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1.
Nat Commun ; 11(1): 4933, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004787

RESUMO

The influence of seasons on biological processes is poorly understood. In order to identify biological seasonal patterns based on diverse molecular data, rather than calendar dates, we performed a deep longitudinal multiomics profiling of 105 individuals over 4 years. Here, we report more than 1000 seasonal variations in omics analytes and clinical measures. The different molecules group into two major seasonal patterns which correlate with peaks in late spring and late fall/early winter in California. The two patterns are enriched for molecules involved in human biological processes such as inflammation, immunity, cardiovascular health, as well as neurological and psychiatric conditions. Lastly, we identify molecules and microbes that demonstrate different seasonal patterns in insulin sensitive and insulin resistant individuals. The results of our study have important implications in healthcare and highlight the value of considering seasonality when assessing population wide health risk and management.


Assuntos
Exposição Ambiental , Resistência à Insulina/fisiologia , Redes e Vias Metabólicas/fisiologia , Microbiota/fisiologia , Estações do Ano , Adulto , Idoso , Glicemia/análise , Glicemia/metabolismo , California , Análise por Conglomerados , Feminino , Nível de Saúde , Humanos , Insulina/metabolismo , Estudos Longitudinais , Masculino , Metabolômica , Pessoa de Meia-Idade , RNA-Seq
2.
Yakugaku Zasshi ; 140(10): 1251-1258, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999204

RESUMO

Natural materials such as crude drugs and foods are mixtures composed of various metabolites. Metabolic profiling is often used to identify possible correlations between a compound's metabolic profile and pharmacologic activity. Direct-injection electron ionization-mass spectrometry (DI-EI-MS) is a novel metabolomics method useful for characterizing biological materials. This review demonstrates the establishment of a DI-EI-MS method for metabolic profiling using several closely related lichen species: Cladonia krempelhuberi, C. gracilis, C. pseudogymnopoda, and C. ramulosa. The qualitative DI-EI-MS method was used to profile major and/or minor constituents in extracts of lichen samples. Each lichen sample could be distinguished by altering the DI-EI-MS electron energy and examining the resulting data using one-way analysis of variance. We also attempted to predict pharmacologic activity using DI-EI-MS metabolomics. Blueberry leaf extracts inhibited the proliferation of adult T-cell leukemia (ATL) cells. Blueberry leaf extracts could be distinguished by principal component analysis based on the absolute intensity of characteristic fragment ions. Twenty cultivars were categorized into four species, and the most appropriate discriminative marker m/z value for identifying each cultivar was selected statistically. Components extracted based on DI-EI-MS analyses could be used to construct a model to predict ATL cell bioactivity. These data suggest that the novel DI-EI-MS metabolomics method is suitable for identifying species of natural materials and predicting their pharmacologic activity. This approach could enhance public health by facilitating evaluations of pharmacologic activity and functionality, leading to the elimination of counterfeit products.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Mirtilos Azuis (Planta)/química , Mirtilos Azuis (Planta)/metabolismo , Líquens/metabolismo , Metabolômica , Extratos Vegetais/farmacologia , Proliferação de Células/efeitos dos fármacos , Previsões , Humanos , Leucemia-Linfoma de Células T do Adulto/patologia , Espectrometria de Massas/métodos , Metabolômica/métodos , Extratos Vegetais/isolamento & purificação
3.
Hum Genomics ; 14(1): 35, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008459

RESUMO

Precision medicine aims to empower clinicians to predict the most appropriate course of action for patients with complex diseases like cancer, diabetes, cardiomyopathy, and COVID-19. With a progressive interpretation of the clinical, molecular, and genomic factors at play in diseases, more effective and personalized medical treatments are anticipated for many disorders. Understanding patient's metabolomics and genetic make-up in conjunction with clinical data will significantly lead to determining predisposition, diagnostic, prognostic, and predictive biomarkers and paths ultimately providing optimal and personalized care for diverse, and targeted chronic and acute diseases. In clinical settings, we need to timely model clinical and multi-omics data to find statistical patterns across millions of features to identify underlying biologic pathways, modifiable risk factors, and actionable information that support early detection and prevention of complex disorders, and development of new therapies for better patient care. It is important to calculate quantitative phenotype measurements, evaluate variants in unique genes and interpret using ACMG guidelines, find frequency of pathogenic and likely pathogenic variants without disease indicators, and observe autosomal recessive carriers with a phenotype manifestation in metabolome. Next, ensuring security to reconcile noise, we need to build and train machine-learning prognostic models to meaningfully process multisource heterogeneous data to identify high-risk rare variants and make medically relevant predictions. The goal, today, is to facilitate implementation of mainstream precision medicine to improve the traditional symptom-driven practice of medicine, and allow earlier interventions using predictive diagnostics and tailoring better-personalized treatments. We strongly recommend automated implementation of cutting-edge technologies, utilizing machine learning (ML) and artificial intelligence (AI) approaches for the multimodal data aggregation, multifactor examination, development of knowledgebase of clinical predictors for decision support, and best strategies for dealing with relevant ethical issues.


Assuntos
Infecções por Coronavirus/genética , Diabetes Mellitus/genética , Neoplasias/genética , Pneumonia Viral/genética , Medicina de Precisão/tendências , Cardiomiopatias , Infecções por Coronavirus/epidemiologia , Análise de Dados , Diabetes Mellitus/epidemiologia , Genômica/tendências , Humanos , Metabolômica/tendências , Neoplasias/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Proteômica/tendências
4.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5300-5303, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019180

RESUMO

Compared to European-Americans (EAs), the incidence of hepatocellular carcinoma (HCC) is higher in African-Americans (AAs) and is associated with more advanced tumor stage at diagnosis and lower survival rates. The increasing burden makes discovery of novel diagnostic, prognostic, and therapeutic biomarkers distinguishing HCC from underlying cirrhosis a significant focus. In this study, we analyzed tissue and serum samples from 40 HCC cases and 25 patients with liver cirrhosis to identify candidate biomarkers that distinguish HCC from cirrhotic patients in a race specific manner. Through integrative analysis of transcriptomic and metabolomic data, we investigated candidate metabolite biomarkers that are specific to AAs and EAs. The results from this demonstrate the utility of integrating transcriptomic and metabolomic data to prioritize clinically and biologically relevant metabolite biomarkers that can increase understanding of molecular mechanisms driving HCC in different racial groups.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Humanos , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Metabolômica
5.
Nat Commun ; 11(1): 4907, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999289

RESUMO

Global alterations in the metabolic network provide substances and energy to support tumor progression. To fuel these metabolic processes, extracellular matrix (ECM) plays a dominant role in supporting the mass transport and providing essential nutrients. Here, we report a fibrinogen and thrombin based coagulation system to construct an artificial ECM (aECM) for selectively cutting-off the tumor metabolic flux. Once a micro-wound is induced, a cascaded gelation of aECM can be triggered to besiege the tumor. Studies on cell behaviors and metabolomics reveal that aECM cuts off the mass transport and leads to a tumor specific starvation to inhibit tumor growth. In orthotopic and spontaneous murine tumor models, this physical barrier also hinders cancer cells from distant metastasis. The in vivo gelation provides an efficient approach to selectively alter the tumor mass transport. This strategy results in a 77% suppression of tumor growth. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasonic treatment, surgery or radiotherapy, implying this strategy is potential to be translated into a clinical combination regimen.


Assuntos
Materiais Biomiméticos/administração & dosagem , Matriz Extracelular/química , Neoplasias/terapia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/efeitos da radiação , Materiais Biomiméticos/química , Materiais Biomiméticos/efeitos da radiação , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/métodos , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos da radiação , Feminino , Fibrinogênio/administração & dosagem , Fibrinogênio/química , Fibrinogênio/efeitos da radiação , Géis , Humanos , Injeções Intravenosas , Metabolômica , Camundongos , Neoplasias/metabolismo , Trombina/administração & dosagem , Trombina/química , Trombina/efeitos da radiação , Terapia por Ultrassom/métodos , Ondas Ultrassônicas
6.
PLoS One ; 15(8): e0238316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866201

RESUMO

BACKGROUND: Perinatally HIV-infected children on anti-retroviral treatment (ART) are reported to have metabolic abnormalities such as dyslipidemia, lipodystrophy, and insulin resistance which potentially increase the risk of diabetes, kidney, liver and cardiovascular disease. OBJECTIVE: To elucidate HIV-mediated metabolic complications that sustain even during ART in perinatally HIV-infected children. METHOD: We have carried out metabolic profiling of the plasma of treatment-naïve and ART-suppressed perinatally HIV-infected children and uninfected controls using 1H nuclear magnetic resonance (NMR) spectroscopy followed by statistical analysis and annotation. RESULT: Validated multivariate analysis showed clear distinction among our study groups. Our results showed elevated levels of lactate, glucose, phosphoenolpyruvic acid, propionic acid, 2-ketobutyric acid and tricarboxylic acid (TCA) cycle metabolites in untreated HIV-infected children compared to uninfected controls. ART normalized the levels of several metabolites, however the level of lactate, phosphoenolpyruvic acid, oxoglutaric acid, oxaloacetic acid, myoinositol and glutamine remained upregulated despite ART in HIV-infected children. Pathway analysis revealed perturbed propanoate metabolism, amino acid metabolism, glycolysis and TCA cycle in untreated and ART-suppressed HIV-infected children. CONCLUSION: Developing therapeutic strategies targeting metabolic abnormalities may be beneficial for preventing diabetes, cardiovascular disease or other associated complications in perinatally HIV-infected children.


Assuntos
Infecções por HIV/metabolismo , Plasma/metabolismo , Antirretrovirais/uso terapêutico , Criança , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Metaboloma/fisiologia , Metabolômica/métodos , Projetos Piloto , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
7.
J Am Soc Mass Spectrom ; 31(10): 2013-2024, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32880453

RESUMO

As corona virus disease 2019 (COVID-19) is a rapidly growing public health crisis across the world, our knowledge of meaningful diagnostic tests and treatment for severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is still evolving. This novel coronavirus disease COVID-19 can be diagnosed using RT-PCR, but inadequate access to reagents, equipment, and a nonspecific target has slowed disease detection and management. Precision medicine, individualized patient care, requires suitable diagnostics approaches to tackle the challenging aspects of viral outbreaks where many tests are needed in a rapid and deployable approach. Mass spectrometry (MS)-based technologies such as proteomics, glycomics, lipidomics, and metabolomics have been applied in disease outbreaks for identification of infectious disease agents such as virus and bacteria and the molecular phenomena associated with pathogenesis. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS) is widely used in clinical diagnostics in the United States and Europe for bacterial pathogen identification. Paper spray ionization mass spectrometry (PSI-MS), a rapid ambient MS technique, has recently open a new opportunity for future clinical investigation to diagnose pathogens. Ultra-high-pressure liquid chromatography coupled high-resolution mass spectrometry (UHPLC-HRMS)-based metabolomics and lipidomics have been employed in large-scale biomedical research to discriminate infectious pathogens and uncover biomarkers associated with pathogenesis. PCR-MS has emerged as a new technology with the capability to directly identify known pathogens from the clinical specimens and the potential to identify genetic evidence of undiscovered pathogens. Moreover, miniaturized MS offers possible applications with relatively fast, highly sensitive, and potentially portable ways to analyze for viral compounds. However, beneficial aspects of these rapidly growing MS technologies in pandemics like COVID-19 outbreaks has been limited. Hence, this perspective gives a brief of the existing knowledge, current challenges, and opportunities for MS-based techniques as a promising avenue in studying emerging pathogen outbreaks such as COVID-19.


Assuntos
Infecções por Coronavirus/etiologia , Lipidômica/métodos , Espectrometria de Massas/métodos , Metabolômica/métodos , Pneumonia Viral/etiologia , Proteômica/métodos , Cromatografia Líquida de Alta Pressão , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Glicômica/métodos , Humanos , Pandemias , Reação em Cadeia da Polimerase , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
8.
Chemosphere ; 258: 127387, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947680

RESUMO

It is well known that serum is an ideal and potential choice to reflect the toxicity of fluoride. However, the effects of fluoride on serum metabolome have not been reported until now. In this study, the models of 3-week-old rats exposed fluoride by breast milk and 11-week-old rats exposed fluoride via breast milk and drinking water containing sodium fluoride (100 mg/L) were established. Using Ultra Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS), as compared with control group, 28 negative (NEG) and 52 positive (POS) metabolites were significantly up-regulated, meanwhile 30 NEG and 21 POS significantly down-regulated metabolites were found in serum of 3-week-old rats exposed to fluoride. For 11-week-old fluorosis rats, there were 119 NEG and 65 POS metabolites significantly increased, and 7 NEG, 5 POS metabolites were obviously decreased. Importantly, nicotinamide, adenosine, 1-Oleoyl-sn-glycero-3-phosphocholine (OGPC), and 1-Stearoyl-sn-glycerol 3-phosphocholine (SGPC) were shared by two models. The metabolites of urea cycle, such as urea and N2-Acetyl-l-ornithine, betaine as a methyl donor, were regarded to reflect the fluorosis degree. These metabolites could be the potential markers of fluorosis, contributing to the prevention and treatment of fluorosis.


Assuntos
Fluoretos/toxicidade , Metaboloma/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Betaína , Cromatografia Líquida , Água Potável/química , Feminino , Humanos , Masculino , Metabolômica , Leite/metabolismo , Ratos , Fluoreto de Sódio , Espectrometria de Massas em Tandem
9.
Nat Commun ; 11(1): 4487, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900998

RESUMO

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.


Assuntos
Envelhecimento Saudável/metabolismo , Metaboloma , Proteoma/metabolismo , Idoso , Estudos de Coortes , Feminino , Envelhecimento Saudável/genética , Voluntários Saudáveis , Humanos , Lipidômica , Estudos Longitudinais , Masculino , Metabolômica , Pessoa de Meia-Idade , Medicina de Precisão , Estudos Prospectivos , Proteômica , Suécia , Transcriptoma
10.
Nat Commun ; 11(1): 4496, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901024

RESUMO

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.


Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inositol/metabolismo , Longevidade/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/genética , Inositol/administração & dosagem , Locomoção/fisiologia , Longevidade/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica , Camundongos , Mitofagia/fisiologia , Modelos Animais , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA-Seq
11.
Medicine (Baltimore) ; 99(37): e22160, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925778

RESUMO

INTRODUCTION: Community-acquired pneumonia (CAP) is the main acute complication of type 2 diabetes mellitus (T2DM) and the main cause of hospitalization for infectious diseases. Unfortunately, in the treatment of type 2 diabetes mellitus complicated with community-acquired pneumonia (T2DM-CAP), modern medicine is still faced with enormous challenges because of insulin resistance and drug-resistant bacteria. In recent decades, clinical and experimental evidence shows that Chinese herbal medicine (CHM) has a certain beneficial effect on diabetes and pneumonia. Therefore, this trial aims to assess the efficacy and safety of CHM plus western medicines for the treatment of T2DM-CAP. METHODS: We propose a double-blind, placebo-controlled, randomized superiority trial.A total of 92 participants with T2DM-CAP will be randomly allocated at a 1:1 ratio to either the experimental group, which will receive modified Ban-Xia-Xie-Xin-Decotion and basic treatment, or the control group, which will receive basic treatment only. The study duration will be 14 days. The primary outcome will be the total clinical effective rate. The secondary outcomes are traditional Chinese medicine symptom score scale, pneumonia severity index, usage time of antibiotic, time required for blood sugar to reach the required level, frequency of hypoglycemia, and chest CT. Liquid chromatograph-mass spectrometry method will be used to explore the blood metabolism profiles of the subjects, to explore the pathogenesis of T2DM-CAP and the mechanism of CHM on T2DM-CAP. Adverse events will also be evaluated. DISCUSSION: This trial will provide evidence of the effectiveness and safety of traditional CHM in treating patients with T2DM-CAP. TRIAL REGISTRATION NUMBER: ChiCTR2000035204.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/epidemiologia , Adolescente , Adulto , Idoso , Infecções Comunitárias Adquiridas , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Humanos , Hipoglicemia/epidemiologia , Masculino , Metabolômica , Pessoa de Meia-Idade , Pneumonia/sangue , Radiografia Torácica , Índice de Gravidade de Doença , Fatores de Tempo , Tomografia Computadorizada por Raios X , Adulto Jovem
12.
Int Heart J ; 61(5): 1014-1021, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32879261

RESUMO

Impaired fatty acid metabolism is associated with heart failure (HF) prognosis. However, specific changes in acylcarnitine profiles and their potential clinical value have not been well explored in patients recovering from acute decompensation.This study recruited 79 HF patients hospitalized because of acute decompensation with a left ventricular ejection fraction (LVEF) of < 40% and 51 normal controls. Patients were dichotomized into two groups, namely, the "improved (IMP) " and the "non-improved (NIMP) " groups, as defined by the changes in LVEF from baseline to 12 months after discharge. Mass spectrometry was used to quantify the acylcarnitine concentrations at baseline and 6 and 12 months after discharge. The IMP and NIMP groups contained 42 and 37 patients, respectively. At baseline, HF patients had higher plasma concentrations of specific long-, medium-, and short-chain acylcarnitines compared to normal controls. From baseline to 12 months post-discharge, the IMP group showed significant decreases in long- and short-chain acylcarnitine concentrations, but significant increases in medium-chain acylcarnitines. In the NIMP group, none of the acylcarnitines significantly decreased, and significant increases were noted in long-, medium-, and short-chain acylcarnitines. Generalized estimating equations demonstrated that nine acylcarnitines could discriminate the IMP group from the NIMP group, including three long-chain (C18:1, C16, and C16:1) and six short-chain acylcarnitines (C5, C5-OH, C4, C4:1-DC, C3, and C2). After adjusting for age, the six short-chain acylcarnitines remained significant. Changes in short-chain acylcarnitine profiles are independently associated with the improvement in cardiac systolic function after acute decompensation.


Assuntos
Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Insuficiência Cardíaca/metabolismo , Metabolômica , Idoso , Carnitina/metabolismo , Estudos de Casos e Controles , Ésteres/metabolismo , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Prognóstico , Volume Sistólico , Sístole
13.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3726-3739, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893565

RESUMO

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Bactérias/classificação , Cromatografia Líquida , Metabolômica , Ratos , Espectrometria de Massas em Tandem
14.
Ecotoxicol Environ Saf ; 203: 111044, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888613

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. METHODS: The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits. RESULTS: The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. CONCLUSIONS: The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.


Assuntos
Poluentes Atmosféricos/toxicidade , Angiotensina I/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Material Particulado/toxicidade , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Acetilglucosaminidase/urina , Angiotensina I/sangue , Animais , Biomarcadores/sangue , Biomarcadores/urina , Hipertensão/urina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , beta-Galactosidase/urina
15.
Nat Commun ; 11(1): 4830, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973134

RESUMO

Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation. First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies.


Assuntos
Melanoma/metabolismo , Metabolômica/métodos , Microscopia/métodos , Análise Espectral Raman/métodos , Apoptose , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Humanos , Gotículas Lipídicas , Metabolismo dos Lipídeos , Lipidômica , Lipídeos , Ácido Oleico , Estearoil-CoA Dessaturase/metabolismo , Transcriptoma
16.
PLoS One ; 15(9): e0237975, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32960892

RESUMO

The swift rise of omics-approaches allows for investigating microbial diversity and plant-microbe interactions across diverse ecological communities and spatio-temporal scales. The environment, however, is rapidly changing. The introduction of invasive species and the effects of climate change have particular impact on emerging plant diseases and managing current epidemics. It is critical, therefore, to take a holistic approach to understand how and why pathogenesis occurs in order to effectively manage for diseases given the synergies of changing environmental conditions. A multi-omics approach allows for a detailed picture of plant-microbial interactions and can ultimately allow us to build predictive models for how microbes and plants will respond to stress under environmental change. This article is designed as a primer for those interested in integrating -omic approaches into their plant disease research. We review -omics technologies salient to pathology including metabolomics, genomics, metagenomics, volatilomics, and spectranomics, and present cases where multi-omics have been successfully used for plant disease ecology. We then discuss additional limitations and pitfalls to be wary of prior to conducting an integrated research project as well as provide information about promising future directions.


Assuntos
Ecologia , Genômica/métodos , Metabolômica/métodos , Metagenômica/métodos , Doenças das Plantas/etiologia , Plantas/imunologia , Proteômica/métodos , Microbiota , Plantas/metabolismo , Biologia de Sistemas
17.
Nat Commun ; 11(1): 4708, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948758

RESUMO

While the field of microbiology has adapted to the study of complex microbiomes via modern meta-omics techniques, we have not updated our basic knowledge regarding the quantitative levels of DNA, RNA and protein molecules within a microbial cell, which ultimately control cellular function. Here we report the temporal measurements of absolute RNA and protein levels per gene within a mixed bacterial-archaeal consortium. Our analysis of this data reveals an absolute protein-to-RNA ratio of 102-104 for bacterial populations and 103-105 for an archaeon, which is more comparable to Eukaryotic representatives' humans and yeast. Furthermore, we use the linearity between the metaproteome and metatranscriptome over time to identify core functional guilds, hence using a fundamental biological feature (i.e., RNA/protein levels) to highlight phenotypical complementarity. Our findings show that upgrading multi-omic toolkits with traditional absolute measurements unlocks the scaling of core biological questions to dynamic and complex microbiomes, creating a deeper insight into inter-organismal relationships that drive the greater community function.


Assuntos
Microbiota/genética , Microbiota/fisiologia , Proteínas/genética , Proteínas/metabolismo , RNA/genética , RNA/metabolismo , Archaea/genética , Archaea/metabolismo , Bactérias/genética , Bactérias/metabolismo , DNA , Perfilação da Expressão Gênica , Genoma Microbiano , Humanos , Metabolômica , Fenótipo , Proteoma , Proteômica , Transcriptoma , Leveduras
18.
Nat Commun ; 11(1): 4706, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943618

RESUMO

Yeast physiology is temporally regulated, this becomes apparent under nutrient-limited conditions and results in respiratory oscillations (YROs). YROs share features with circadian rhythms and interact with, but are independent of, the cell division cycle. Here, we show that YROs minimise energy expenditure by restricting protein synthesis until sufficient resources are stored, while maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells sequester and store metabolic resources via increased transport, autophagy and biomolecular condensation. Replete stores trigger increased H+ export which stimulates TORC1 and liberates proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates translational bursting, liquidation of storage carbohydrates, increased ATP turnover, and the export of osmolytes. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints selected for temporal organisation that promotes oscillatory behaviour.


Assuntos
Metabolismo Energético/fisiologia , Células Eucarióticas/fisiologia , Proteostase/fisiologia , Autofagia/fisiologia , Reatores Biológicos , Ritmo Circadiano , Glicogênio/metabolismo , Resposta ao Choque Térmico , Ionomicina , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metabolômica , Chaperonas Moleculares , Concentração Osmolar , Pressão Osmótica , Oxigênio/metabolismo , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Proteoma , Proteômica , Ribossomos , Leveduras/fisiologia
20.
PLoS Biol ; 18(8): e3000830, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810128

RESUMO

Plants are attacked by herbivores, which often specialize on different tissues, and in response, have evolved sophisticated resistance strategies that involve different types of chemical defenses frequently targeted to different tissues. Most known phytohormones have been implicated in regulating these defenses, with jasmonates (JAs) playing a pivotal role in complex regulatory networks of signaling interactions, often generically referred to as "cross talk." The newly identified class of phytohormones, strigolactones (SLs), known to regulate the shoot architecture, remain unstudied with regard to plant-herbivore interactions. We explored the role of SL signaling in resistance to a specialist weevil (Trichobaris mucorea) herbivore of the native tobacco, Nicotiana attenuata, that attacks the root-shoot junction (RSJ), the part of the plant most strongly influenced by alterations in SL signaling (increased branching). As SL signaling shares molecular components, such as the core F-box protein MORE AXILLARY GROWTH 2 (MAX2), with another new class of phytohormones, the karrikins (KARs), which promote seed germination and seedling growth, we generated transformed lines, individually silenced in the expression of NaMAX2, DWARF 14 (NaD14: the receptor for SL) and CAROTENOID CLEAVAGE DIOXYGENASE 7 (NaCCD7: a key enzyme in SL biosynthesis), and KARRIKIN INSENSITIVE 2 (NaKAI2: the KAR receptor). The mature stems of all transgenic lines impaired in the SL, but not the KAR signaling pathway, overaccumulated anthocyanins, as did the stems of plants attacked by the larvae of weevil, which burrow into the RSJs to feed on the pith of N. attenuata stems. T. mucorea larvae grew larger in the plants silenced in the SL pathway, but again, not in the KAI2-silenced plants. These phenotypes were associated with elevated JA and auxin (indole-3-acetic acid [IAA]) levels and significant changes in the accumulation of defensive compounds, including phenolamides and nicotine. The overaccumulation of phenolamides and anthocyanins in the SL pathway-silenced plants likely resulted from antagonism between the SL and JA pathway in N. attenuata. We show that the repressors of SL signaling, suppressor of max2-like (NaSMXL6/7), and JA signaling, jasmonate zim-domain (NaJAZs), physically interact, promoting NaJAZb degradation and releasing JASMONATE INSENSITIVE 1 (JIN1/MYC2) (NaMYC2), a critical transcription factor promoting JA responses. However, the increased performance of T. mucorea larvae resulted from lower pith nicotine levels, which were inhibited by increased IAA levels in SL pathway-silenced plants. This inference was confirmed by decapitation and auxin transport inhibitor treatments that decreased pith IAA and increased nicotine levels. In summary, SL signaling tunes specific sectors of specialized metabolism in stems, such as phenylpropanoid and nicotine biosynthesis, by tailoring the cross talk among phytohormones, including JA and IAA, to mediate herbivore resistance of stems. The metabolic consequences of the interplay of SL, JA, and IAA signaling revealed here could provide a mechanism for the commonly observed pattern of herbivore tolerance/resistance trade-offs.


Assuntos
Herbivoria/fisiologia , Interações Hospedeiro-Parasita , Lactonas/metabolismo , Caules de Planta/metabolismo , Caules de Planta/parasitologia , Transdução de Sinais , Tabaco/metabolismo , Tabaco/parasitologia , Animais , Antocianinas/metabolismo , Ciclopentanos/metabolismo , Ácidos Indolacéticos/metabolismo , Larva , Metabolômica , Oxilipinas/metabolismo , Proteínas de Plantas/metabolismo , Interferência de RNA , Gorgulhos/fisiologia
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