
9.
Biomed Chromatogr ; 35(10): e5183, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34058018

RESUMO

Dyslipidemia is a common, chronic metabolic disease associated with cardiovascular complications. Due to the multiplicity of etiological factors, the pathogenesis of dyslipidemia is still unclear. In this study, we combined proteomics and metabolomics methods to analyze the plasma of patients with dyslipidemia and healthy subjects. isobaric tags for relative and absolute quantification (iTRAQ) markers, combined with LC-MS/MS proteomics technology and the UHPLC/Orbitfast-X Tribrid system, were used to establish the metabolite profile in clinical dyslipidemia. A total of 137 differentially expressed proteins, mainly related to biological processes such as protein activation cascades, adaptive immune responses, complement activation, acute inflammatory responses, and regulation of acute inflammatory responses, were identified. These proteins are involved in the regulation of important metabolic pathways, such as immunity and inflammation, coagulation and hemostasis, lipid metabolism, and oxidation and antioxidant defenses. The analysis of clinical metabolites showed there were 69 different metabolites in plasma, mainly related to glycerolipid, sphingolipid, porphyrin, α-linolenic acid, linoleic acid, and arachidonic acid metabolism, suggesting that the regulation of inflammation and lipid metabolism may be disturbed in patients with dyslipidemia. Among these, significant changes were observed in indole-3-propionic acid (IPA), which is considered as a potential biomarker of dyslipidemia. The combined analysis of proteins and metabolites showed that arachidonic acid, linoleic acid, and lipid metabolic pathways were closely related to dyslipidemia. IPA may be a potential biomarker. The information provided in this study may provide new insights into the pathogenesis of animal models of dyslipidemia and related disease models, as well as potential intervention targets.


Assuntos
Dislipidemias , Metaboloma/fisiologia , Metabolômica/métodos , Proteoma/análise , Proteômica/métodos , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteínas Sanguíneas/análise , Cromatografia Líquida , Dislipidemias/sangue , Dislipidemias/metabolismo , Humanos , Redes e Vias Metabólicas , Espectrometria de Massas em Tandem , Adulto Jovem
10.
Plant Cell ; 33(3): 492-510, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33955498

RESUMO

The optimal extraction of information from untargeted metabolomics analyses is a continuing challenge. Here, we describe an approach that combines stable isotope labeling, liquid chromatography- mass spectrometry (LC-MS), and a computational pipeline to automatically identify metabolites produced from a selected metabolic precursor. We identified the subset of the soluble metabolome generated from phenylalanine (Phe) in Arabidopsis thaliana, which we refer to as the Phe-derived metabolome (FDM) In addition to identifying Phe-derived metabolites present in a single wild-type reference accession, the FDM was established in nine enzymatic and regulatory mutants in the phenylpropanoid pathway. To identify genes associated with variation in Phe-derived metabolites in Arabidopsis, MS features collected by untargeted metabolite profiling of an Arabidopsis diversity panel were retrospectively annotated to the FDM and natural genetic variants responsible for differences in accumulation of FDM features were identified by genome-wide association. Large differences in Phe-derived metabolite accumulation and presence/absence variation of abundant metabolites were observed in the nine mutants as well as between accessions from the diversity panel. Many Phe-derived metabolites that accumulated in mutants also accumulated in non-Col-0 accessions and was associated to genes with known or suspected functions in the phenylpropanoid pathway as well as genes with no known functions. Overall, we show that cataloguing a biochemical pathway's products through isotopic labeling across genetic variants can substantially contribute to the identification of metabolites and genes associated with their biosynthesis.


Assuntos
Arabidopsis/metabolismo , Estudo de Associação Genômica Ampla/métodos , Metaboloma/fisiologia , Arabidopsis/genética , Marcação por Isótopo , Espectrometria de Massas , Metaboloma/genética , Metabolômica/métodos , Estudos Retrospectivos
11.
Obesity (Silver Spring) ; 29(6): 1074-1082, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34029446

RESUMO

OBJECTIVE: The purpose of this study was to characterize the metabolomic profiles of shift workers and day workers and to discover the effect of shift work on workers' metabolic health. METHODS: A total of 824 participants aged 25 to 55 years were recruited, and 485 (275 shift workers and 210 day workers) completed the study. The mean age of the shift workers was 37.32 (5.53) years old, and that of day workers was 36.50 (7.83) years old. Serum and salivary samples were collected for the detection of key biochemical indicators (melatonin, cholesterol, and low-density lipoprotein cholesterol) and for metabolome profile analyses. RESULTS: Compared with female day workers, female shift workers had a higher BMI, waist circumference, and hip circumference. Correspondingly, we identified 76 significant metabolites (false discovery rate < 0.05) in shift workers, including L-tryptophan, acylcarnitines, and several fatty acids. Three pathways that presented significant differences were biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and ubiquinone and other terpenoid-quinone biosynthesis. CONCLUSIONS: Compared with day workers, shift workers were more prone to weight gain and central obesity and were at a higher risk for impaired lipid metabolism with disrupted circadian rhythms.


Assuntos
Ritmo Circadiano/fisiologia , Metaboloma/fisiologia , Jornada de Trabalho em Turnos , Adulto , Estudos de Casos e Controles , Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Feminino , Humanos , Metabolismo dos Lipídeos/fisiologia , Masculino , Melatonina/sangue , Metabolômica , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/etiologia , Obesidade/metabolismo , Jornada de Trabalho em Turnos/estatística & dados numéricos , Transtornos do Sono do Ritmo Circadiano/complicações , Transtornos do Sono do Ritmo Circadiano/epidemiologia , Transtornos do Sono do Ritmo Circadiano/metabolismo , Local de Trabalho/estatística & dados numéricos
12.
Nat Commun ; 12(1): 3178, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039963

RESUMO

Living systems formed and evolved under constraints that govern their interactions with the inorganic world. These interactions are definable using basic physico-chemical principles. Here, we formulate a comprehensive set of ten governing abiotic constraints that define possible quantitative metabolomes. We apply these constraints to a metabolic network of Escherichia coli that represents 90% of its metabolome. We show that the quantitative metabolomes allowed by the abiotic constraints are consistent with metabolomic and isotope-labeling data. We find that: (i) abiotic constraints drive the evolution of high-affinity phosphate transporters; (ii) Charge-, hydrogen- and magnesium-related constraints underlie transcriptional regulatory responses to osmotic stress; and (iii) hydrogen-ion and charge imbalance underlie transcriptional regulatory responses to acid stress. Thus, quantifying the constraints that the inorganic world imposes on living systems provides insights into their key characteristics, helps understand the outcomes of evolutionary adaptation, and should be considered as a fundamental part of theoretical biology and for understanding the constraints on evolution.


Assuntos
Adaptação Fisiológica , Escherichia coli/fisiologia , Metaboloma/fisiologia , Estresse Fisiológico , Ácidos/metabolismo , Evolução Biológica , Escherichia coli/química , Proteínas de Escherichia coli/análise , Proteínas de Escherichia coli/metabolismo , Regulação da Expressão Gênica/fisiologia , Hidrogênio/metabolismo , Magnésio/metabolismo , Redes e Vias Metabólicas/fisiologia , Metabolômica , Osmose , Proteínas de Transporte de Fosfato/metabolismo , Fosfatos/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-34052752

RESUMO

Detailed metabolic profiling of needles of five Pinus species was investigated using complementary HPLC-MS/MS techniques together with supervised and unsupervised chemometric tools. This resulted in putative identification of 44 compounds belonging to flavonoids, phenolics, lignans, diterpenes and fatty acids. Unsupervised principal component analysis showed that differences were maintained across the metabolites characteristic of each Pinus species, are mainly related to di-O-p-coumaroyltrifolin, p-coumaroyl quinic acid derivative, arachidonic acid, hydroxypalmitic acid, isopimaric acid and its derivative. A supervised Partial Least Squares regression analysis was performed to correlate HPLC-MS/MS profiles with the variation observed in the in vitro anticholinesterase, antiaging and anti-diabetic potential. All investigated Pinus extracts exerted their antiaging activity via increasing telomerase and TERT levels in normal human melanocytes cells compared to the control (untreated cells). Profound inhibition activities of acetylcholinesterase and dipeptidyl peptidase-4 were also observed with P. pinea and P. canariensis extracts having comparable antidiabetic activities to sitagliptin as a standard antidiabetic drug. Our findings suggested that pine needles are a good source of phenolics and diterpenoids that have possible health promoting activities in management and alleviation of diabetic conditions and Alzheimer disease.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Metaboloma/fisiologia , Pinus , Espectrometria de Massas em Tandem/métodos , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Diterpenos/análise , Diterpenos/química , Diterpenos/metabolismo , Flavonoides/análise , Flavonoides/química , Flavonoides/metabolismo , Hipoglicemiantes/análise , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Metabolômica , Pinus/química , Pinus/metabolismo , Extratos Vegetais/química , Substâncias Protetoras/análise , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Extração em Fase Sólida/métodos
14.
Lab Invest ; 101(9): 1281-1288, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34021261

RESUMO

Urachal adenocarcinomas (UrC) are rare but aggressive. Despite being of profound therapeutic relevance, UrC cannot be differentiated by histomorphology alone from other adenocarcinomas of differential diagnostic importance. As no reliable tissue-based diagnostic biomarkers are available, we aimed to detect such by integrating mass-spectrometry imaging-based metabolomics and digital pathology, thus allowing for a multimodal approach on the basis of spatial information. To achieve this, a cohort of UrC (n = 19) and colorectal adenocarcinomas (CRC, n = 27) as the differential diagnosis of highest therapeutic relevance was created, tissue micro-arrays (TMAs) were constructed, and pathological data was recorded. Hematoxylin and eosin (H&E) stained tissue sections were scanned and annotated, enabling an automized discrimination of tumor and non-tumor areas after training of an adequate algorithm. Spectral information within tumor regions, obtained via matrix-assisted laser desorption/ionization (MALDI)-Orbitrap-mass spectrometry imaging (MSI), were subsequently extracted in an automated workflow. On this basis, metabolic differences between UrC and CRC were revealed using machine learning algorithms. As a result, the study demonstrated the feasibility of MALDI-MSI for the evaluation of FFPE tissue in UrC and CRC with the potential to combine spatial metabolomics data with annotated histopathological data from digitalized H&E slides. The detected Area under the curve (AUC) of 0.94 in general and 0.77 for the analyte taurine alone (diagnostic accuracy for taurine: 74%) makes the technology a promising tool in this differential diagnostic dilemma situation. Although the data has to be considered as a proof-of-concept study, it presents a new adoption of this technology that has not been used in this scenario in which reliable diagnostic biomarkers (such as immunohistochemical markers) are currently not available.


Assuntos
Metabolômica/métodos , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Neoplasias da Bexiga Urinária , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Metaboloma/fisiologia , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-34052558

RESUMO

Ginkgolides from Ginkgo Biloba have significantly therapeutic effect to cardiovascular and cerebrovascular diseases. However, the biosynthetic pathway of ginkgolides has not been fully elucidated until now. As ginkgolides are synthesized in the ginkgo roots, the accumulation of ginkgolides intermediate metabolites varies greatly between roots and leaves. As Methyl jasmonate (MeJA) can effectively enhance the biosynthesis of ginkgolides, a novel method based on MeJA induction and differential metabolomics was used to screen the differentially intermediate metabolites among ginkgo leaves, roots and roots-MJ-3. Two differential intermediate metabolites (dehydroabietadienal and 1, 2, 3, 4, 4a, 9, 10, 10a-Octahydro-6-hydroxy-7-isopropyl-1, 4a-dimethyl-1-phenanthrenemethanol) were identified in ginkgo roots by UPLC-QTOF-MS. Then, a new ginkgolides biosynthetic pathway was proposed based on differential metabolomics. This study provides a novel method for the elucidation of nature product precursor and is helpful to promote the clarification of ginkgolides biosynthetic pathway.


Assuntos
Acetatos/metabolismo , Ciclopentanos/metabolismo , Ginkgo biloba/metabolismo , Ginkgolídeos , Metaboloma/fisiologia , Oxilipinas/metabolismo , Cromatografia Líquida de Alta Pressão , Ginkgolídeos/análise , Ginkgolídeos/metabolismo , Metabolômica , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Espectrometria de Massas em Tandem
16.
Future Microbiol ; 16: 577-588, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33973485

RESUMO

Aim: To understand the pathological progress of COVID-19 and to explore the potential biomarkers. Background: The COVID-19 pandemic is ongoing. There is metabolomics research about COVID-19 indicating the rich information of metabolomics is worthy of further data mining. Methods: We applied bioinformatics technology to reanalyze the published metabolomics data of COVID-19. Results: Benzoate, ß-alanine and 4-chlorobenzoic acid were first reported to be used as potential biomarkers to distinguish COVID-19 patients from healthy individuals; taurochenodeoxycholic acid 3-sulfate, glucuronate and N,N,N-trimethyl-alanylproline betaine TMAP are the top classifiers in the receiver operating characteristic curve of COVID-severe and COVID-nonsevere patients. Conclusion: These unique metabolites suggest an underlying immunoregulatory treatment strategy for COVID-19.


Assuntos
COVID-19/sangue , COVID-19/diagnóstico , Metaboloma/fisiologia , Metabolômica , Benzoatos/sangue , Biomarcadores/sangue , COVID-19/imunologia , Clorobenzoatos/sangue , Cromatografia Líquida , Biologia Computacional , Ácido Glucurônico/sangue , Humanos , Espectrometria de Massas , Ressonância Magnética Nuclear Biomolecular , SARS-CoV-2/imunologia , Ácido Tauroquenodesoxicólico/análogos & derivados , Ácido Tauroquenodesoxicólico/sangue , beta-Alanina/sangue
17.
Trends Parasitol ; 37(8): 747-761, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33896683

RESUMO

Nearly half a million people die annually due to mosquito-borne diseases. Despite aggressive mosquito population-control efforts, current strategies are limited in their ability to control these vectors. A better understanding of mosquito metabolism through modern approaches can contribute to the discovery of novel metabolic targets and/or regulators and lead to the development of better mosquito-control strategies. Currently, cutting-edge technologies such as gas or liquid chromatography-mass spectrometry-based metabolomics are considered 'mature technologies' in many life-science disciplines but are still an emerging area of research in medical entomology. This review primarily discusses recent developments and progress in the application of mass spectrometry-based metabolomics to answer multiple biological questions related to mosquito metabolism.


Assuntos
Culicidae/metabolismo , Espectrometria de Massas , Metabolômica , Animais , Culicidae/genética , Metaboloma/fisiologia , Metabolômica/instrumentação , Metabolômica/tendências
18.
PLoS One ; 16(4): e0249648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891605

RESUMO

Metabolomics analysis of blood from patients (n = 42) undergoing surgery for suspected lung cancer was performed in this study. Venous and arterial blood was collected in both Streck and Heparin tubes. A total of 96 metabolites were detected, affected by sex (n = 56), collection tube (n = 33), and blood location (n = 8). These metabolites belonged to a wide array of compound classes including lipids, acids, pharmaceutical agents, signalling molecules, vitamins, among others. Phospholipids and carboxylic acids accounted for 28% of all detected compounds. Out of the 33 compounds significantly affected by collection tube, 18 compounds were higher in the Streck tubes, including allantoin and ketoleucine, and 15 were higher in the Heparin tubes, including LysoPC(P-16:0), PS 40:6, and chenodeoxycholic acid glycine conjugate. Based on our results, it is recommended that replicate blood samples from each patient should be collected in different types of blood collection tubes for a broader range of the metabolome. Several metabolites were found at higher concentrations in cancer patients such as lactic acid in Squamous Cell Carcinoma, and lysoPCs in Adenocarcinoma and Acinar Cell Carcinoma, which may be used to detect early onset and/or to monitor the progress of the cancer patients.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Nucleicos Livres/isolamento & purificação , Feminino , Testes Hematológicos , Heparina/sangue , Heparina/química , Humanos , Neoplasias Pulmonares/sangue , Masculino , Metaboloma/efeitos dos fármacos , Metaboloma/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Fatores Sexuais
19.
Biomed Chromatogr ; 35(9): e5133, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33811357

RESUMO

The overall chemical composition of Bupleurum marginatum var. stenophyllum and Bupleurum chinense DC. was compared in this study. Metabolites were identified using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Multivariate statistical analysis techniques such as principal component analysis were used to conduct metabonomics analysis and study the correlation between different components. Principal component analysis results showed a clear distinction among medicinal materials of different origins and divided them into different categories, consistent with the results of hierarchical cluster analysis. Both partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) showed that the two materials could be distinguished clearly. Using PLS-DA and OPLS-DA combined with the S-plot and a variable importance in the projection (VIP) score >1, 24 differential metabolites were screened and identified; all of the metabolites were triterpenoid saponins. In addition, SPSS 25.0 and Metabo Analyst 4.0 were used to analyze significant differences in the relative contents of different compounds in the two materials. This study has successfully provided not only a new direction for research based on the chemical substances identified and the quality evaluation of Bupleuri Radix but also a better theoretical basis for the expansion of medicinal sources and their clinical application.


Assuntos
Bupleurum , Medicamentos de Ervas Chinesas , Metaboloma/fisiologia , Metabolômica/métodos , Bupleurum/química , Bupleurum/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Espectrometria de Massas/métodos , Análise de Componente Principal
20.
Biomed Chromatogr ; 35(9): e5136, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33844331

RESUMO

Myelodysplastic syndrome (MDS) is a neoplastic disease originating from hematopoietic stem cells. Currently, hematopoietic stem cell transplantation (HSCT) is the most effective cure, although lenalidomide, azacytidine, and decitabine have been applied to relieve symptoms of MDS. The purpose of this study was to evaluate the changes in endogenous metabolites by applying a UHPLC-MS (ultra-high-performance liquid chromatography-MS) metabolomics approach and to investigate metabolic pathways related to MDS. An untargeted metabolomics approach based on UHPLC-MS in combination with multivariate data analysis, including partial least squares discrimination analysis and orthogonal partial least squares discriminant analysis, was established to investigate potential biomarkers in the plasma of MDS patients. As a result, 29 biomarkers were identified to distinguish between MDS patients, HSCT patients, and healthy controls, which were mainly related to inflammation regulation, amino acid metabolism, fatty acid metabolism, and energy metabolism. To our knowledge, this is the first time where plasma metabolomics was combined with HSCT to study the pathogenesis and therapeutic target of MDS. The identification of biomarkers and analysis of metabolic pathways could offer the possibility of discovering new therapeutic targets for MDS in the future.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Metaboloma/fisiologia , Metabolômica/métodos , Síndromes Mielodisplásicas/metabolismo , Adulto , Aminoácidos/metabolismo , Biomarcadores/sangue , Ácidos Graxos/metabolismo , Feminino , Humanos , Masculino , Redes e Vias Metabólicas/fisiologia , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Adulto Jovem
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