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1.
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
2.
Aquat Toxicol ; 227: 105625, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32927179

RESUMO

Here we report the molecular networks associated with the mucosal and systemic responses to peracetic acid (PAA), a candidate oxidative chemotherapeutic in Atlantic salmon (Salmo salar). Smolts were exposed to different therapeutic doses (0, 0.6 and 2.4 mg/L) of PAA for 5 min, followed by a re-exposure to the same concentrations for 30 min 2 weeks later. PAA-exposed groups have higher external welfare score alterations, especially 2 weeks after the re-exposure. Cases of fin damage and scale loss were prevalent in the PAA-exposed groups. Transcriptomic profiling of mucosal tissues revealed that the skin had 12.5 % more differentially regulated genes (DEGs) than the gills following PAA exposure. The largest cluster of DEGs, both in the skin and gills, were involved in tissue extracellular matrix and metabolism. There were 22 DEGs common to both mucosal tissues, which were represented primarily by genes involved in the biophysical integrity of the mucosal barrier, including cadherin, collagen I α 2 chain, mucin-2 and spondin 1a. The absence of significant clustering in the plasma metabolomes amongst the three treatment groups indicates that PAA treatment did not induce any global metabolomic disturbances. Nonetheless, five metabolites with known functions during oxidative stress were remarkably affected by PAA treatments such as citrulline, histidine, tryptophan, methionine and trans-4-hydroxyproline. Collectively, these results indicate that salmon were able to mount mucosal and systemic adaptive responses to therapeutic doses of PAA and that the molecules identified are potential markers for assessing the health and welfare consequences of oxidant exposure.


Assuntos
Metaboloma , Transcriptoma , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Doenças dos Peixes/genética , Perfilação da Expressão Gênica , Brânquias/efeitos dos fármacos , Membrana Mucosa/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo , Salmo salar/metabolismo
3.
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
4.
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
5.
Nat Commun ; 11(1): 4608, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929085

RESUMO

Actinobacteria produce antibacterial and antifungal specialized metabolites. Many insects harbour actinobacteria on their bodies or in their nests and use these metabolites for protection. However, some actinobacteria produce metabolites that are toxic to insects and the evolutionary relevance of this toxicity is unknown. Here we explore chemical interactions between streptomycetes and the fruit fly Drosophila melanogaster. We find that many streptomycetes produce specialized metabolites that have potent larvicidal effects against the fly; larvae that ingest spores of these species die. The mechanism of toxicity is specific to the bacterium's chemical arsenal: cosmomycin D producing bacteria induce a cell death-like response in the larval digestive tract; avermectin producing bacteria induce paralysis. Furthermore, low concentrations of volatile terpenes like 2-methylisoborneol that are produced by streptomycetes attract fruit flies such that they preferentially deposit their eggs on contaminated food sources. The resulting larvae are killed during growth and development. The phenomenon of volatile-mediated attraction and specialized metabolite toxicity suggests that some streptomycetes pose an evolutionary risk to insects in nature.


Assuntos
Bactérias/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/microbiologia , Actinobacteria/fisiologia , Animais , Antraciclinas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Canfanos/toxicidade , Morte Celular/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/microbiologia , Metaboloma , Esporos Bacterianos/metabolismo , Esporos Bacterianos/fisiologia , Streptomyces/fisiologia , Análise de Sobrevida , Compostos Orgânicos Voláteis/farmacologia
6.
Ecotoxicol Environ Saf ; 203: 111033, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888611

RESUMO

Diamide insecticides, such as chlorantraniliprole, cyantraniliprole, and tetrachlorantraniliprole, are a new class of insecticides that selectively target insects by affecting calcium homeostasis. While this class of insecticides are effective on a wide range of insect pests, the toxicities of diamide insecticides vary among species and life stages. In this study, we addressed the mechanism underlying the different responses of Plutella xylostella and Pieris rapae to diamide insecticides. The susceptibility to insecticides of P. xylostella and P. rapae larvae was assessed 2 and 4 days after exposure to chlorantraniliprole, cyantraniliprole, and tetrachlorantraniliprole. P. xylostella larvae treated with distilled water (Group A), chlorantraniliprole (Group B), cyantraniliprole (Group C), and tetrachlorantraniliprole (Group D) and P. rapae larvae treated with distilled water (Group E), chlorantraniliprole (Group F), cyantraniliprole (Group G) and tetrachlorantraniliprole (Group H) were subjected to metabolomics analysis. The differential metabolites in the B vs. F, C vs. G, and D vs. H groups were analyzed, followed by pathway enrichment analysis. Chlorantraniliprole, cyantraniliprole, and tetrachlorantraniliprole all showed high toxicities for P. xylostella and P. rapae larvae. P. rapae larvae were more sensitive to the diamide insecticides than P. xylostella larvae. There were 65 overlapped differential metabolites between P. xylostella and P. rapae larvae treated with these three diamide insecticides. Pathway analysis showed that the differential metabolites were closely related with fatty acid biosynthesis and metabolism-related pathways. The differential regulation of fatty acid biosynthesis and metabolism may contribute to the different response to diamide insecticides in P. xylostella and P. rapae.


Assuntos
Borboletas/efeitos dos fármacos , Diamida/farmacologia , Inseticidas/farmacologia , Metaboloma/efeitos dos fármacos , Mariposas/efeitos dos fármacos , Animais , Borboletas/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Mariposas/metabolismo , Especificidade da Espécie
7.
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
8.
PLoS One ; 15(9): e0237981, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903271

RESUMO

Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicina Hidroximetiltransferase/metabolismo , Neoplasias Pulmonares/patologia , Metaboloma , Proteoma/análise , Serina/metabolismo , Animais , Antifúngicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Glicina Hidroximetiltransferase/antagonistas & inibidores , Glicina Hidroximetiltransferase/genética , Células HeLa , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Domínios e Motivos de Interação entre Proteínas , Benzoato de Sódio/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Crit Care Resusc ; 22(3): 227-236, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32900329

RESUMO

OBJECTIVE: The systemic inflammatory response syndrome (SIRS) is a dysregulated response that contributes to critical illness. Adjunctive acetylsalicylic acid (ASA) treatment may offer beneficial effects by increasing the synthesis of specialised proresolving mediators (a subset of polyunsaturated fatty acid-derived lipid mediators). DESIGN: Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial. SETTING: Four interdisciplinary intensive care units (ICUs) in Australia. PARTICIPANTS: Critically ill patients with SIRS. INTERVENTIONS: ASA 100 mg 12-hourly or placebo, administered within 24 hours of ICU admission and continued until ICU day 7, discharge or death, whichever came first. MAIN OUTCOME MEASURES: Interleukin-6 (IL-6) serum concentration at 48 hours after randomisation and, in a prespecified subgroup of patients, serum lipid mediator concentrations measured by mass spectrometry. RESULTS: The trial was discontinued in December 2017 due to slow recruitment and after the inclusion of 48 patients. Compared with placebo, ASA did not decrease IL-6 serum concentration at 48 hours. In the 32 patients with analysis of lipid mediators, low-dose ASA increased the concentration of 15-hydroxyeicosatetraenoic acid, a proresolving precursor of lipoxin A4, and reduced the concentration of the proinflammatory cytochrome P-dependent mediators 17-HETE (hydroxyeicosatetraenoic acid), 18-HETE and 20-HETE. In the eicosapentaenoic acid pathway, ASA significantly increased the concentration of the anti-inflammatory mediators 17,18-DiHETE (dihydroxyeicosatetraenoic acid) and 14,15-DiHETE. CONCLUSIONS: In ICU patients with SIRS, low-dose ASA did not significantly alter serum IL-6 concentrations, but it did affect plasma concentrations of certain lipid mediators. The ability to measure lipid mediators in clinical samples and to monitor the effect of ASA on their levels unlocks a potential area of biological investigation in critical care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).


Assuntos
Aspirina/administração & dosagem , Estado Terminal , Citocinas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Austrália , Método Duplo-Cego , Estudos de Viabilidade , Humanos , Interleucina-6/sangue , Lipídeos , Resultado do Tratamento
10.
Ecotoxicol Environ Saf ; 205: 111102, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32836152

RESUMO

The increased production and environmental release of graphene nanoparticles has raised concerns about its environmental impact, but the effects of graphene on living organisms at the metabolic level remain unknown. In this study, we used matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)-based untargeted metabolomics to investigate the metabolic response of juvenile earthworms (Eisenia fetida) to graphene exposure in soil tests for the first time. Our results reveal that graphene-exposure significantly disturbs earthworm metabolome, and graphene toxicity on earthworm shows non-concentration-dependent effect. Alanine, phenylalanine, proline, glutamate, arginine, histidine, maltose, glucose, malate, succinate, myo-inositol, and spermidine were successfully screened as significantly change compounds in earthworms for the exposure of graphene. The heterogeneous distributions of these metabolites in earthworm were also clearly imaged by MALDI-MSI. Our MSI results fully showed that the metabolite expression levels in juvenile earthworms significantly changed (up-/down-regulation) after exposure to graphene nanoparticles. This work improves our understanding of graphene nanoparticle toxicity to juvenile earthworms and also enables the continued progression of MALDI-MSI-based metabolomics as an emerging, reliable, and rapid ecotoxicological tool for assessing contaminant toxicity.


Assuntos
Grafite/toxicidade , Oligoquetos/fisiologia , Poluentes do Solo/toxicidade , Alanina/metabolismo , Animais , Grafite/metabolismo , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Oligoquetos/efeitos dos fármacos , Solo/química , Poluentes do Solo/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
PLoS Pathog ; 16(8): e1008815, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32833996

RESUMO

Although therapeutics targeting viral metabolic processes have been considered as promising strategies to treat herpesvirus infection, the metabolic requirements of gallid alphaherpesvirus 1 (ILTV), which is economically important to the poultry industry worldwide, remain largely unknown. Using the ILTV-susceptible but nonpermissive chicken cell line DF-1 and the ILTV-permissive chicken cell line LMH as models, the present study explored the metabolic requirements of ILTV by global transcriptome analysis and metabolome assays of ILTV infected cell lines in combination with a set of functional validations. The extensive metabolic exploration demonstrated that ILTV infection tended to promote a metabolic shift from glycolysis to fatty acid (FA) and nucleotide biosynthesis and utilizes glutamine independently of glutaminolysis, without significant general effect on the TCA cycle. In addition, different metabolic pathways were found to be required for distinct stages of ILTV replication. Glucose and glutamine were required for the transcription of viral immediate early gene ICP4 and subsequent steps of viral replication. However, FA synthesis was essential for assembly but not required for other upstream steps of ILTV replication. Moreover, the metabolic requirements of ILTV infection revealed in chicken cell lines were further validated in chicken primary cells isolated from chicken embryo kidneys and chicken embryo livers. The present study, to the best of our knowledge, provides the first global metabolic profile of animal herpesviruses and illustrates the main characteristics of the metabolic program of ILTV.


Assuntos
Infecções por Herpesviridae/metabolismo , Herpesvirus Galináceo 1/metabolismo , Metaboloma , Replicação Viral , Animais , Galinhas , Glicólise , Infecções por Herpesviridae/virologia
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(8): 874-881, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32800035

RESUMO

OBJECTIVE: To study the features of blood lipid metabolic profile in overweight/obese boys aged 9-12 years and the possible mechanism of overweight/obesity in children. METHODS: According to body mass index (BMI), 72 boys, aged 9-12 years, were divided into a control group with 42 boys and an overweight/obesity group with 30 boys. Fasting venous blood samples were collected early in the morning. BMI, waist-hip ratio, body composition, and blood lipids were measured. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry technique was used to analyze the serum lipid compounds. A statistical analysis and visualization of the data were performed. RESULTS: Compared with the control group, the overweight/obesity group had significantly higher waist-hip ratio, body fat percentage, and triglyceride level (P<0.05) and a significantly lower level of high-density lipoprotein cholesterol (P<0.05). The metabolomic analysis identified 150 differentially expressed lipid compounds between the two groups, mainly glycerolipids (40.7%), glycerophospholipids (24.7%), fatty acyls (10.7%), and sphingolipids (7.3%). The levels of most of glycerolipids were significantly upregulated in the overweight/obesity group, while those of most of glycerophospholipids and sphingolipids were downregulated in this group. Key lipids with differential expression were enriched into two KEGG metabolic pathways, i.e., ether lipid metabolism pathway and terpenoid backbone biosynthesis pathway (P<0.05), and might further affected the biosynthesis and metabolism of downstream coenzyme Q and other terpenoids (P=0.06). CONCLUSIONS: Disordered lipid metabolic profile is observed in overweight/obese boys aged 9-12 years, with increases in most glycerolipids and reductions in glycerophospholipids and sphingolipids. Overweight/obese boys may have disorders in ether lipid metabolism and biosynthesis of terpenoid and even coenzyme Q.


Assuntos
Metaboloma , Obesidade Pediátrica , Índice de Massa Corporal , Criança , Humanos , Lipídeos , Masculino , Sobrepeso
14.
Yakugaku Zasshi ; 140(8): 963-968, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741869

RESUMO

Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metaboloma , Metabolômica , Sunitinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo
15.
Wiad Lek ; 73(7): 1373-1376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32759423

RESUMO

OBJECTIVE: The aim: To assess carbohydrate and lipid metabolic profiles of tuberculosis patients with bilateral injuries of the lungs and mycobacteria excretion. PATIENTS AND METHODS: Materials and methods: Seventy two newly diagnosed pulmonary TB patients were examined. Group I - 17 newly diagnosed TB patients who had unilateral pulmonary lesions and had no mycobacteria excretion. Group II - 55 newly diagnosed TB patients who had bilateral pulmonary lesions and mycobacteria excretion. The control group included 20 healthy persons. Fasting insulin level, indices of lipidogram were measured, oral glucose tolerance test was performed. Statistical processing of the obtained results was carried out by analyzing the contingency tables using the StatisticaBasicAcademic 13 for Windows software package. RESULTS: Results: Tuberculosis patients develop insulin resistance - condition that is a precursor to developing type 2 diabetes and metabolic disorder of lipid exchange - dyslipidemia. Patients with bilateral pulmonary lesions and mycobacteria excretion have the most pronounced disorders of carbohydrate and lipid metabolism compared to patients with limited lesions of the lungs. CONCLUSION: Conclusions: We suppose that mycobacteria excretion and bilateral lesions of lungs may be the markers of the degree of carbohydrate and lipid metabolism disorders in patients with pulmonary tuberculosis.


Assuntos
Tuberculose , Carboidratos , Diabetes Mellitus Tipo 2 , Humanos , Metabolismo dos Lipídeos , Lipídeos , Metaboloma
16.
Nat Commun ; 11(1): 4334, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859911

RESUMO

The metabolome includes not just known but also unknown metabolites; however, metabolite annotation remains the bottleneck in untargeted metabolomics. Ion mobility - mass spectrometry (IM-MS) has emerged as a promising technology by providing multi-dimensional characterizations of metabolites. Here, we curate an ion mobility CCS atlas, namely AllCCS, and develop an integrated strategy for metabolite annotation using known or unknown chemical structures. The AllCCS atlas covers vast chemical structures with >5000 experimental CCS records and ~12 million calculated CCS values for >1.6 million small molecules. We demonstrate the high accuracy and wide applicability of AllCCS with medium relative errors of 0.5-2% for a broad spectrum of small molecules. AllCCS combined with in silico MS/MS spectra facilitates multi-dimensional match and substantially improves the accuracy and coverage of both known and unknown metabolite annotation from biological samples. Together, AllCCS is a versatile resource that enables confident metabolite annotation, revealing comprehensive chemical and metabolic insights towards biological processes.


Assuntos
Espectrometria de Mobilidade Iônica/métodos , Metaboloma/fisiologia , Metabolômica/métodos , Algoritmos , Fenômenos Biológicos , Confiabilidade dos Dados , Bases de Dados Factuais , Redes e Vias Metabólicas , Software , Espectrometria de Massas em Tandem
17.
J Assoc Physicians India ; 68(8): 51-54, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32738842

RESUMO

Background and objective: Nonalcoholic fatty liver disease (NAFLD) is conventionally considered to be a disease of obese subjects. Recent data suggests increasing incidence of NAFLD among lean subjects also. The aim of this study was to evaluate the metabolic profile of lean subjects with NAFLD and compare it with obese subjects with NAFLD. We also aimed to compare the same with lean subjects without NAFLD. Methods: This study included 250 subjects with NAFLD and 500 non-NAFLD controls. Clinical, anthropological and biochemical data were collected. Subjects with body mass index (BMI) >= 25 kg/m2 were taken as obese and subjects with BMI <25 kg/m2 were taken as lean. Study population was divided into four groups i.e. lean subjects with NAFLD (LN), obese subjects with NAFLD (ON), lean subjects without NAFLD (LNN) and obese subjects without NAFLD (ONN). Results: Out of 250 NAFLD subjects, 69 (27.6%) were lean. Out of 69 lean subjects with NAFLD, 54 (78.3%) were having diabetes mellitus. Metabolic profile (including lipid profile, diabetic profile) of lean subjects with NAFLD was significantly abnormal in comparison to lean non-NAFLD subjects. Proportion of subjects with metabolic syndrome was also comparable in both lean and obese NAFLD groups. Despite having comparable BMI, LN groups had significantly higher waist circumference (WC) than LNN. Mean total cholesterol, triglyceride, LDL were significantly higher in obese NAFLD in comparison to lean NAFLD. Mean HDL and VLDL were comparable among both groups. Mean FBS, HbA1c, fasting insulin and HOMA-IR were significantly higher among lean NAFLD group in comparison to obese NAFLD group. Obese NAFLD group had significantly higher levels of SGPT and SGOT as compared to lean NAFLD group. Conclusion: Lean NAFLD has significantly higher WC in comparison to non-NAFLD counterparts suggesting possible association with central adiposity. Lean and obese NAFLD share common set of metabolic abnormalities, albeit with varying intensity. Lean NAFLD has more severe insulin resistance in comparison to obese NAFLD. Lean NAFLD subjects appeared to have less severe transaminasemia.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Índice de Massa Corporal , Humanos , Metaboloma , Obesidade , Circunferência da Cintura
18.
Ecotoxicol Environ Saf ; 205: 111166, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827966

RESUMO

N, N-Dimethylformamide (DMF) is a universal organic solvent which widely used in various industries, and a considerable amount of DMF is detected in industrial effluents. Accumulating animal and epidemiological studies have identified liver injury as an early toxic effect of DMF exposure; however, the detailed mechanisms remain poorly understood. In this study, we systematically integrated the quantitative proteomics, lipidomics, and metabolomics data obtained from the primary human hepatocytes exposed to DMF, to depict the complicated biochemical reactions correlated to liver damage. Eventually, we identified 284 deregulated proteins (221 downregulated and 63 upregulated) and 149 deregulated lipids or metabolites (99 downregulated and 50 upregulated) induced by DMF exposure. Further, the integration of the protein-metabolite (lipid) interactions revealed that N-glycan biosynthesis (involved in the endoplasmic reticulum stress and the unfolded protein response), bile acid metabolism (involved in the lipid metabolism and the inflammatory process), and mitochondrial dysfunction and glutathione depletion (both contributed to reactive oxygen species) were the typical biochemical reactions disturbed by DMF exposure. In summary, our study identified the versatile protein, lipid, and metabolite molecules in multiple signaling and metabolic pathways involved in DMF induced liver injury, and provided new insights to elucidate the toxic mechanisms of DMF.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dimetilformamida/toxicidade , Poluentes Ambientais/toxicidade , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Proteoma/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glutationa/metabolismo , Hepatócitos/metabolismo , Humanos , Lipidômica , Metabolômica , Cultura Primária de Células , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Testes de Toxicidade/métodos
19.
Ecotoxicol Environ Saf ; 205: 111152, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846297

RESUMO

Root exudates are the most direct manifestation of the response of plants changes in the external environment. Therefore, based on non-targeted gas chromatography-time-of-flight mass spectrometry and metabolomics, the response of Sedum plumbizincicola root exudates to Cd stress was used to reveal the possible mechanism of resistance to or accumulation of Cd. The results showed that Cd significantly changed the composition and contents of S. plumbizincicola root exudates. A total of 155 metabolites were identified in S. plumbizincicola root exudates, among which 33 showed significant differences under Cd stress, including organic acids, amino acids, lipids, and polyols. Cd stress suppressed organic acid metabolism and lipid metabolism in S. plumbizincicola and significantly affected amino acid metabolism. There were 16 metabolic pathways related to Cd stress, among which arginine and proline metabolism, valine, leucine, and isoleucine biosynthesis, glycine, serine, and threonine metabolism, glutathione metabolism, and purine metabolism were the key pathways with the highest correlation, and were closely related to the stress resistance of S. plumbizincicola.


Assuntos
Cádmio/toxicidade , Metaboloma/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Exsudatos de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacos , Sedum/efeitos dos fármacos , Poluentes do Solo/toxicidade , Adaptação Fisiológica/efeitos dos fármacos , Bioacumulação/efeitos dos fármacos , Biodegradação Ambiental , Cádmio/metabolismo , Metabolômica , Raízes de Plantas/metabolismo , Sedum/metabolismo , Poluentes do Solo/análise
20.
Bioresour Technol ; 316: 123910, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32750640

RESUMO

The present study investigated the bacterial community, metabolome and biotransformation of phenolic compounds in sainfoin silage inoculated either with or without Lactobacillus plantarum. Our results revealed that the epiphytic microbiota of wilted sainfoin mainly comprised Acinetobacter, Spingomonas, Pseudomonas, Lactobacillus, Delftia and Aquabacterium. After ensiling, L. acetotolerans, L. buchneri, L. plantarum, L. pentosus and Clostridium tyrobutricum were the dominant species. Compared to the control, the inoculant L. plantarum increased the relative abundance of L. buchneri while decreased that of the other dominant species. The ensiling process increased the concentrations of 21 flavones, 16 flavonols, 16 flavonoids, 14 flavanones and 9 isoflavones while decreased other 32 flavones and 11 anthocyanins, which mainly modulated by the "isoflavonoid biosynthesis" and "flavonoid biosynthesis" pathways. The inoculant L. plantarum mainly reduced the concentrations of 10 flavones. Compared with the control, the inoculant L. plantarum mainly affected the metabolism pathways related to carbohydrates and nitrogen.


Assuntos
Lactobacillus plantarum , Microbiota , Biotransformação , Fermentação , Metaboloma , Silagem/análise , Zea mays
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