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1.
J Appl Toxicol ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166782

RESUMO

Benzo[a]pyrene (B[a]P), a typical carcinogenic polycyclic aromatic hydrocarbon, exists worldwide in vehicle exhaust, cigarette smoke and other polluted environments. Recent studies have demonstrated a strong association between B[a]P and lung cancer. However, whether B[a]P at human blood equivalent level can promote epithelial-mesenchymal transition (EMT), a crucial molecular event during cell malignant transformation, remains unclear. Besides, whether B[a]P facilitates this progress via aryl hydrocarbon receptor (AhR) signaling pathway also lacks scientific evidence. In our study, the transwell assay showed that 5 µg/L of B[a]P promoted BEAS-2B cell invasion and migration. In addition, the mRNA and protein expression levels of AhR and its target genes involved in B[a]P metabolism, such as AhR nuclear translocator, heat shock protein 90 and CYP1A1, were significantly increased by B[a]P exposure. Moreover, the mRNA expression levels of downstream regulatory factors related to both AhR signaling pathway and EMT, such as NRF2, K-RAS and hypoxia-inducible factor 1-alpha, were significantly increased. Furthermore, the expression level of the epithelial marker E-cadherin was significantly downregulated, while the mRNA expression of mesenchymal phenotype markers, N-cadherin, fibronectin and vimentin, were significantly upregulated. Notably, the above changes induced by B[a]P were significantly attenuated or even stopped by resveratrol (RSV), a natural phenol, also an AhR inhibitor, when the AhR signaling pathway was inhibited by RSV, demonstrating the regulatory role of AhR signaling pathway in B[a]P-induced EMT. In conclusion, B[a]P at the human blood equivalent level induces BEAS-2B cell invasion and migration through the AhR signaling pathway.

2.
Medicine (Baltimore) ; 98(42): e17338, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626090

RESUMO

RATIONALE: Unicompartmental knee arthroplasty (UKA) is an effective method to treat single compartment disease of the knee joint. Report about the complications of UKA, especially tibial plateau fractures, is rare. Given its rarity, its pathogenesis is not well described, and a standard of treatment is still not established. Therefore, relevant studies and analysis of this complication have a significant effect on helping physicians avoid risks and guide clinical diagnosis and treatment. PATIENT CONCERNS: The 1st case corresponds to a 70-year-old male patient who complained of knee pain, difficulty walking, nocturnal rest pain, and elevated skin temperature at 3 weeks after the left knee arthroplasty. The second case is a 72-year-old female patient who complained of left knee pain and swelling during movement at 2 weeks after the left knee arthroplasty. DIAGNOSIS: The 1st case showed a fracture of the medial malleolus of the left knee and a secondary depression of the medial tibial plateau in X-rays and the second case showed a fracture of the medial malleolus of the left knee in computed tomography (CT) and X-rays. INTERVENTIONS: The 1st case was treated with plate and screw fixation and the second case was treated conservatively and immobilized using brace and remained nonweight bearing for 6 weeks. OUTCOMES: After 1 year, both patients have good joint activity, and there was no pain or loosening of the prosthesis and fragment displacement. LESSONS: The incidence of tibial plateau fractures (TPF) related to UKA might be low, but fatal and difficult to treat. Its pathogenesis determines procedure-related factors; when fracture develops, treatment should be based on the degree of displacement, stability of implant fixation, etc.


Assuntos
Artroplastia do Joelho/efeitos adversos , Tratamento Conservador/métodos , Fixação Interna de Fraturas/métodos , Complicações Pós-Operatórias/terapia , Fraturas da Tíbia/terapia , Idoso , Idoso de 80 Anos ou mais , Braquetes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/etiologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
3.
Sci Total Environ ; 691: 874-884, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31326811

RESUMO

Exposure to fine particulate matter (PM2.5) increases the risk of metabolic diseases, such as cancer and cardiovascular disease. Disturbed hepatocyte metabolism accelerates the incidence and progression of metabolic diseases. However, toxic effects of PM2.5 on hepatocyte metabolism remain unclear. Accordingly, an untargeted metabolomics approach based on liquid chromatography-mass spectrometry was used to characterize comprehensive metabolic responses of HepG2 cells to PM2.5 exposure and to discover potential therapeutic targets for PM2.5-induced metabolic dysregulation in metabolic diseases. Metabolomics revealed that exposure to liposoluble extracts of PM2.5 samples (LE) triggered substantial changes in 46 metabolic pathways, mainly involved in lipid, amino acid, nucleotide and carbohydrate metabolism, in HepG2 cells. Notably, LE exposure induced accumulation of FFAs and medium-chained acylcarnitines (6-12 carbons), but decreased levels of short-chained acylcarnitines (<5 carbons) in HepG2 cells. Meanwhile, levels of citrate/isocitrate and aconitate were decreased, while 2-hydroxyglutate and succinate accumulated in HepG2 cells treated with LE. Additionally, levels of adenosine triphosphate, guanosine triphosphate, uridine triphosphate and cytidine triphosphate were decreased; however, contents of adenosine monophosphate, guanosine monophosphate, purines and pyrimidines were increased in HepG2 cells treated with LE. Moreover, levels of glutathione, Glu-Cys, Cys-Gly, lipoic acid, methionine sulfoxide, methionine and S-adenosyl-L-methionine were increased, while those of most amino acids were decreased in HepG2 cells treated with LE. These data demonstrated that LE exposure triggered accumulation of FAAs and oncometabolites (2-hydroxyglutate and succinate), mitochondrial dysfunctions characterized by incomplete FFA oxidation and reduced energy supply from TCA cycle and oxidative phosphorylation, disturbances in methylation and redox homeostasis, and the inhibition of most amino acid metabolism in HepG2 cells. Above metabolic disorders indicates potential therapeutic targets for treating PM2.5-induced injury and diseases. To the best of our knowledge, this study provides the first evidence that LE exposure triggered accumulation of medium-chain acylcarnitines, oncometabolites, purines and pyrimidines in HepG2 cells.


Assuntos
Poluentes Atmosféricos/toxicidade , Metaboloma/efeitos dos fármacos , Material Particulado/toxicidade , Cromatografia Líquida , Glutationa , Células Hep G2 , Hepatócitos , Humanos , Lipídeos , Redes e Vias Metabólicas , Metabolômica , Oxirredução , Espectrometria de Massas em Tandem
4.
J Cell Mol Med ; 23(6): 4313-4325, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957417

RESUMO

Disordered intestinal metabolism is highly correlated with atherosclerotic diseases. Resveratrol protects against atherosclerotic diseases. Accordingly, this study aims to discover novel intestinal proatherosclerotic metabolites and potential therapeutic targets related to the anti-atherosclerotic effects of resveratrol. An untargeted metabolomics approach was employed to discover novel intestinal metabolic disturbances during atherosclerosis and resveratrol intervention. We found that multiple intestinal metabolic pathways were significantly disturbed during atherosclerosis and responsive to resveratrol intervention. Notably, resveratrol abolished intestinal fatty acid and monoglyceride accumulation in atherosclerotic mice. Meanwhile, oleate accumulation was one of the most prominent alterations in intestinal metabolism. Moreover, resveratrol attenuated oleate-triggered accumulation of total cholesterol, esterified cholesterol and neutral lipids in mouse RAW 264.7 macrophages by activating ABC transporter A1/G1-mediated cholesterol efflux through PPAR (peroxisome proliferator-activated receptor) α/γ activation. Furthermore, we confirmed that PPARα and PPARγ activation by WY14643 and pioglitazone, respectively, alleviated oleate-induced accumulation of total cholesterol, esterified cholesterol and neutral lipids by accelerating ABC transporter A1/G1-mediated cholesterol efflux. This study provides the first evidence that resveratrol abolishes intestinal fatty acid and monoglyceride accumulation in atherosclerotic mice, and that resveratrol suppresses oleate-induced accumulation of total cholesterol, esterified cholesterol and neutral lipids in macrophages by activating PPARα/γ signalling.

5.
Toxicology ; 420: 11-20, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30935970

RESUMO

Although the production of polychlorinated biphenyl 77 (PCB77) has already been banned globally, PCB77 is still used for a wide range of commercial purposes. Previous evidence has demonstrated that the PCB77 administration should be responsible for the gut microbiota variations and the host health risk. However, the host disorders and bacterial functions involved in PCB77 exposure remain largely unknown. Few studies have been performed to illuminate the correlation between the bacterial functions and disorders. Furthermore, it is urgently needed to find specific strains as potential biomarkers to monitor PCB77 pollution and associated disorders. This study was designed to investigate the effects of PCB77 on gut microbiota and induced disorders in female mice. Obtained results indicated that PCB77 exposure induced gut microbiota dysbiosis, obesity, hyperlipidemia, hepatic lipid accumulation, and liver injury in mice. Functional prediction based on the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) algorithm showed that exposure to PCB77 weakened the bacterial functions relating to lipid and energy metabolism, and immune system disease. Experimental findings were consistent with the result of the PICRUSt functional prediction. Importantly, three PCB77-associated bacterial taxa were screened out as potential biomarkers for the assessment of PCB77 pollution. This study provides previously unknown knowledge linking PCB77 administration, gut microbiota functional profile and lipid abnormalities, which is of important clinical significance for therapies treating PCB77-associated diseases.

6.
Metabolomics ; 15(3): 36, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30830452

RESUMO

INTRODUCTION: Macrophage metabolism contributes to the progression of metabolic diseases, and peroxisome proliferator-activated receptors (PPARs) play vital roles in macrophage metabolism and the treatment of metabolic diseases. However, the role of PPARs in metabolic reprogramming related to lipid accumulation in macrophages, a key pathological event in metabolic diseases, remains unclear. OBJECTIVES: We aimed to identify PPAR-mediated metabolic reprogramming and potential therapeutic targets associated with lipid accumulation in macrophages. METHODS: Following treatment with oleate, oleate + WY-14643 and oleate + pioglitazone to induce alterations in PPAR signaling, lipids and relevant metabolism, macrophage samples were analyzed employing an untargeted metabolomics based on gas chromatography-mass spectrometry. RESULTS: The metabolomics approach revealed that multiple metabolic pathways were altered during lipid accumulation in oleate-treated macrophages and responsive to WY-14643 and pioglitazone treatment. Notably, levels of most metabolites involved in amino acid metabolism and nucleotide metabolism were accumulated in oleate-treated macrophages, and these effects were alleviated or abolished by PPARA/G activation. Additionally, during oleate-induced lipid accumulation and lipid lowering with WY-14643 and pioglitazone in macrophages, levels of most amino acids were positively associated with neutral lipid, total cholesterol, cholesterol ester, total free fatty acid and triglyceride levels but negatively associated with expression of genes related to PPARA/G signaling. Furthermore, glycine was found to be a potential biomarker for assessing lipid accumulation and the lipid-lowering effects of PPARA/G in oleate-treated macrophages. CONCLUSION: The results of this study revealed a high correlation of amino acid metabolism with lipid accumulation and the lipid-lowering effects of PPARA/G in macrophages.

7.
Environ Pollut ; 248: 269-278, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30798028

RESUMO

Exposure to ambient particular matters (PM) has been associated with the development of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study aimed to explore the role of miRNA-mRNA regulation underlying abnormal lipid metabolism triggered by PM2.5liposoluble extracts. We confirmed that 72-h exposure to liposoluble extracts of PM2.5 from Nanjing at 25 µg/cm2 induced lipid accumulation in HepG2 cells by promoting uptake of free fatty acids (FFAs). Notably, lipid accumulation induced by PM2.5 liposoluble extracts was associated with decreased expression of miR-26a and consequent upregulation of fatty acid translocase (FAT, also known as CD36). Using gain- and loss-of-function assays, we demonstrated that miR-26a negatively regulated CD36 to mediate lipid accumulation in HepG2 cells. We further confirmed that miR-26a directly acted on the 3' untranslated region (3'UTR) of CD36. Furthermore, overexpression of miR-26a abolished steatosis in HepG2 cells treated with PM2.5 liposoluble extracts by suppressing CD36. In addition, we demonstrated that PM2.5 liposoluble extracts caused inflammation in HepG2 cells by raising p65 phosphorylation, thereby fuelling the transition from simple non-alcoholic fatty liver to non-alcoholic steatohepatitis. In conclusion, this study demonstrated a novel mechanism by which miR-26a-CD36 pathway mediated lipid accumulation induced by PM2.5 liposoluble extracts in hepatocytes. Lipid accumulation and inflammation induced by PM2.5 liposoluble extracts implied the potential role of PM2.5 in developing NAFLD.


Assuntos
Poluentes Atmosféricos/toxicidade , Material Particulado/toxicidade , Testes de Toxicidade , Animais , Transporte Biológico , Células Hep G2 , Hepatócitos , Humanos , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica , Material Particulado/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Transdução de Sinais , Regulação para Cima
8.
Cell Death Dis ; 10(2): 39, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30674874

RESUMO

Lipid accumulation in macrophages interacts with microenvironment signals and accelerates diabetic atherosclerosis. However, the molecular mechanisms by which macrophage metabolism interacts with microenvironment signals during lipid accumulation are not clearly understood. Accordingly, an untargeted metabolomics approach was employed to characterize the metabolic reprogramming, and to identify potential regulatory targets related to lipid accumulation in macrophages treated with oleate, an important nutrient. The metabolomics approach revealed that multiple metabolic pathways were significantly disturbed in oleate-treated macrophages. We discovered that amino acids, nucleosides, lactate, monoacylglycerols, total free fatty acids (FFAs), and triglycerides (TGs) accumulated in oleate-treated macrophages, but these effects were effectively attenuated or even abolished by resveratrol. Notably, 1-monooleoylglycerol and 2-monooleoylglycerol showed the largest fold changes in the levels among the differential metabolites. Subsequently, we found that oleate triggered total FFA and TG accumulation in macrophages by accelerating FFA influx through the activation of Fatp1 expression, but this effect was attenuated by resveratrol via the activation of PPARα and PPARγ signaling. We verified that the activation of PPARα and PPARγ by WY14643 and pioglitazone, respectively, attenuated oleate triggered total FFA and TG accumulation in macrophages by repressing FFA import via the suppression of Fatp1 expression. Furthermore, the inhibition of Fatp1 by tumor necrosis factor α alleviated oleate-induced total FFA and TG accumulation in macrophages. This study provided the first demonstration that accumulation of amino acids, nucleosides, lactate, monoacylglycerols, total FFAs, and TGs in oleate-treated macrophages is effectively attenuated or even abolished by resveratrol, and that the activation of PPARα and PPARγ attenuates oleate-induced total FFA and TG accumulation via suppression of Fatp1 expression in macrophages. Therapeutic strategies aim to activate PPAR signaling, and to repress FFA import and triglyceride synthesis are promising approaches to reduce the risk of obesity, diabetes and atherosclerosis.

9.
Sci Total Environ ; 653: 274-282, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30412872

RESUMO

There is growing evidence that polychlorinated biphenyl 126 (PCB126) not only has adverse effects on host health but also has the ability to shift gut microbiota, which is recently recognized as a crucial factor determining numerous physiological processes. However, the interplay between the gut microbiota and host health remains largely unknown. Herein, adult female C57BL/6 mice were orally exposed to environmentally relevant low-dose of PCB126, at 50 µg/kg body weight once per week for 6 weeks. This study aims to illuminate how PCB126 influences gut microbiota variations and host disorders and to further identify the correlation between the gut microbiota and metabolic markers of host disorders. Obtained results demonstrated that the PCB126 administration induced gut microbiota dysbiosis in mice, with changes both in the gut microbiota constitution and structure. PCB126 administration also simultaneously altered the physiological status of serum and liver, as evaluated by dyslipidemia, liver lipid accumulation and injury, and non-alcoholic fatty liver disease. Importantly, Spearman's correlation analysis suggested that several specific bacterial taxa were positively and significantly related to metabolic markers of the mentioned disorders. Moreover, based on the co-occurrence network map, some of the bacterial taxa may synergistically regulate host physiology. This work provides new insight into the mechanism underlying the interaction between the gut microbiota and host disorders. It is expected that gut microbiota modulation should be another novel way used for the prevention and treatment of PCB126-triggered diseases.


Assuntos
Disbiose/induzido quimicamente , Dislipidemias/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Bifenilos Policlorados/toxicidade , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL
10.
Environ Pollut ; 242(Pt A): 914-921, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30373036

RESUMO

Bisphenol A (BPA) exposure receives great ecotoxicological concern. However, gaps in knowledge, such as metabolism of BPA and inconsistent reports on reproductive toxicity, still exist. In this study, a marine fish model (Oryzias melastigma) was exposed to serial concentrations of BPA throughout its whole life cycle. The level of BPA-glucuronide (BPAG) dramatically increased throughout the embryonic stage since 4 dpf. Accordingly, the mRNA level and enzymatic activity of UDP-glucuronosyltransferases (UGTs) increased across the embryonic stage. The mRNA level of UGT2 subtype rather than UGT1 or UGT5 showed a concentration dependent response to BPA exposure. BPA exposure led to the morphological disruption of the chorion and villi as shown by scanning electron microscopy; however, the hatchability was not significantly influenced after exposure. Newly hatching larvae were continuously exposed to BPA for 120 days. Lower mRNA levels of hormone metabolism-related genes, decreased ratio of E2/T, slower ovary development and decreased egg production confirmed the inhibitory effect of BPA on reproduction. Overall, our results showed the conjugation of BPA into BPAG by UGT2 at the embryonic stage and convinced the reproductive toxicity from multiple levels after whole life exposure to BPA.


Assuntos
Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Testes de Toxicidade Crônica , Poluentes Químicos da Água/toxicidade , Animais , Compostos Benzidrílicos/metabolismo , Feminino , Glucuronídeos , Glucuronosiltransferase , Larva/efeitos dos fármacos , Oryzias/embriologia , Fenóis/metabolismo , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/metabolismo
11.
Environ Pollut ; 239: 332-341, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29674211

RESUMO

Polychlorinated biphenyls (PCBs), one type of lipophilic pollutant, are ubiquitous in daily life. PCBs exposure has been implicated in the alterations of gut microbial community which is profoundly associated with diverse metabolic disorders, including obesity. High-fat diet (H) is a dietary pattern characterized by a high percentage of fat. According to the theory that similarities can be easily solvable in each other, PCBs and H exposures are inevitably and objectively coexistent in a real living environment, prompting great concerns about their individual and combined effects on hosts. However, the effects of PCBs-H interactions on gut microbiota and obesity are still incompletely understood. In the present study, the effects of PCBs and/or H on the gut microbiota alteration and obesity risk in mice were examined and the interactions between PCBs and H were investigated. Obtained results showed that PCBs and/or H exposure induced prominent variations in the gut microbiota composition and diversity. Exposure to PCBs also resulted in higher body fat percentage, greater size of abdominal subcutaneous adipocytes and increased expression of proinflammatory cytokines including TNF-α, iNOS and IL-6. Such PCBs-induced changes could be further enhanced upon the co-exposure of H, implying that obese individuals may be vulnerable to PCBs exposure. Taken together, the present study is helpful for a better understanding of the gut microbiota variation influenced by PCBs and/or H exposure, and furthermore, provides a novel insight into the mechanism of PCBs-H interactions on host adiposity.


Assuntos
Dieta Hiperlipídica , Disbiose/induzido quimicamente , Poluentes Ambientais/toxicidade , Obesidade/induzido quimicamente , Bifenilos Policlorados/toxicidade , Gordura Abdominal , Animais , Exposição Dietética , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos
12.
J Environ Sci (China) ; 66: 155-164, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29628082

RESUMO

Epidemiological studies have demonstrated that fine particulate matter (PM2.5) exposure causes airway inflammation, which may lead to lung cancer. The activation of epithelial-mesenchymal transition (EMT) is assumed to be a crucial step in lung tumor metastasis and development. We assessed the EMT effect of low concentrations (0, 0.1, 1.0, and 5.0µg/mL) of PM2.5 organic extract on a human bronchial epithelial cell line (BEAS-2B). PM2.5 samples were collected from three cities (Shanghai, Ningbo, and Nanjing) in the Yangtze River Delta (YRD) region in autumn 2014. BEAS-2B cells were exposed to the PM2.5 extract to assess cell viability, invasion ability as well as the relative mRNA and protein expressions of EMT markers. Our findings revealed that BEAS-2B cells changed from the epithelial to mesenchymal phenotype after exposure. In all groups, PM2.5 exposure dose-dependently decreased the expression of E-cadherin and increased the expression of Vimentin. The key transcription factors, including ZEB1 and Slug, were significantly up-regulated upon exposure. These results indicated that the PM2.5 organic extract induced different degrees of EMT progression in BEAS-2B cells. The cell invasion ability increased in a concentration-dependent manner after 48hr of treatment with the extract. This study offers a novel insight into the effects of PM2.5 on EMT and the potential health risks associated with PM2.5 in the YRD region.


Assuntos
Poluentes Atmosféricos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Material Particulado/toxicidade , Sobrevivência Celular/efeitos dos fármacos , China , Células Epiteliais , Humanos , Testes de Toxicidade
13.
Int J Cancer ; 143(2): 396-407, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29441565

RESUMO

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Metabolômica/métodos , Neoplasias da Próstata/patologia , Ciclo do Ácido Cítrico , Fumaratos/análise , Cromatografia Gasosa-Espectrometria de Massas , Regulação Neoplásica da Expressão Gênica , Humanos , Malatos/análise , Masculino , Gradação de Tumores , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Análise de Sequência de RNA
14.
Cell Physiol Biochem ; 45(3): 1136-1148, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29439261

RESUMO

BACKGROUND/AIMS: Abdominal obesity is recognized as the main reason of metabolic syndrome, which is closely related to disordered skeletal and/or abdominal muscle metabolic functions. Metabolomics is a comprehensive assessment system in biological metabolites. The aim of our present study is to investigate the diet-induced metabolic risk factors by metabolic in the abdominal muscles and clarify the relationship between atheroprotective effects of Resveratrol (Rev) and abdominal muscles metabolic components during the development of atherosclerosis. METHODS: The mice were randomly divided into three groups including normal group (N), high fat diet (HFD or H) group and high fat diet with Rev treated group (HR). GC-MS combined with pattern recognition approaches were employed to obtain comprehensive metabolic signatures and related differential metabolites after 24 week HFD feeding. Oil Red O staining and Electron microscopy technology (EMT) were employed to detect the size of fatty plaques and intracellular lipid accumulation, respectively. RESULTS: The result indicated that 22 types of metabolites in the abdominal muscles were obviously altered by HFD feeding group. Moreover, Rev treatment obviously increased 11 different kinds of metabolites, most of which were involved in the carbohydrate, amino acid and lipid metabolisms. Importantly, these elevated different metabolites were involved in pathways mainly related to galactose metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism in abdominal muscles. Oil Red O staining and Electron microscopy showed less lipid accumulation in the lesions and decreased intracellular lipid deposition in the foam cells in HR group. CONCLUSIONS: We concluded that Rev produced a beneficial effect partially by modulating multiple metabolism pathways and metabolites in the abdominal muscles, which may provide a new protective mechanism of Rev on the progression of atherosclerosis. These notably changed metabolites might be potential biomarkers or therapeutic targets during development of metabolic syndrome and atherosclerosis.


Assuntos
Músculos Abdominais/metabolismo , Dieta Hiperlipídica , Estilbenos/farmacologia , Aminoácidos/análise , Aminoácidos/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/prevenção & controle , Metabolismo dos Carboidratos/efeitos dos fármacos , Análise Discriminante , Cromatografia Gasosa-Espectrometria de Massas , Análise dos Mínimos Quadrados , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/análise , Doenças Metabólicas/etiologia , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Monossacarídeos/análise , Monossacarídeos/metabolismo , Resveratrol , Fatores de Risco , Estilbenos/uso terapêutico
15.
J Environ Sci (China) ; 64: 23-31, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29478644

RESUMO

Environmental risks of organic chemicals have been greatly determined by their persistence, bioaccumulation, and toxicity (PBT) and physicochemical properties. Major regulations in different countries and regions identify chemicals according to their bioconcentration factor (BCF) and octanol-water partition coefficient (Kow), which frequently displays a substantial correlation with the sediment sorption coefficient (Koc). Half-life or degradability is crucial for the persistence evaluation of chemicals. Quantitative structure activity relationship (QSAR) estimation models are indispensable for predicting environmental fate and health effects in the absence of field- or laboratory-based data. In this study, 39 chemicals of high concern were chosen for half-life testing based on total organic carbon (TOC) degradation, and two widely accepted and highly used QSAR estimation models (i.e., EPI Suite and PBT Profiler) were adopted for environmental risk evaluation. The experimental results and estimated data, as well as the two model-based results were compared, based on the water solubility, Kow, Koc, BCF and half-life. Environmental risk assessment of the selected compounds was achieved by combining experimental data and estimation models. It was concluded that both EPI Suite and PBT Profiler were fairly accurate in measuring the physicochemical properties and degradation half-lives for water, soil, and sediment. However, the half-lives between the experimental and the estimated results were still not absolutely consistent. This suggests deficiencies of the prediction models in some ways, and the necessity to combine the experimental data and predicted results for the evaluation of environmental fate and risks of pollutants.


Assuntos
Monitoramento Ambiental/métodos , Poluentes Ambientais/toxicidade , Compostos Orgânicos/toxicidade , Relação Quantitativa Estrutura-Atividade , Monitoramento Ambiental/normas , Poluentes Ambientais/química , Modelos Químicos , Compostos Orgânicos/química , Medição de Risco/métodos
16.
Arch Toxicol ; 92(3): 1023-1035, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29222745

RESUMO

Exposure to ambient particulate matter (PM) has been linked to the increasing incidence and mortality of lung cancer, but the principal toxic components and molecular mechanism remain to be further elucidated. In this study, human lung adenocarcinoma A549 cells were treated with serial concentrations of water-extracted PM10 (WE-PM10) collected from Beijing, China. Our results showed that exposure to 25 and 50 µg/ml of WE-PM10 for 48 h significantly suppressed miR-26a to upregulate lin-28 homolog B (LIN28B), and in turn activated interleukin 6 (IL6) and signal transducer and activator of transcription 3 (STAT3) in A549 cells, subsequently contributing to enhanced epithelial-mesenchymal transition and accelerated migration and invasion. In vivo pulmonary colonization assay further indicated that WE-PM10 enhanced the metastatic ability of A549 cells. In addition, luciferase reporter assay demonstrated that 3' untranslated region of LIN28B was a direct target of miR-26a. Last but not the least, the key toxic contribution of metals in WE-PM10 was confirmed by the finding that removal of metals through chelation significantly rescued WE-PM10-mediated inflammatory, carcinogenic and metastatic responses. Taken together, miR-26a could act as the tumor suppressor in PM10-related lung cancer, and PM10-bound metals promoted lung cancer cell metastasis through downregulation of miR-26a that directly mediated LIN28B expression.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Material Particulado/toxicidade , Proteínas de Ligação a RNA/genética , Células A549 , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Metais/análise , Metais/toxicidade , Camundongos Endogâmicos BALB C , Material Particulado/química , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncotarget ; 8(61): 103032-103046, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262542

RESUMO

Speckle-type POZ protein (SPOP), as a cullin-based E3 ubiquitin ligase, has been identified as one of the most frequently mutated genes in prostate cancer (PCa). However, whether SPOP mutations contribute to metabolic reprogramming in PCa remains unknown. Here, integrated studies of transcriptomics and metabolomics as well as lipidomics were performed in matched PCa tumor (PCT) and adjacent non-tumor (ANT) tissues, followed by correlation analysis of SPOP mutations with altered metabolic pathways in SPOP-mutated PCa patients. Interestingly, transcriptomics profiling showed that all SPOP mutations (with 16.7% frequency, 11/66) occurred at the conserved residues in the substrate binding domain of meprin and TRAF homology (MATH). The results of integrated analysis indicated that three metabolic pathways, including tricarboxylic acid (TCA) cycle, fatty acid metabolism and glycerophospholipid metabolism, exhibited obvious upregulation in SPOP-mutated PCT tissues. Furthermore, both correlation analyses based on integrated data and cBioportal revealed that FH, ELOVL2 and ACADL genes might be involved in SPOP-mutation-related upregulation of these metabolic pathways. Taken together, our study provided new insights in understanding the relationship between metabolic pathways and SPOP mutations in PCa.

18.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(9): 869-882, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28483554

RESUMO

Exposure to Bisphenol A (BPA) has been associated with the development of nonalcoholic fatty liver disease (NAFLD) but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study was designed to explore whether exposure to BPA-triggered abnormal steatosis and lipid accumulation in the liver could be modulated by miR-192. We showed that male post-weaning C57BL/6 mice exposed to 50µg/kg/day of BPA by oral gavage for 90days displayed a NAFLD-like phenotype. In addition, we found in mouse liver and human HepG2 cells that BPA-induced hepatic steatosis and lipid accumulation were associated with decreased expression of miR-192, upregulation of SREBF1 and a series of genes involved in de novo lipogenesis. Downregulation of miR-192 in BPA-exposed hepatocytes could be due to defective pre-miR-192 processing by DROSHA. Using HepG2 cells, we further confirmed that miR-192 directly acted on the 3'UTR of SREBF1, contributing to dysregulation of lipid homeostasis in hepatocytes. MiR-192 mimic and lentivirus-mediated overexpression of miR-192 improved BPA-induced hepatic steatosis by suppressing SREBF1. Lastly, we noted that lipid accumulation was not a strict requirement for developing insulin resistance in mice after BPA treatment. In conclusion, this study demonstrated a novel mechanism in which NAFLD associated with BPA exposure arose from alterations in the miR-192-SREBF1 axis.


Assuntos
Compostos Benzidrílicos/farmacologia , Regulação para Baixo/genética , Fígado Gorduroso/patologia , Lipídeos/fisiologia , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fenóis/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Animais , Linhagem Celular Tumoral , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Regulação para Cima/genética
19.
Sci Total Environ ; 595: 752-758, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28407592

RESUMO

Bisphenol A (BPA) and its halogenated compounds (H-BPAs) are widely detected in the environmental media and organisms. However, their toxicological effects, especially chronic exposure at low doses, have not been fully compared. In this study, the effects of BPA and H-BPAs on the reproduction and development of Oryzias melastigma were systematically assessed and compared at various developmental stages. BPA and its derivatives tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) elicited the acceleration of embryonic heartbeat. BPA did not show any significant impact on the hatching time and rate of embryos. In contrast, both TBBPA and TCBPA led to the delayed hatching and decreased hatching rate. Accordingly, the expressions of hatching enzyme significantly decreased upon exposure and TCBPA was found to be more toxic than TBBPA. The body weight and gonadsomatic index (GSI) of the treated fish were relatively lower than the control fish upon long-term (four months from larvae to adult) exposure to BPA rather than H-BPAs. Slowed oocyte development occurred in the ovary, and the estrogen level decreased after exposure to BPA rather than H-BPAs. In male fish, no significant alteration was observed in the testis for all groups. The concentration of testosterone significantly decreased upon exposure to BPA rather than H-BPAs. The effects of these three chemicals on the estrogen-related gene expressions were different under various developmental stages. Our study indicated the importance of considering both the exposure stages and structure-activity relationship when assessing the eco-toxicological impact of pollutants.


Assuntos
Compostos Benzidrílicos/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Oryzias , Fenóis/toxicidade , Reprodução/efeitos dos fármacos , Animais , Feminino , Masculino
20.
Sci Rep ; 6: 35257, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27734936

RESUMO

Tetrabromobisphenol A and tetrachlorobisphenol A are halogenated bisphenol A (H-BPA), and has raised concerns about their adverse effects on the development of fetuses and infants, however, the molecular mechanisms are unclear, and related metabolomics studies are limited. Accordingly, a metabolomics study based on gas chromatography-mass spectrometry was employed to elucidate the molecular developmental toxicology of H-BPA using the marine medaka (Oryzias melastigmas) embryo model. Here, we revealed decreased synthesis of nucleosides, amino acids and lipids, and disruptions in the TCA (tricarboxylic acid) cycle, glycolysis and lipid metabolism, thus inhibiting the developmental processes of embryos exposed to H-BPA. Unexpectedly, we observed enhanced neural activity accompanied by lactate accumulation and accelerated heart rates due to an increase in dopamine pathway and a decrease in inhibitory neurotransmitters following H-BPA exposure. Notably, disorders of the neural system, and disruptions in glycolysis, the TCA cycle, nucleoside metabolism, lipid metabolism, glutamate and aspartate metabolism induced by H-BPA exposure were heritable. Furthermore, lactate and dopa were identified as potential biomarkers of the developmental toxicity of H-BPA and related genetic effects. This study has demonstrated that the metabolomics approach is a useful tool for obtaining comprehensive and novel insights into the molecular developmental toxicity of environmental pollutants.


Assuntos
Biomarcadores/metabolismo , Clorofenóis/toxicidade , Doenças Metabólicas/metabolismo , Metabolômica , Bifenil Polibromatos/toxicidade , Teratogênios/toxicidade , Aminoácidos/metabolismo , Animais , Ciclo do Ácido Cítrico , Relação Dose-Resposta a Droga , Glicólise , Metabolismo dos Lipídeos , Nucleosídeos/metabolismo , Oryzias/embriologia
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