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1.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230210

RESUMO

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Assuntos
COVID-19/imunologia , Ácido Cinurênico/imunologia , SARS-CoV-2 , Adulto , Idoso , COVID-19/sangue , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Ácido Cinurênico/sangue , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/imunologia , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/imunologia , Triptofano/metabolismo
2.
Nat Commun ; 12(1): 4343, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267224

RESUMO

Aberrant sterol lipid metabolism is associated with physiological dysfunctions in the aging brain and aging-dependent disorders such as neurodegenerative diseases. There is an unmet demand to comprehensively profile sterol lipids spatially and temporally in different brain regions during aging. Here, we develop an ion mobility-mass spectrometry based four-dimensional sterolomics technology leveraged by a machine learning-empowered high-coverage library (>2000 sterol lipids) for accurate identification. We apply this four-dimensional technology to profile the spatially resolved landscapes of sterol lipids in ten functional regions of the mouse brain, and quantitatively uncover ~200 sterol lipids uniquely distributed in specific regions with concentrations spanning up to 8 orders of magnitude. Further spatial analysis pinpoints age-associated differences in region-specific sterol lipid metabolism, revealing changes in the numbers of altered sterol lipids, concentration variations, and age-dependent coregulation networks. These findings will contribute to our understanding of abnormal sterol lipid metabolism and its role in brain diseases.


Assuntos
Química Encefálica , Encéfalo/metabolismo , Lipídeos/química , Esteróis/análise , Envelhecimento/fisiologia , Animais , Feminino , Isomerismo , Lipidômica/métodos , Lipídeos/análise , Aprendizado de Máquina , Camundongos Endogâmicos C57BL , Esteróis/química , Esteróis/metabolismo , Espectrometria de Massas em Tandem/métodos
3.
Sci Rep ; 11(1): 13482, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188068

RESUMO

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach-inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1-6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.

4.
Toxicol Sci ; 183(2): 338-351, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33693819

RESUMO

1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States. Although it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500, and 5,000mg/L) in their drinking water for 1 or 4 weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double-strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces, and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

5.
medRxiv ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32935119

RESUMO

Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID- 19, kynurenic acid (KA) and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.

6.
Metabolites ; 10(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575361

RESUMO

The progress in the discovery and validation of metabolite biomarkers for the detection of colorectal cancer (CRC) has been hampered by the lack of reproducibility between study cohorts. The majority of discovery-phase biomarker studies have used patient blood samples to identify disease-related metabolites, but this pre-validation phase is confounded by non-specific disease influences on the metabolome. We therefore propose that metabolite biomarker discovery would have greater success and higher reproducibility for CRC if the discovery phase was conducted in tumor tissues, to find metabolites that have higher specificity to the metabolic consequences of the disease, that are then validated in blood samples. This would thereby eliminate any non-tumor and/or body response effects to the disease. In this study, we performed comprehensive untargeted metabolomics analyses on normal (adjacent) colon and tumor tissues from CRC patients, revealing tumor tissue-specific biomarkers (n = 39/group). We identified 28 highly discriminatory tumor tissue metabolite biomarkers of CRC by orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate analyses (VIP > 1.5, p < 0.05). A stepwise selection procedure was used to identify nine metabolites that were the most predictive of CRC with areas under the curve (AUCs) of >0.96, using various models. We further identified five biomarkers that were specific to the anatomic location of tumors in the colon (n = 236). The combination of these five metabolites (S-adenosyl-L-homocysteine, formylmethionine, fucose 1-phosphate, lactate, and phenylalanine) demonstrated high differentiative capability for left- and right-sided colon cancers at stage I by internal cross-validation (AUC = 0.804, 95% confidence interval, CI 0.670-0.940). This study thus revealed nine discriminatory biomarkers of CRC that are now poised for external validation in a future independent cohort of samples. We also discovered a discrete metabolic signature to determine the anatomic location of the tumor at the earliest stage, thus potentially providing clinicians a means to identify individuals that could be triaged for additional screening regimens.

7.
Sci Rep ; 10(1): 4905, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184446

RESUMO

Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.


Assuntos
Neoplasias do Colo/metabolismo , Biomarcadores Tumorais , Neoplasias Colorretais/metabolismo , Humanos , Espectrometria de Massas
8.
Methods Mol Biol ; 2104: 447-467, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31953830

RESUMO

The exposome is the cumulative measure of environmental influences and associated biological responses across the life span, with critical relevance for understanding how exposures can impact human health. Metabolomics analysis of biological samples offers unique advantages for examining the exposome. Simultaneous analysis of external exposures, biological responses, and host susceptibility at a systems level can help establish links between external exposures and health outcomes. As metabolomics technologies continue to evolve for the study of the exposome, metabolomics ultimately will help provide valuable insights for exposure risk assessment, and disease prevention and management. Here, we discuss recent advances in metabolomics, and describe data processing protocols that can enable analysis of the exposome. This chapter focuses on using liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics for analysis of the exposome, including (1) preprocessing of untargeted metabolomics data, (2) identification of exposure chemicals and their metabolites, and (3) methods to establish associations between exposures and diseases.


Assuntos
Análise de Dados , Exposição Ambiental , Saúde Ambiental , Expossoma , Metabolômica , Cromatografia Líquida , Saúde Ambiental/métodos , Espectrometria de Massas , Metabolômica/estatística & dados numéricos , Pesquisa , Medição de Risco
9.
Transl Oncol ; 13(1): 42-56, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760268

RESUMO

Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided colon cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men, but have a higher propensity for RCC. The reason for this difference is not known; however, identification of sex-specific differences in gene expression by tumor anatomical location in the colon could provide further insight. Moreover, it could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancers using four publicly available annotated data sets housed in the National Center for Biotechnology Information's Gene Expression Omnibus. We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared with women with LCC. Specifically, we showed the downregulation of 5' AMP-activated protein kinase alpha subunit (AMPKα) and anti-tumor immune responses in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.

10.
Biomed Res Int ; 2020: 8826456, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33415160

RESUMO

N6-methyladenosine (m6A) plays an important role in many cancers. However, few studies have examined the role of m6A in colorectal CRC. To examine the effect of m6A on CRC, we studied the genome of 591 CRC cases from The Cancer Genome Atlas (TCGA). The relationship between the messenger RNA (mRNA) expression, copy number variation (CNVs), and mutations of m6A "Writers," "Readers," and "Erasers," prognosis, immune cell infiltration, and genetic mutations in CRC cases were analyzed. CNVs and mutations were found in thirteen m6A regulators. As expected, gain and amplification of m6A regulators increased the mRNA expression of these regulators, while deletion led to reduction in the mRNA expression. Moreover, CNVs and mutation of these regulators were significantly associated with APC, TP53, and microsatellite instability (MSI) status (p < 0.001, p < 0.001, and p = 0.029, respectively). CNVs of m6A regulators also correlated with inferred immune cell infiltration in CRC tissues, especially in colon tissues. Additionally, alterations of RBM15, YTHDF2, YTHDC1, YTHDC2, and METTL14 genes were related to the worse overall survival and disease-free survival (DFS) of CRC patients. Specifically, the deletion status of "Writers" was also correlated to the DFS of CRC patients (p = 0.02). Gene set enrichment analysis found that FTO was involved in mRNA 3' end processing, polyubiquitin binding, and RNA polymerase promoter elongation, while YTHDC1 was related to interferon-alpha and gamma response. In conclusion, a novel relationship was identified between CNVs and mutations of m6A regulators with prognosis and inferred immune function of CRC. These findings will improve the understanding of the relationship of m6A in CRC.


Assuntos
Adenosina/análogos & derivados , Neoplasias Colorretais/genética , Bases de Dados Genéticas , Genes Neoplásicos , Adenosina/metabolismo , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Variações do Número de Cópias de DNA/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Análise Multivariada , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Metabolites ; 9(10)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546636

RESUMO

Metabolomics studies of the early-life exposome often use maternal urine specimens to investigate critical developmental windows, including the periconceptional period and early pregnancy. During these windows changes in kidney function can impact urine concentration. This makes accounting for differential urinary dilution across samples challenging. Because there is no consensus on the ideal normalization approach for urinary metabolomics data, this study's objective was to determine the optimal post-analytical normalization approach for untargeted metabolomics analysis from a periconceptional cohort of 45 women. Urine samples consisted of 90 paired pre- and post-implantation samples. After untargeted mass spectrometry-based metabolomics analysis, we systematically compared the performance of three common approaches to adjust for urinary dilution-creatinine adjustment, specific gravity adjustment, and probabilistic quotient normalization (PQN)-using unsupervised principal components analysis, relative standard deviation (RSD) of pooled quality control samples, and orthogonal partial least-squares discriminant analysis (OPLS-DA). Results showed that creatinine adjustment is not a reliable approach to normalize urinary periconceptional metabolomics data. Either specific gravity or PQN are more reliable methods to adjust for urinary concentration, with tighter quality control sample clustering, lower RSD, and better OPLS-DA performance compared to creatinine adjustment. These findings have implications for metabolomics analyses on urine samples taken around the time of conception and in contexts where kidney function may be altered.

12.
Anal Chem ; 91(18): 11897-11904, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31436405

RESUMO

SWATH-MS-based data-independent acquisition mass spectrometry (DIA-MS) technology has been recently developed for untargeted metabolomics due to its capability to acquire all MS2 spectra with high quantitative accuracy. However, software tools for deconvolving multiplexed MS/MS spectra from SWATH-MS with high efficiency and high quality are still lacking in untargeted metabolomics. Here, we developed a new software tool, namely, DecoMetDIA, to deconvolve multiplexed MS/MS spectra for metabolite identification and support the SWATH-based untargeted metabolomics. In DecoMetDIA, multiple model peaks are selected to model the coeluted and unresolved chromatographic peaks of fragment ions in multiplexed spectra and decompose them into a linear combination of the model peaks. DecoMetDIA enabled us to reconstruct the MS2 spectra of metabolites from a variety of different biological samples with high coverages. We also demonstrated that the deconvolved MS2 spectra from DecoMetDIA were of high accuracy through comparison to the experimental MS2 spectra from data-dependent acquisition (DDA). Finally, about 90% of deconvolved MS2 spectra in various biological samples were successfully annotated using software tools such as MetDNA and Sirius. The results demonstrated that the deconvolved MS2 spectra obtained from DecoMetDIA were accurate and valid for metabolite identification and structural elucidation. The comparison of DecoMetDIA to other deconvolution software such as MS-DIAL demonstrated that it performs very well for small polar metabolites. DecoMetDIA software is freely available at https://github.com/ZhuMSLab/DecoMetDIA .


Assuntos
Metabolômica , Software , Espectrometria de Massas em Tandem
13.
Ann Clin Transl Neurol ; 6(5): 945-953, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31139692

RESUMO

Increasing evidence indicates that immune system dysfunction affects anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aims to investigate the relationship between adhesion molecules and the pathophysiology in anti-NMDAR encephalitis. Soluble forms of Intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), and L-selectin (sL-selectin), were measured in the CSF and serum of 26 participants with anti-NMDAR encephalitis, 11 patients with schizophrenia and 22 patients with noninflammatory disorders. CSF levels of sICAM-1, sVCAM-1 and sL-selectin were significantly elevated in the anti-NMDAR encephalitis group. sVCAM-1 levels were positively associated with modified Rankin scale score in anti-NMDAR encephalitis patients at the onset and 3-month follow-up.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/fisiopatologia , Moléculas de Adesão Celular/sangue , Adolescente , Adulto , Selectina E/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Selectina L/sangue , Masculino , Pessoa de Meia-Idade , Molécula 1 de Adesão de Célula Vascular/sangue
14.
Nat Commun ; 10(1): 1516, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944337

RESUMO

Large-scale metabolite annotation is a challenge in liquid chromatogram-mass spectrometry (LC-MS)-based untargeted metabolomics. Here, we develop a metabolic reaction network (MRN)-based recursive algorithm (MetDNA) that expands metabolite annotations without the need for a comprehensive standard spectral library. MetDNA is based on the rationale that seed metabolites and their reaction-paired neighbors tend to share structural similarities resulting in similar MS2 spectra. MetDNA characterizes initial seed metabolites using a small library of MS2 spectra, and utilizes their experimental MS2 spectra as surrogate spectra to annotate their reaction-paired neighbor metabolites, which subsequently serve as the basis for recursive analysis. Using different LC-MS platforms, data acquisition methods, and biological samples, we showcase the utility and versatility of MetDNA and demonstrate that about 2000 metabolites can cumulatively be annotated from one experiment. Our results demonstrate that MetDNA substantially expands metabolite annotation, enabling quantitative assessment of metabolic pathways and facilitating integrative multi-omics analysis.


Assuntos
Redes e Vias Metabólicas , Metabolômica/métodos , Modelos Biológicos , Algoritmos , Animais , Cromatografia Líquida/métodos , Bases de Dados Factuais , Drosophila/metabolismo , Regulação da Expressão Gênica , Gluconeogênese , Metaboloma , Metabolômica/instrumentação , Espectrometria de Massas em Tandem/métodos , Transcriptoma
15.
Metabolites ; 9(1)2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30609717

RESUMO

The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy's synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

16.
Methods Mol Biol ; 1859: 263-274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30421235

RESUMO

Targeted metabolomics aims to analyze a set of pre-selected metabolites from biologically relevant metabolic pathways. The triple quadrupole mass spectrometry (QqQ-MS) based multiple reaction monitoring (MRM) technique is the most widely approach used for targeted metabolomics, and features high selectivity and sensitivity, good reproducibility and wide dynamic range in quantitative analysis. Here, we describe an MRM based targeted metabolomics workflow for the quantitative analysis of 200 polar metabolites in central carbon metabolic pathways, including the data acquisition method and the automated data processing procedures using our in-house R package MRMAnalyzer. The workflow described in this chapter combines a hydrophilic interaction liquid chromatography (HILIC) separation and positive/negative ion polarity switching based MS detection, and is able to acquire data from multiple types of biological samples such as bacteria, cultured mammalian cells, animal tissues and biofluids (e.g., serum and urine). Finally, the MRMAnalyzer software can automatically process the generated large-scale data set with high efficiency. We hope it is a valuable and efficient workflow for researchers to facilitate the respective biological studies using targeted metabolomics.


Assuntos
Carbono/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Líquidos Corporais/metabolismo , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Processamento Eletrônico de Dados/métodos , Escherichia coli/metabolismo , Células HeLa , Ensaios de Triagem em Larga Escala/instrumentação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fígado/metabolismo , Redes e Vias Metabólicas , Metabolômica/instrumentação , Camundongos , Software , Espectrometria de Massas em Tandem/instrumentação
17.
Elife ; 72018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29809154

RESUMO

Epigenetic alteration has been implicated in aging. However, the mechanism by which epigenetic change impacts aging remains to be understood. H3K27me3, a highly conserved histone modification signifying transcriptional repression, is marked and maintained by Polycomb Repressive Complexes (PRCs). Here, we explore the mechanism by which age-modulated increase of H3K27me3 impacts adult lifespan. Using Drosophila, we reveal that aging leads to loss of fidelity in epigenetic marking and drift of H3K27me3 and consequential reduction in the expression of glycolytic genes with negative effects on energy production and redox state. We show that a reduction of H3K27me3 by PRCs-deficiency promotes glycolysis and healthy lifespan. While perturbing glycolysis diminishes the pro-lifespan benefits mediated by PRCs-deficiency, transgenic increase of glycolytic genes in wild-type animals extends longevity. Together, we propose that epigenetic drift of H3K27me3 is one of the molecular mechanisms that contribute to aging and that stimulation of glycolysis promotes metabolic health and longevity.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Histonas/genética , Longevidade , Proteínas do Grupo Polycomb/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epigênese Genética , Feminino , Glicólise , Histonas/metabolismo , Masculino , Proteínas do Grupo Polycomb/genética
18.
Anal Chem ; 90(6): 4062-4070, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29485856

RESUMO

The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).


Assuntos
Espectrometria de Massas/métodos , Metaboloma , Metabolômica/métodos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Humanos , Células Jurkat , Reprodutibilidade dos Testes , Fluxo de Trabalho
19.
Shanghai Kou Qiang Yi Xue ; 27(6): 661-663, 2018 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-30899953

RESUMO

PURPOSE: To standardize the teaching process of interns in dental technology so as to make the learning progress and process goals more clearly and improve the teaching quality. METHODS: Thirty-two junior interns were selected from medical colleges and universities from 2014 to 2017, based on same learning ability, learning attitude, learning achievement and hands-on ability ,they were randomly divided into 2 groups. The experimental group adopted the goal teaching method, using relevant teaching materials, applying theory to practice closely, and trying to standardize practice. The control group entered the production lines directly without teaching materials, the students were all owed only to see, think and manipulate. The data were analyzed with SPSS 18.0 software package. RESULTS: The exam scores of the students in the experimental group were significantly higher than that of the students in the control group. Moreover, the satisfaction with the teaching methods of the experimental group was significantly higher than that of the control group (P<0.05). CONCLUSIONS: The target teaching method is effective in teaching dental technology. Students clearly understand the study progress, process goals and their operational performance is significantly improved.


Assuntos
Educação em Odontologia , Aprendizagem , Tecnologia Odontológica , Logro , Humanos , Estudantes , Ensino , Tecnologia Odontológica/educação , Universidades
20.
J Diabetes Res ; 2017: 8756978, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28761879

RESUMO

OBJECTIVE: To investigate the relationship between alcohol consumption and diabetic lower extremity arterial disease (LEAD) in hospitalized patients with type 2 diabetes mellitus (T2DM). METHODS: We evaluated 138 hospitalized patients with T2DM who consumed alcohol and 833 who did not. We used propensity score matching to reduce the confounding bias between groups. Additionally, a logistic regression analysis was performed with the matched data to evaluate the LEAD risk. RESULTS: In total, 119 pairs of patients who did and did not consume alcohol were matched. According to the logistic regression analysis, patients who consumed >8 U of alcohol/day had a higher risk of LEAD (odds ratio (OR): 6.35, 95% confidence interval (CI): 1.78-22.65) than patients who did not consume alcohol. Additionally, after adjusting for age, gender, region, occupation, smoking status, body mass index, weight change, and duration of diabetes, the OR of peripheral artery disease after >20 years of alcohol consumption was 3.48 (95% CI: 1.09-11.15). Furthermore, we observed a significant dose-response relationship between alcohol consumption and LEAD. CONCLUSIONS: Alcohol consumption may be a risk factor of LEAD in patients with T2DM. Patients with T2DM should be advised to stop drinking, to prevent the onset of LEAD.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/etnologia , Grupo com Ancestrais do Continente Asiático , Distribuição de Qui-Quadrado , China , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/etnologia , Feminino , Humanos , Pacientes Internados , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etnologia , Pontuação de Propensão , Medição de Risco , Fatores de Risco , Adulto Jovem
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