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1.
PLoS One ; 15(4): e0231072, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275684

RESUMO

A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.


Assuntos
Hipertrigliceridemia/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Índice de Massa Corporal , Colesterol/sangue , Feminino , Homeostase/genética , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia , Insulina/metabolismo , Resistência à Insulina/genética , Gordura Intra-Abdominal/patologia , Lipídeos/sangue , Pulmão/metabolismo , Pulmão/patologia , Masculino , Metaboloma/genética , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco
2.
Nat Commun ; 11(1): 1213, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139676

RESUMO

Inducible gene expression systems are vital tools for the advancement of synthetic biology. Their application as genetically encoded biosensors has the potential to contribute to diagnostics and to revolutionise the field of microbial cell factory development. Currently, the number of compounds of biological interest by far exceeds the number of available biosensors. Here, we address this limitation by developing a generic genome-wide approach to identify transcription factor-based inducible gene expression systems. We construct and validate 15 functional biosensors, provide a characterisation workflow to facilitate forward engineering efforts, exemplify their broad-host-range applicability, and demonstrate their utility in enzyme screening. Previously uncharacterised interactions between sensors and compounds of biological relevance are identified by employing the largest reported library of metabolite-responsive biosensors in an automated high-throughput screen. With the rapidly growing genomic data these innovative capabilities offer a platform to vastly increase the number of biologically detectable molecules.


Assuntos
Genoma , Metaboloma/genética , Bactérias/genética , Bactérias/metabolismo , Técnicas Biossensoriais , Enzimas/metabolismo , Regulação Bacteriana da Expressão Gênica , Especificidade de Hospedeiro , Ligantes , Engenharia Metabólica , Reprodutibilidade dos Testes , beta-Alanina/metabolismo
3.
PLoS One ; 15(3): e0230154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32150567

RESUMO

To gain better insight into the regulatory networks of anthocyanin biosynthesis, an integrated analysis of the metabolome and transcriptome in purple and green leaves of Tetrastigma hemsleyanum was conducted. Transcript and metabolite profiles were archived by RNA-sequencing data analysis and LC-ESI-MS/MS, respectively. There were 209 metabolites and 4211 transcripts that were differentially expressed between purple and green leaves. Correlation tests of anthocyanin contents and transcriptional changes showed 141 significant correlations (Pearson correlation coefficient >0.8) between 16 compounds and 14 transcripts involved in the anthocyanin biosynthesis pathway. Some novel genes and metabolites were discovered as potential candidate targets for the improvement of anthocyanin content and superior cultivars.


Assuntos
Antocianinas/metabolismo , Metaboloma/genética , Folhas de Planta/metabolismo , Transcriptoma/genética , Vitaceae/genética , Antocianinas/genética , Cor , Biologia Computacional , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Proteínas de Plantas/genética , Espectrometria de Massas em Tandem , Vitaceae/química , Vitaceae/metabolismo
4.
Nat Commun ; 11(1): 1148, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123170

RESUMO

Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Sangue/metabolismo , Metaboloma/genética , Idoso , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Tomografia por Emissão de Pósitrons , Fatores Sexuais
5.
N Engl J Med ; 382(9): 835-844, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101665

RESUMO

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).


Assuntos
Mutação em Linhagem Germinativa , Transtornos do Crescimento/genética , Hipoglicemia/genética , Fator 1 Induzível por Hipóxia/deficiência , Mitocôndrias/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Expressão Gênica , Crescimento/genética , Humanos , Masculino , Metaboloma/genética , Metaboloma/fisiologia , Síndrome , Adulto Jovem
6.
PLoS One ; 15(1): e0225392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917799

RESUMO

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Idade de Início , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Metaboloma/genética , Camundongos , Camundongos Transgênicos , Caracteres Sexuais , Cromossomos Sexuais/genética , Cromossomos Sexuais/metabolismo
7.
BMC Plant Biol ; 20(1): 9, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906853

RESUMO

BACKGROUND: Zygophyllum is an important medicinal plant, with notable properties such as resistance to salt, alkali, and drought, as well as tolerance of poor soils and shifting sand. However, the response mechanism of Zygophyllum spp. to abiotic stess were rarely studied. RESULTS: Here, we aimed to explore the salt-tolerance genes of Zygophyllum plants by transcriptomic and metabolic approaches. We chose Z. brachypterum, Z. obliquum and Z. fabago to screen for salt tolerant and sensitive species. Cytological observation showed that both the stem and leaf of Z. brachypterum were significantly thicker than those of Z. fabago. Then, we treated these three species with different concentrations of NaCl, and found that Z. brachypterum exhibited the highest salt tolerance (ST), while Z. fabago was the most sensitive to salt (SS). With the increase of salt concentration, the CAT, SOD and POD activity, as well as proline and chlorophyll content in SS decreased significantly more than in ST. After salt treatment, the proportion of open stomata in ST decreased significantly more than in SS, although there was no significant difference in stomatal number between the two species. Transcriptomic analysis identified a total of 11 overlapping differentially expressed genes (DEGs) in the leaves and roots of the ST and SS species after salt stress. Two branched-chain-amino-acid aminotransferase (BCAT) genes among the 11 DEGs, which were significantly enriched in pantothenate and CoA biosynthesis, as well as the valine, leucine and isoleucine biosynthesis pathways, were confirmed to be significantly induced by salt stress through qRT-PCR. Furthermore, overlapping differentially abundant metabolites showed that the pantothenate and CoA biosynthesis pathways were significantly enriched after salt stress, which was consistent with the KEGG pathways enriched according to transcriptomics. CONCLUSIONS: In our study, transcriptomic and metabolomic analysis revealed that BCAT genes may affect the pantothenate and CoA biosynthesis pathway to regulate the salt tolerance of Zygophyllum species, which may constitute a newly identified signaling pathway through which plants respond to salt stress.


Assuntos
Coenzima A/metabolismo , Metaboloma/genética , Tolerância ao Sal/genética , Transcriptoma/genética , Zygophyllum , Coenzima A/genética , Perfilação da Expressão Gênica , Genes de Plantas , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Folhas de Planta/citologia , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Raízes de Plantas/citologia , Raízes de Plantas/metabolismo , Estômatos de Plantas/citologia , Estômatos de Plantas/ultraestrutura , Transdução de Sinais/genética , Transaminases/genética , Transaminases/metabolismo , Zygophyllum/anatomia & histologia , Zygophyllum/genética , Zygophyllum/metabolismo
8.
Nat Med ; 26(1): 110-117, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31932804

RESUMO

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).


Assuntos
Estudos Epidemiológicos , Microbioma Gastrointestinal/genética , Metaboloma/genética , Preparações Farmacêuticas , Índice de Massa Corporal , Fatores de Confusão Epidemiológicos , Endofenótipos , Humanos , Fígado/metabolismo , Modelos Biológicos , Mapas de Interação de Proteínas
9.
Biomed Chromatogr ; 34(3): e4769, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31808565

RESUMO

This study was designed to investigate the metabolic and transcriptional alterations in seminal fluid caused by asthenozoospermia (AS). To address these issues, a method of metabonomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and real-time quantitative PCR (RT-qPCR) was performed to identify some crucial biomarkers and transcription levels of the enzymes in seminal fluid. Seminal fluid samples were collected from 87 AS patients and 73 healthy males with normozoospermia. The quantitative analysis by UPLC-MS/MS showed that 19 metabolites in seminal plasma were associated with AS, and they were involved in several metabolic pathways, such as energy metabolism, purine metabolism, methionine cycle, and branched chain amino acid metabolism. Among these metabolites, the levels of citric acid, malic acid, succinic acid, and pyruvic acid, which are related to energy metabolism, were collectively reduced in the AS group, whereas the lactic acid level was enhanced. These results indicated that lesser energy source (adenosine triphosphate) was produced through the anaerobic glycolysis pathway rather than via aerobic catabolism of suger and tricarboxylic acid cycle, resulting in reduced power of sperms. Meanwhile, partial least squares discriminant analysis showed significant differences in metabolic profiles between the AS and control groups. In addition, RT-qPCR results revealed that the expression levels of four genes encoding fructokinase citrate synthase, succinate dehydrogenase, and spermine synthase, which were related to energy metabolism, were decreased in the AS group. The 23 descriptors with differential expression in AS may be valuable for the diagnosis and sequential study on AS. These results will help highlight the role of sperm inactivity in AS pathogenesis.


Assuntos
Astenozoospermia , Metaboloma , Sêmen , Aminoácidos/análise , Aminoácidos/metabolismo , Astenozoospermia/genética , Astenozoospermia/metabolismo , Cromatografia Líquida de Alta Pressão , Humanos , Masculino , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Metaboloma/genética , Metaboloma/fisiologia , Metabolômica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sêmen/química , Sêmen/metabolismo , Espectrometria de Massas em Tandem
10.
Biochim Biophys Acta Gen Subj ; 1864(1): 129454, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676292

RESUMO

BACKGROUND: The execution of many genetic programs, influenced by environmental conditions, is epigenetically controlled. Thus, small molecules of the intermediate metabolism being precursors of most of nutrition-deriving epigenetic modifications, sense the cell surrounding environment. METHODS: Here we describe histone H4K16 acetylation distribution in S. cerevisiae nhp6ab mutant, using ChIP-seq analysis; its transcription profile by RNA-seq and its metabolic features by studying the metabolome. We then intersected these three -omic approaches to unveil common crosspoints (if any). RESULTS: In the nhp6ab mutant, the glucose metabolism is switched to pathways leading to Acetyl-CoA synthesis. These enhanced pathways could lead to histone hyperacetylation altering RNA transcription, particularly of those metabolic genes that maintain high Acetyl-CoA availability. CONCLUSIONS: Thus, the absence of chromatin regulators like Nhp6 A and B, interferes with a regulative circular mechanism where histone modification, transcription and metabolism influence each other and contribute to clarify the more general phenomenon in which gene regulation feeds metabolic alterations on epigenetic basis. GENERAL SIGNIFICANCE: This study allowed us to identify, in these two factors, a common element of regulation in metabolism and chromatin acetylation state that could represent a powerful tool to find out relationships existing between metabolism and gene expression in more complex systems.


Assuntos
Cromatina/genética , Proteínas de Ligação a DNA/genética , Proteínas HMGN/genética , Metaboloma/genética , Proteínas de Saccharomyces cerevisiae/genética , Acetilcoenzima A/genética , Acetilação , Epigênese Genética/genética , Glucose/metabolismo , Histonas/genética , Processamento de Proteína Pós-Traducional/genética , RNA-Seq , Saccharomyces cerevisiae/genética
11.
Molecules ; 25(1)2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31877955

RESUMO

For the analysis of volatile bacterial compounds, solid phase microextraction (SPME) is currently the most widely used metabolite concentration technique. Recently, the potential of stir bar sorptive extraction (SBSE) for this use has been demonstrated. These two approaches were therefore used in combination with gas-chromatography coupled with mass-spectrometry (GC-MS) for the analysis of volatile and semi-volatile bacterial compounds produced by Staphylococcus aureus. In both cases, SPME and SBSE/headspace sorptive extraction (HSSE) enrichment was carried out in two coating phases. A whole analytical and statistical process was developed to differentiate the metabolites produced from the metabolites consumed. The results obtained with SBSE/HSSE and SPME were compared and showed the recovery of 90% of the compounds by SBSE/HSSE. In addition, we were able to detect the production of 12 volatile/semi-volatile compounds by S. aureus, six of which had never been reported before. The extraction by SBSE/HSSE showed higher concentration capacities and greater sensitivity than SPME concerning bacterial compounds, suggesting that this technique may therefore become the new preferred option for bacterial volatile and semi-volatile compound analysis.


Assuntos
Hidrocarbonetos Aromáticos/química , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/metabolismo , Compostos Orgânicos Voláteis/química , Aminas/química , Aminas/isolamento & purificação , Cromatografia Gasosa-Espectrometria de Massas , Hidrocarbonetos Aromáticos/isolamento & purificação , Metaboloma/genética , Microextração em Fase Sólida , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/química , Compostos Orgânicos Voláteis/isolamento & purificação
12.
Molecules ; 24(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731402

RESUMO

Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as carcinogenic. Although carcinogenesis might be a multifactorial process, it has been postulated that these helminth produce/excrete oxysterols and estrogen-like metabolites that might act as initiators of their infection-associated carcinogenesis. Current treatment and control of these infections rely on a single drug, praziquantel, that mainly targets the parasites and not the pathologies related to the infection including cancer. Thus, there is a need to search for novel therapeutic alternatives that might include combinations of drugs and drug repurposing. Based on these concepts, we propose a novel therapeutic strategy that combines drugs with molecule antioxidants. We evaluate the efficacy of a novel therapeutic strategy to prevent the formation of putative carcinogenic metabolites precursors and DNA adducts. Firstly, we used a methodology previously established to synthesize metabolites precursors and DNA adducts in the presence of CYP450. Then, we evaluated the inhibition of their formation induced by drugs and antioxidants alone or in combination. Drugs and resveratrol alone did not show a significant inhibitory effect while N-acetylcysteine inhibited the formation of most metabolite precursors and DNA adducts. Moreover, the combinations of classical drugs with antioxidants were more effective rather than compounds alone. This strategy might be a valuable tool to prevent the initiation of helminth infection-associated carcinogenesis.


Assuntos
Antioxidantes/farmacologia , Neoplasias/tratamento farmacológico , Opistorquíase/tratamento farmacológico , Esquistossomose Urinária/tratamento farmacológico , Acetilcisteína/química , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Carcinógenos/química , Adutos de DNA/efeitos dos fármacos , Combinação de Medicamentos , Humanos , Metaboloma/efeitos dos fármacos , Metaboloma/genética , Neoplasias/metabolismo , Neoplasias/parasitologia , Opistorquíase/complicações , Opistorquíase/metabolismo , Opistorquíase/parasitologia , Opisthorchis/efeitos dos fármacos , Opisthorchis/patogenicidade , Praziquantel/farmacologia , Resveratrol/farmacologia , Schistosoma haematobium/efeitos dos fármacos , Schistosoma haematobium/patogenicidade , Esquistossomose Urinária/complicações , Esquistossomose Urinária/metabolismo , Esquistossomose Urinária/parasitologia
13.
Nutrients ; 11(11)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717805

RESUMO

Selenium is a nonmetal trace element that is critical for several redox reactions and utilized to produce the amino acid selenocysteine (Sec), which can be incorporated into selenoproteins. Selenocysteine lyase (SCL) is an enzyme which decomposes Sec into selenide and alanine, releasing the selenide to be further utilized to synthesize new selenoproteins. Disruption of the selenocysteine lyase gene (Scly) in mice (Scly-/- or Scly KO) led to obesity with dyslipidemia, hyperinsulinemia, glucose intolerance and lipid accumulation in the hepatocytes. As the liver is a central regulator of glucose and lipid homeostasis, as well as selenium metabolism, we aimed to pinpoint hepatic molecular pathways affected by the Scly gene disruption. Using RNA sequencing and metabolomics, we identified differentially expressed genes and metabolites in the livers of Scly KO mice. Integrated omics revealed that biological pathways related to amino acid metabolism, particularly alanine and glycine metabolism, were affected in the liver by disruption of Scly in mice with selenium adequacy. We further confirmed that hepatic glycine levels are elevated in male, but not in female, Scly KO mice. In conclusion, our results reveal that Scly participates in the modulation of hepatic amino acid metabolic pathways.


Assuntos
Aminoácidos/metabolismo , Liases , Metaboloma/genética , Transcriptoma/genética , Animais , Feminino , Liases/genética , Liases/metabolismo , Liases/fisiologia , Masculino , Metabolômica , Camundongos , Camundongos Knockout , Selênio/metabolismo
14.
Metabolomics ; 15(12): 151, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31741127

RESUMO

INTRODUCTION: Brown planthopper (BPH) is a phloem feeding insect that causes annual disease outbreaks, called hopper burn in many countries throughout Asia, resulting in severe damage to rice production. Currently, mechanistic understanding of BPH resistance in rice plant is limited, which has caused slow progression on developing effective rice varieties as well as effective farming practices against BPH infestation. OBJECTIVE: To reveal rice metabolic responses during 8 days of BPH attack, this study examined polar metabolome extracts of BPH-susceptible (KD) and its BPH-resistant isogenic line (IL308) rice leaves. METHODS: Ultra high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) was combined with multi-block PCA to analyze potential metabolites in response to BPH attack. RESULTS: This multivariate statistical model revealed different metabolic response patterns between the BPH-susceptible and BPH-resistant varieties during BPH infestation. The metabolite responses of the resistant IL308 variety occurred on Day 1, which was significantly earlier than those of the susceptible KD variety which showed an induced response by Days 4 and 8. BPH infestation caused metabolic perturbations in purine, phenylpropanoid, flavonoid, and terpenoid pathways. While found in both susceptible and resistant rice varieties, schaftoside (1.8 fold), iso-schaftoside (1.7 fold), rhoifolin (3.4 fold) and apigenin 6-C-α-L-arabinoside-8-C-ß-L-arabinoside levels (1.6 fold) were significantly increased in the resistant variety by Day 1 post-infestation. 20-hydroxyecdysone acetate (2.5 fold) and dicaffeoylquinic acid (4.7 fold) levels were considerably higher in the resistant rice variety than those in the susceptible variety, both before and after infestation, suggesting that these secondary metabolites play important roles in inducible and constitutive defenses against the BPH infestation. CONCLUSIONS: These potential secondary metabolites will be useful as metabolite markers and/or bioactive compounds for effective and durable approaches to address the BPH problem.


Assuntos
Oryza/química , Oryza/metabolismo , Metabolismo Secundário/fisiologia , Animais , Cromatografia Líquida de Alta Pressão/métodos , Resistência à Doença/genética , Didrogesterona/análogos & derivados , Didrogesterona/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Hemípteros/metabolismo , Hemípteros/parasitologia , Hemípteros/fisiologia , Metaboloma/genética , Oryza/genética , Fenótipo
15.
Nat Commun ; 10(1): 4788, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636271

RESUMO

Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipids, across distinct time points as well as information on statin usage. We increase effective sample size by an average of two-fold by applying the Covariates for Multi-phenotype Studies (CMS) approach, identifying 588 significant SNP-metabolite associations, including 228 new associations. Our analysis pinpoints a small number of master metabolic regulator genes, balancing the relative proportion of dozens of metabolite levels. We further identify associations to changes in metabolic levels across time as well as genetic interactions with statin at both the master metabolic regulator and genome-wide level.


Assuntos
Pleiotropia Genética , Síndrome Metabólica/genética , Metaboloma/genética , Idoso , Aminoácidos/genética , Aminoácidos/metabolismo , Estudos de Coortes , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Lipoproteínas IDL/genética , Lipoproteínas IDL/metabolismo , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/genética , Lipoproteínas VLDL/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
PLoS One ; 14(9): e0222353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31532787

RESUMO

Menopause is an endocrine-related transition that induces a number of physiological and potentially pathological changes in middle-aged and elderly women. The intention of this research was to investigate the influence of menopause on the intricate relationships between major biochemical metabolites. The study involved metabolic profiling of 186 metabolic markers measured in blood plasma collected from 120 healthy female participants. We developed a method of network analysis using differential correlation that enabled us to detect and characterize differences in metabolites and changes in inter-relationships in pre- and post-menopausal women. A topological analysis was performed on the differential network that uncovered metabolite differences in pre-and post-menopausal women. In this analysis, our method identified two key metabolites, sphingomyelins and phosphatidylcholines, which may be useful in directing further studies into menopause-specific differences in the metabolome, and how these differences may underlie the body's response to stress and disease following the transition from pre- to post-menopausal status for women.


Assuntos
Menopausa/genética , Menopausa/fisiologia , Metaboloma/genética , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Menopausa/sangue , Metabolômica/métodos , Pessoa de Meia-Idade , Fosfatidilcolinas/genética , Esfingomielinas/genética , Adulto Jovem
17.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505804

RESUMO

The screening of drug metabolites in biological matrixes and structural characterization based on product ion spectra is among the most important, but also the most challenging due to the significant interferences from endogenous species. Traditionally, metabolite detection is accomplished primarily on the basis of predicted molecular masses or fragmentation patterns of prototype drug metabolites using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Although classical techniques are well-suited for achieving the partial characterization of prototype drug metabolites, there is a pressing need for a strategy to enable comprehensive drug metabolism depiction. Therefore, we present drug metabolite clusters (DMCs), different from, but complementary to, traditional approaches for mining the information regarding drugs and their metabolites on the basis of raw, processed, or identified tandem mass spectrometry (MS/MS) data. In this paper, we describe a DMC-based data-mining method for the metabolite identification of 5-hydroxy-6,7,3',4'-tetramethoxyflavone (HTF), a typical hydroxylated-polymethoxyflavonoid (OH-PMF), which addressed the challenge of creating a thorough metabolic profile. Consequently, eight primary metabolism clusters, sixteen secondary metabolism clusters, and five tertiary metabolism clusters were proposed and 106 metabolites (19 potential metabolites included) were detected and identified positively and tentatively. These metabolites were presumed to generate through oxidation (mono-oxidation, di-oxidation), methylation, demethylation, methoxylation, glucuronidation, sulfation, ring cleavage, and their composite reactions. In conclusion, our study expounded drug metabolites in rats and provided a reference for further research on therapeutic material basis and the mechanism of drugs.


Assuntos
Mineração de Dados , Flavonas/metabolismo , Metaboloma/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Desmetilação/efeitos dos fármacos , Flavonas/farmacologia , Humanos , Hidroxilação/efeitos dos fármacos , Hidroxilação/genética , Metaboloma/genética , Metilação/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Ratos , Espectrometria de Massas em Tandem
18.
Nat Med ; 25(9): 1442-1452, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477907

RESUMO

Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.


Assuntos
Bactérias/genética , Microbioma Gastrointestinal/genética , Filogenia , Seleção Genética/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , Bancos de Espécimes Biológicos , Fezes/microbiologia , Variação Genética/genética , Genoma Bacteriano/genética , Humanos , Metaboloma/genética
19.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370187

RESUMO

This paper compares the differences in metabolites of vanilla beans at five different curing stages. Key vanilla flavors, vanillin precursors and main enzymes during the curing process of Hainan vanilla beans were also analyzed. Hundreds of metabolites were detected based on metabolic analyses of a widely targeted metabolome technique, compared with blanched vanilla beans (BVB), sweating vanilla beans (SVB) and drying vanilla beans (DVB), the total peak intensity of cured vanilla beans (CVB) is on the rise. The score plots of principal component analysis indicated that the metabolites were generally similar at the same curing stages, but for the different curing stages, they varied substantially. During processing, vanillin content increased while glucovanillin content decreased, and vanillic acid was present in sweating beans, but its content was reduced in drying beans. Both p-hydroxybenzaldehyde and p-hydroxybenzoic acid showed the maximum contents in cured beans. Ferulic acid was mainly produced in drying beans and reduced in cured beans. p-coumaric acid increased during the curing process. Vanillyl alcohol in drying beans (0.22%) may be formed by the hydrolysis of glucoside, whose conversion into vanillin may explain its decrease during the curing stage. ß-Glucosidase enzymatic activity was not detected in blanched and sweating beans, but was observed after drying. Peroxidase activity decreased during curing by 94% in cured beans. Polyphenol oxidase activity was low in earlier stages, whereas cellulase activity in processed beans was higher than in green beans, except for cured beans. This study contributes to revealing the formation of flavor components and the biosynthesis pathway of vanillin.


Assuntos
Benzaldeídos/química , Aromatizantes/metabolismo , Metaboloma/genética , Vanilla/genética , Benzaldeídos/metabolismo , Aromatizantes/química , Manipulação de Alimentos , Humanos , Sementes/genética , Sementes/crescimento & desenvolvimento , Paladar/genética , Vanilla/enzimologia
20.
Genome Biol ; 20(1): 172, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443695

RESUMO

BACKGROUND: In ruminants, early rumen development is vital for efficient fermentation that converts plant materials to human edible food such as milk and meat. Here, we investigate the extent and functional basis of host-microbial interactions regulating rumen development during the first 6 weeks of life. RESULTS: The use of microbial metagenomics, together with quantification of volatile fatty acids (VFAs) and qPCR, reveals the colonization of an active bacterial community in the rumen at birth. Colonization of active complex carbohydrate fermenters and archaea with methyl-coenzyme M reductase activity was also observed from the first week of life in the absence of a solid diet. Integrating microbial metagenomics and host transcriptomics reveals only 26.3% of mRNA transcripts, and 46.4% of miRNAs were responsive to VFAs, while others were ontogenic. Among these, one host gene module was positively associated with VFAs, while two other host gene modules and one miRNA module were negatively associated with VFAs. Eight host genes and five miRNAs involved in zinc ion binding-related transcriptional regulation were associated with a rumen bacterial cluster consisting of Prevotella, Bacteroides, and Ruminococcus. CONCLUSION: This three-way interaction suggests a potential role of bacteria-driven transcriptional regulation in early rumen development via miRNAs. Our results reveal a highly active early microbiome that regulates rumen development of neonatal calves at the cellular level, and miRNAs may coordinate these host-microbial interactions.


Assuntos
Bactérias/genética , Metagenoma/genética , Microbiota/genética , Rúmen/microbiologia , Ruminantes/crescimento & desenvolvimento , Ruminantes/genética , Transcriptoma/genética , Animais , Animais Recém-Nascidos , Bovinos , Epitélio/crescimento & desenvolvimento , Ácidos Graxos Voláteis/metabolismo , Redes Reguladoras de Genes , Metaboloma/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Ruminantes/microbiologia , Desmame
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