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2.
Food Chem Toxicol ; 156: 112439, 2021 Oct.
Article de Anglais | MEDLINE | ID: mdl-34303773

RÉSUMÉ

Both phthalate exposure and obesity are positively associated with metabolic disorders. The study aimed to investigate whether DEHP exposure caused metabolic disorders in an obesity-dependent manner. Both lean and diet-induced obese mice were subjected to environmentally relevant DEHP exposure. DEHP-treated obese mice exhibited higher glucose intolerance and insulin resistance than obese mice; the metabolic disorders were accompanied by increased blood levels of leptin, LDL cholesterol, and alanine transaminase. In obese mice, DEHP enhanced macrophage infiltration into epididymal white adipose tissue (eWAT) and hepatic tissue, and promoted hepatic steatosis/steatohepatitis. The DEHP effects were not observed in lean mice. Transcriptomic changes in eWAT and hepatic tissue were determined with microarray analysis. Results indicated that obesity and DEHP synergistically regulated carbohydrate uptake, lipolysis, and abnormality of adipose tissue, via the upstream regulators Pparg, Lipe, Cd44, and Irs1. Meanwhile, obesity and DEHP differentially modulated transcriptomic changes in hepatic tissue. Obesity was associated with lipid/cholesterol synthesis, lipid accumulation, and inflammation in hepatic tissue via the upstream regulators Zbtb20 and Nr1i2. In obese mice, DEHP exposure caused hepatic injury, cell migration, and changes in glycogen quantity mainly via Cd44. Microarray analysis suggested the potential mechanism underlying the early onset of metabolic disorders in DEHP-treated obese mice.


Sujet(s)
Régime alimentaire , Phtalate de bis[2-éthylhexyle]/toxicité , Maladies métaboliques/anatomopathologie , Obésité/complications , Tissu adipeux blanc/anatomopathologie , Animaux , Poids/effets des médicaments et des substances chimiques , Cholestérol LDL/sang , Glucose/métabolisme , Hyperglycémie provoquée , Leptine/sang , Foie/métabolisme , Foie/anatomopathologie , Mâle , Maladies métaboliques/complications , Maladies métaboliques/métabolisme , Souris , Souris de lignée C57BL , Obésité/métabolisme , Transcriptome
3.
Oncogene ; 40(30): 4847-4858, 2021 07.
Article de Anglais | MEDLINE | ID: mdl-34155349

RÉSUMÉ

Small cell lung cancer (SCLC) continues to cause poor clinical outcomes due to limited advances in sustained treatments for rapid cancer cell proliferation and progression. The transcriptional factor Forkhead Box M1 (FOXM1) regulates cell proliferation, tumor initiation, and progression in multiple cancer types. However, its biological function and clinical significance in SCLC remain unestablished. Analysis of the Cancer Cell Line Encyclopedia and SCLC datasets in the present study disclosed significant upregulation of FOXM1 mRNA in SCLC cell lines and tissues. Gene set enrichment analysis (GSEA) revealed that FOXM1 is positively correlated with pathways regulating cell proliferation and DNA damage repair, as evident from sensitization of FOXM1-depleted SCLC cells to chemotherapy. Furthermore, Foxm1 knockout inhibited SCLC formation in the Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) mouse model associated with increased levels of neuroendocrine markers, Ascl1 and Cgrp, and decrease in Yap1. Consistently, FOXM1 depletion in NCI-H1688 SCLC cells reduced migration and enhanced apoptosis and sensitivity to cisplatin and etoposide. SCLC with high FOXM1 expression (N = 30, 57.7%) was significantly correlated with advanced clinical stage, extrathoracic metastases, and decrease in overall survival (OS), compared with the low-FOXM1 group (7.90 vs. 12.46 months). Moreover, the high-FOXM1 group showed shorter progression-free survival after standard chemotherapy, compared with the low-FOXM1 group (3.90 vs. 8.69 months). Our collective findings support the utility of FOXM1 as a prognostic biomarker and potential molecular target for SCLC.


Sujet(s)
Marqueurs biologiques tumoraux , Protéine M1 à motif en tête de fourche/génétique , Tumeurs du poumon/étiologie , Tumeurs du poumon/mortalité , Carcinome pulmonaire à petites cellules/étiologie , Carcinome pulmonaire à petites cellules/mortalité , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Animaux , Lignée cellulaire tumorale , Prolifération cellulaire , Modèles animaux de maladie humaine , Femelle , Protéine M1 à motif en tête de fourche/métabolisme , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes tumoraux , Humains , Immunohistochimie , Estimation de Kaplan-Meier , Tumeurs du poumon/diagnostic , Mâle , Souris , Souris transgéniques , Adulte d'âge moyen , Grading des tumeurs , Stadification tumorale , Pronostic , Carcinome pulmonaire à petites cellules/diagnostic , Microtomographie aux rayons X , Tests d'activité antitumorale sur modèle de xénogreffe
4.
Int J Nanomedicine ; 15: 8411-8426, 2020.
Article de Anglais | MEDLINE | ID: mdl-33149584

RÉSUMÉ

BACKGROUND: Gold nanoparticles with high biocompatibility and immunomodulatory properties have potential applications in the development of new diagnostic and therapeutic strategies for nanomedicine. Nanoparticles targeting macrophages can manipulate or control immunological diseases. This study assessed the activity of dendrimer-encapsulated gold nanodots (AuNDs) with three surface modifications [ie, outfacing groups with primary amine (AuNDs-NH2), hydroxyl (AuNDs-OH), and quaternary ammonium ions (AuNDs-CH3)] regulated macrophage function and antioxidant response through Nrf2-dependent pathway. METHODS: AuNDs were prepared and characterized. Intracellular distribution of AuNDs in human macrophages was observed through confocal microscopy. The activity of AuNDs was evaluated using macrophage functions and antioxidant response in the human macrophage cell line THP-1. RESULTS: AuNDs-NH2 and AuNDs-CH3, but not AuNDs-OH, drove the obvious Nrf2-antioxidant response element pathway in THP-1 cells. Of the three, AuNDs-NH2 considerably increased mRNA levels and antioxidant activities of heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 in THP-1 cells. IL-6 mRNA and protein expression was mediated through Nrf2 activation in AuNDs-NH2-treated macrophages. Furthermore, Nrf2 activation by AuNDs-NH2 increased the phagocytic ability of THP-1 macrophages. CONCLUSION: AuNDs-NH2 had immunomodulatory activities in macrophages. The findings of the present work suggested that AuNDs have potential effects against chronic inflammatory diseases via the Nrf2 pathway.


Sujet(s)
Amines/composition chimique , Antioxydants/métabolisme , Or/composition chimique , Macrophages/métabolisme , Nanoparticules métalliques/composition chimique , Thérapie moléculaire ciblée , Facteur-2 apparenté à NF-E2/métabolisme , Cytokines/métabolisme , Endotoxines/métabolisme , Heme oxygenase-1/métabolisme , Humains , Médiateurs de l'inflammation/métabolisme , Stress oxydatif , Phagocytose , Phosphorylation , Espèces réactives de l'oxygène/métabolisme , Cellules THP-1
5.
Environ Pollut ; 267: 115548, 2020 Dec.
Article de Anglais | MEDLINE | ID: mdl-32892025

RÉSUMÉ

The level of di-(2-ethylhexyl) phthalate (DEHP) is elevated in chronic kidney disease patients undergoing dialysis. However, statins are unable to reduce the cardiovascular events in chronic dialysis patients. In this study, we investigated the effects of DEHP on statin-conferred pleiotropic effects and the underlying molecular mechanism in peritoneal dialysis (PD) patients and endothelial cells (ECs). In PD patients with serum DEHP level ≥0.0687 µg/mL, statin treatment was not associated with lower risk of cardiovascular disease. In ECs, exposure to DEHP abrogated the simvastatin-induced NO bioavailability and EC-related functions. Additionally, DEHP abolished the anti-inflammatory effect of simvastatin on the tumor necrosis factor α-induced upregulation of adhesion molecules and monocyte adhesion to ECs. Mechanistically, DEHP blunted the activation of transient receptor potential vanilloid type 1 (TRPV1), which is required for NO production by simvastatin in ECs. Notably, DEHP increased the activity and expression of protein phosphatase 2B (PP2B), a negative regulator of TRPV1 activity. The effect of DEHP on PP2B activation was mediated by the activation of the NADPH oxidase/reactive oxygen species (NOX-ROS) pathway. Inhibition of PP2B activity by pharmacological antagonists prevented the inhibitory effects of DEHP on simvastatin-induced Ca2+ influx, NO bioavailability, and EC migration, proliferation, tube formation, and anti-inflammatory action. Collectively, DEHP activates the NOX-ROS-PP2B pathway, which in turns inhibits TRPV1/Ca2+-dependent signaling and abrogates the statin-conferred pleiotropic protection in ECs.


Sujet(s)
Phtalate de bis[2-éthylhexyle] , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase , Insuffisance rénale chronique , Phtalate de bis[2-éthylhexyle]/toxicité , Cellules endothéliales , Humains , Acides phtaliques , Dialyse rénale , Insuffisance rénale chronique/thérapie
6.
Food Chem Toxicol ; 142: 111487, 2020 Aug.
Article de Anglais | MEDLINE | ID: mdl-32522588

RÉSUMÉ

Mono(2-ethylhexyl)phthalate (MEHP) promotes adipogenesis via PPARγ. PPARγ agonists, e.g., rosiglitazone (RSG), enhance adipocyte browning. However, scientific evidence regarding MEHP as a browning chemical is lacking. This study combined 3T3-L1 adipocytes and C57BL/6J mice to examine the potential roles of MEHP in browning. MEHP and the browning agent RSG caused similar energy metabolism in adipocytes. Both MEHP and RSG caused transcriptional changes involved in browning-associated thermogenesis, energy homeostasis, inflammatory response, and glucose uptake. MEHP-treated adipocytes exhibited brown adipocyte-like characteristics, i.e., increased mitochondrial proton leak, triiodothyronine-induced Bmp8b expression, decreased inflammation, and smaller lipid droplets. Increased PDK4 and PEPCK1 in MEHP/RSG-treated adipocytes could block glucose utilization for mitochondrial respiration. Mitochondrial/peroxisomal biogenesis and fatty acid ß-oxidation in MEHP-treated adipocytes were enhanced. Candidate genes in promoting browning of MEHP-treated adipocytes were highlighted. In di(2-ethylhexyl)phthalate (DEHP)-treated mice, transcriptional changes in white adipose tissue (WAT) were associated with adipocyte differentiation, lipid synthesis, carbohydrate uptake, and WAT/brown adipose tissue (BAT) quantity. PPARγ and NR4A1 were predicted as the top two upstream regulators in orchestrating transcriptional changes. DEHP-treated mice exhibited actively expressed browning marker genes (i.e., Pparg, Adrb1, Adrb3, Ppargc1a, and Ucp1) in WAT, increased blood FGF21 levels, and higher amounts of BAT, supporting the browning-like effects in vivo.


Sujet(s)
Adipocytes bruns/effets des médicaments et des substances chimiques , Phtalate de bis[2-éthylhexyle]/analogues et dérivés , Cellules 3T3-L1 , Adipocytes bruns/métabolisme , Animaux , Phtalate de bis[2-éthylhexyle]/toxicité , Métabolisme énergétique/effets des médicaments et des substances chimiques , Expression des gènes/effets des médicaments et des substances chimiques , Glucose/métabolisme , Techniques in vitro , Mâle , Souris , Souris de lignée C57BL , Mitochondries/métabolisme , Phosphoenolpyruvate carboxykinase (ATP)/métabolisme , Pyruvate dehydrogenase acetyl-transferring kinase
7.
Biosci Rep ; 40(4)2020 04 30.
Article de Anglais | MEDLINE | ID: mdl-32255176

RÉSUMÉ

Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer frequently leached out from polyvinyl chloride (PVC) products and is quickly metabolized to its monoester equivalent mono(2-ethylhexyl) phthalate (MEHP) once enters organisms. Exposure to DEHP/MEHP through food chain intake has been shown to modified metabolism but its effect on the development of metabolic myopathy of skeletal muscle (SKM) has not been revealed so far. Here, we found that MEHP repressed myogenic terminal differentiation of proliferating myoblasts (PMB) and confluent myoblasts (CMB) but had weak effect on this process once it had been initiated. The transition of mitochondria (MITO) morphology from high efficient filamentary network to low efficient vesicles was triggered by MEHP, implying its negative effects on MITO functions. The impaired MITO functions was further demonstrated by reduced MITO DNA (mtDNA) level and SDH enzyme activity as well as highly increased reactive oxygen species (ROS) in cells after MEHP treatment. The expression of metabolic genes, including PDK4, CPT1b, UCP2, and HO1, was highly increased by MEHP and the promoters of PDK4 and CPT1b were also activated by MEHP. Additionally, the stability of some subunits in the oxidative phosphorylation system (OXPHOS) complexes was found to be reduced by MEHP, implying defective oxidative metabolism in MITO and which was confirmed by repressed palmitic acid oxidation in MEHP-treated cells. Besides, MEHP also blocked insulin-induced glucose uptake. Taken together, our results suggest that MEHP is inhibitory to myogenesis and is harmful to MITO functions in SKM, so its exposure should be avoided or limited.


Sujet(s)
Phtalate de bis[2-éthylhexyle]/analogues et dérivés , Mitochondries/effets des médicaments et des substances chimiques , Muscles squelettiques/effets des médicaments et des substances chimiques , Myoblastes/effets des médicaments et des substances chimiques , Plastifiants/toxicité , Animaux , Différenciation cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire , Phtalate de bis[2-éthylhexyle]/métabolisme , Phtalate de bis[2-éthylhexyle]/toxicité , Humains , Potentiel de membrane mitochondriale/effets des médicaments et des substances chimiques , Souris , Mitochondries/anatomopathologie , Myopathies mitochondriales/induit chimiquement , Myopathies mitochondriales/anatomopathologie , Développement musculaire/effets des médicaments et des substances chimiques , Muscles squelettiques/cytologie , Muscles squelettiques/anatomopathologie , Myoblastes/cytologie , Myoblastes/anatomopathologie , Oxydoréduction/effets des médicaments et des substances chimiques , Phosphorylation oxydative/effets des médicaments et des substances chimiques , Plastifiants/métabolisme , Espèces réactives de l'oxygène/métabolisme , Tests de toxicité aigüe
8.
Environ Health ; 18(1): 107, 2019 12 09.
Article de Anglais | MEDLINE | ID: mdl-31818305

RÉSUMÉ

BACKGROUND: Although no human illness to date is confirmed to be attributed to engineered nanoparticles, occupational epidemiological studies are needed to verify the health effects of nanoparticles. This study used a repeated measures design to explore the potential adverse health effects of workers handling nanomaterials. METHODS: Study population was 206 nanomaterial-handling workers and 108 unexposed controls, who were recruited from 14 nanotechnology plants. They were followed up no less than two times in four years. A questionnaire was used to collect potential confounders and detailed work conditions. Control banding was adopted to categorize risk level for each participant as a surrogate marker of exposure. Health hazard markers include cardiopulmonary dysfunction markers, inflammation and oxidative damage markers, antioxidant enzymes activity, and genotoxicity markers. The Generalized Estimating Equation model was applied to analyze repeated measurements. RESULTS: In comparison to the controls, a significant dose-dependent increase on risk levels for the change of superoxide dismutase (p<0.01) and a significant increase of glutathione peroxidase change in risk level 1 was found for nanomaterial-handling workers. However, the change of cardiovascular dysfunction, lung damages, inflammation, oxidative damages, neurobehavioral and genotoxic markers were not found to be significantly associated with nanomaterials handling in this panel study. CONCLUSIONS: This repeated measurement study suggests that there was no evidence of potential adverse health effects under the existing workplace exposure levels among nanomaterials handling workers, except for the increase of antioxidant enzymes.


Sujet(s)
Marqueurs biologiques/analyse , Nanostructures/effets indésirables , Nanotechnologie , Exposition professionnelle/effets indésirables , Adulte , Antioxydants/métabolisme , Altération de l'ADN/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Femelle , Études de suivi , Humains , Inflammation/induit chimiquement , Inflammation/épidémiologie , Études longitudinales , Mâle , Adulte d'âge moyen , Stress oxydatif/effets des médicaments et des substances chimiques , Taïwan/épidémiologie
9.
Toxicol In Vitro ; 59: 246-254, 2019 Sep.
Article de Anglais | MEDLINE | ID: mdl-31009676

RÉSUMÉ

Previous studies revealed that cellular accumulation of mono(2-ethylhexyl)phthalate (MEHP) disturbed energy metabolism in adipocytes, where glucose uptake was significantly increased. The present study aimed to determine the mechanisms underlying the increased glucose uptake. MEHP-treated 3T3-L1 adipocytes exhibited a significantly increased glucose uptake activity. Immunoblot analysis suggested that the insulin-induced signals were not responsible for the increased glucose uptake. qPCR analysis revealed that both Glut1 and Glut4 genes were highly expressed during adipogenesis; Glut1 mRNA levels in MEHP-treated adipocytes were significantly increased. Moreover, MEHP-treated adipocytes exhibited significantly increased levels of fibroblast growth factor 21 (FGF21) in both mRNA and secreted protein. FGF21 is a peptide hormone with pleiotropic effects on regulation of insulin sensitivity and glucose/lipid homeostasis. We found that MEHP, FGF21, and lactate in culture medium together enhanced Fgf21 gene expression in MEHP-treated adipocytes. FGF21 signaling requires fibroblast growth factor receptor (FGFR) and ßKlotho. Fgfr family and ßKlotho genes were actively expressed during adipogenesis; mRNA levels of Fgfr3 and Fgfr4 genes in MEHP-treated adipocytes were significantly increased. Roles of FGF21/FGFR and phosphoinositide 3-kinase (PI3K)/AKT signal axes in regulation of glucose uptake were determined. We demonstrated that FGF21/FGFR signals played the major roles in up-regulation of the basal glucose uptake in MEHP-treated adipocytes. The in vitro evidence suggests that cellular FGF21 secretion enhances the basal glucose uptake in MEHP-treated adipocytes.


Sujet(s)
Cellules 3T3-L1/effets des médicaments et des substances chimiques , Adipocytes/effets des médicaments et des substances chimiques , Phtalate de bis[2-éthylhexyle]/analogues et dérivés , Facteurs de croissance fibroblastique/métabolisme , Glucose/métabolisme , Cellules 3T3-L1/métabolisme , Adipocytes/métabolisme , Animaux , Phtalate de bis[2-éthylhexyle]/pharmacologie , Insuline/métabolisme , Souris , Phosphatidylinositol 3-kinases/métabolisme , Protéines proto-oncogènes c-akt/métabolisme
10.
Chemosphere ; 203: 239-252, 2018 Jul.
Article de Anglais | MEDLINE | ID: mdl-29621680

RÉSUMÉ

In this study, the polychlorinated dibenzo-p-dioxin/furan (PCDD/F) levels in 381 soil samples coming from different background areas (n = 238) and contaminated areas (n = 143) in Taiwan were investigated from 2011 to 2015 using high resolution gas chromatograph/high resolution mass spectrometry (HRGC/HRMS). The contaminated areas showed higher PCDD/F contamination as compared to the background areas (1230 vs 749 pg/g dry weight (dw)); 14.0 vs 6.25 pg WHO2005-TEQ/g dw). The lowest levels were recorded in the outlying islands (1.28 pg WHO2005-TEQ/g dw). PCDD/F congener distribution profiles in the background and contaminated areas as well as on the islands varied. OCDD was the dominant congener in almost all locations, including the northern background (87.7%) and central contaminated (74.2%) areas. Other dominant species included OCDF and 1,2,3,4,6,7,8-HpCDD. Levels of PCDD/F-TEQs in Taiwanese soils, including the background areas, were higher than in some developing countries and regions with global background levels due to high industrialization except for the contaminated areas. Geographic differences in dioxin-contaminated soils were also shown in this study. Higher soil dioxin-TEQs were observed in locations with high populations and population densities. Despite the limitations, the economic status of Taiwan represented by the annual averaged family income (AAFI) was positively correlated to soil dioxin-TEQs.


Sujet(s)
Dibenzofuranes polychlorés/analyse , Dibenzodioxines polychlorées/analyse , Polluants du sol/analyse , Développement économique , Surveillance de l'environnement , Chromatographie gazeuse-spectrométrie de masse , Iles , Polychlorobiphényles/analyse , Sol/composition chimique , Polluants du sol/économie , Taïwan
11.
Environ Sci Technol ; 51(24): 14262-14272, 2017 Dec 19.
Article de Anglais | MEDLINE | ID: mdl-29192765

RÉSUMÉ

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed throughout the atmosphere as mixtures attached to ambient particulate matter (PM). PAHs usually elicit similar toxicological pathways but do so with varying levels of efficacy. In this study, we utilized high-throughput screening (HTS) in vitro data of PAHs to predict health risks associated with coarse and fine PM. PM samples with 22 PAH compounds obtained from residential areas close to industrial parks in central Taiwan were analyzed. On the basis of the PM-bound PAH concentrations and their activities reported in HTS assays, we developed a probabilistic model for estimating cumulative exposure of humans to PAHs. Activity-to-exposure ratio (AER) values were calculated to compare relative risks of activating the aryl hydrocarbon receptor (AhR), nuclear factor erythroid 2-related factor 2 (Nrf2), and tumor suppressor gene (p53) when children or adults were exposed to fine or coarse PM in different seasons. On the basis of AER values, the risk of fine PM exposure was relatively higher than the risk of exposure to coarse PM in pathway activation. Children as a susceptible population had a risk of the activating AhR pathway greater than that of adults. Particularly higher risks were observed in winter than in summer. Among three pathways, AhR was the most sensitive one activated by exposure to PAHs. In addition, the activation of the AhR, Nrf2, and p53 pathways was compared by in vitro reporter assays with and without the pre-extraction of PAHs from PM. Our proposed novel approach accounts for mixture toxicities in characterizing in vitro pathway-based risks via inhalation exposure to ambient PAHs.


Sujet(s)
Matière particulaire , Hydrocarbures aromatiques polycycliques , Appréciation des risques , Polluants atmosphériques , Humains , Saisons , Taïwan
12.
Sci Rep ; 7(1): 15320, 2017 11 10.
Article de Anglais | MEDLINE | ID: mdl-29127306

RÉSUMÉ

Nickel compounds have been classified as carcinogens and shown to be associated with induction of epithelial-mesenchymal transition (EMT) in fibrogenesis and tumorigenesis, as well as the crucial role of microRNAs (miRNAs) and their related genes in controlling EMT and cancer metastasis. Thus, the mechanisms involved in the regulation of EMT in nickel-treated cells are of potential interest in understanding lung fibrosis and tumor progression. We investigated the miRNA-dependent mechanisms involved in nickel-induced EMT in lung epithelial cells. Nickel increased miR-4417 expression and decreased its target gene TAB2 expression. Treatment of cells with TGF-ß inhibitor SB525334 significantly blocked NiCl2 and TGF-ß-induced EMT. The expression of miR-4417 was abolished by SB525334 in TGF-ß-treated cells, but not in nickel-treated cells. Both overexpression of miR-4417 and silencing of TAB2 induced fibronectin expression, but did not reduce E-cadherin expression. Moreover, oral administration of nickel promoted lung tumor growth in nude mice that had received BEAS-2B transformed cells by intravenous injection. The induction of EMT by nickel is mediated through multiple pathways. Induction of abundant miR-4417 and reduction of TAB2 expression following nickel exposure and may be involved in nickel-induced fibronectin. These findings provide novel insight into the roles of nickel in fibrogenesis and tumor progression.


Sujet(s)
Transformation cellulaire néoplasique/métabolisme , Cellules épithéliales/métabolisme , Tumeurs du poumon/métabolisme , Poumon/métabolisme , microARN/métabolisme , Nickel/toxicité , Fibrose pulmonaire/métabolisme , ARN tumoral/métabolisme , Muqueuse respiratoire/métabolisme , Lignée de cellules transformées , Transformation cellulaire néoplasique/induit chimiquement , Transformation cellulaire néoplasique/anatomopathologie , Cellules épithéliales/anatomopathologie , Humains , Poumon/anatomopathologie , Tumeurs du poumon/induit chimiquement , Tumeurs du poumon/anatomopathologie , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/anatomopathologie , Muqueuse respiratoire/anatomopathologie
13.
J Appl Toxicol ; 37(12): 1537-1546, 2017 Dec.
Article de Anglais | MEDLINE | ID: mdl-28849599

RÉSUMÉ

The study aimed to examine effects of environmental estrogens at body burden levels on energy metabolism in fat cells. Acclimation of T47D-KBluc cells in estrogen-deprived medium was established for high performance of estrogen-responsive luciferase reporter assay. With the assay, relative estrogenic potency of four selected estrogen receptor (ER) agonists, i.e. diethylstilbestrol, ß-estradiol, 4-nonylphenol and bisphenol A, were determined. Immunoblot analysis revealed that the ER agonists at both EC80 and EC100 caused rapid and transient phosphorylation of extracellular signal-regulated kinases (ERK) in an ER-dependent manner. 3T3-L1 adipocytes treated with the ER agonists at EC80 for 24 hours exhibited significant downregulation in mitochondrial respiration and glycolytic function. Importantly, EC80 values of 4-nonylphenol (6.0 × 10-10  m) and bisphenol A (1.0 × 10-8  m) are in the range of human body burdens. The finding that estrogenic chemicals at body burden levels cause significant impact on fat cell energy metabolism raises an important public health issue that deserves more attention.


Sujet(s)
Adipocytes/effets des médicaments et des substances chimiques , Adipogenèse/effets des médicaments et des substances chimiques , Métabolisme énergétique/effets des médicaments et des substances chimiques , Oestrogènes nonstéroïdiens/toxicité , Oestrogènes/toxicité , Récepteurs des oestrogènes/métabolisme , Cellules 3T3-L1 , Adipocytes/métabolisme , Animaux , Charge corporelle , Relation dose-effet des médicaments , Souris
14.
Cell Biol Toxicol ; 33(6): 511-526, 2017 12.
Article de Anglais | MEDLINE | ID: mdl-28083810

RÉSUMÉ

Cellular accumulation of mono(2-ethylhexyl)phthalate (MEHP) has been recently demonstrated to disturb fat cell energy metabolism; however, the underlying mechanism remained unclear. The study aimed to determine how MEHP influenced fat cell transcriptome and how the changes might contribute to bioenergetics. Because of the pivotal role of PPARγ in energy metabolism of fat cells, comparative microarray analysis of gene expression in 3T3-L1 adipocytes treated with both MEHP and rosiglitazone was performed. Pathway enrichment analysis and gene ontology (GO) enrichment analysis revealed that both treatments caused up-regulation of genes involved in PPAR signaling/energy metabolism-related pathways and down-regulation of genes related to adipokine/inflammation signals. MEHP/rosiglitazone-treated adipocytes exhibited increased levels of lipolysis, glucose uptake, and glycolysis; the gene expression profiles provided molecular basis for the functional changes. Moreover, MEHP was shown to induce nuclear translocation and activation of PPARγ. The similarity in gene expression and functional changes in response to MEHP and rosiglitazone suggested that MEHP influenced bioenergetics and adipokine network mainly via PPARγ. Importantly, adipokine levels in C57BL/6J mice with di(2-ethylhexyl)phthalate (DEHP) treatments provided in vivo evidence for microarray results. On the basis of correlation between gene expression and functional assays, possible involvements of genes in bioenergetics of MEHP-treated adipocytes were proposed.


Sujet(s)
Adipocytes/effets des médicaments et des substances chimiques , Adipokines/métabolisme , Phtalate de bis[2-éthylhexyle]/analogues et dérivés , Cellules 3T3-L1 , Adipocytes/métabolisme , Adipokines/génétique , Animaux , Phtalate de bis[2-éthylhexyle]/pharmacologie , Métabolisme énergétique/effets des médicaments et des substances chimiques , Acides gras/métabolisme , Expression des gènes/effets des médicaments et des substances chimiques , Analyse de profil d'expression de gènes/méthodes , Glucose/métabolisme , Mâle , Souris , Souris de lignée C57BL , Analyse sur microréseau , Récepteur PPAR gamma/génétique , Récepteur PPAR gamma/métabolisme , Rosiglitazone , Thiazolidinediones/pharmacologie
15.
Oncotarget ; 7(31): 49310-49321, 2016 Aug 02.
Article de Anglais | MEDLINE | ID: mdl-27384479

RÉSUMÉ

The development of resistance to platinum drugs in cancer cells severely reduces the efficacy of these drugs. Thus, the discovery of novel drugs or combined strategies to overcome drug resistance is imperative. In addition to our previous finding that combined D-penicillamine with platinum drugs exerts synergistic cytotoxicity, we recently identified a novel therapeutic strategy by combining an iron chelating agent desferal with platinum drugs to overcome platinum resistance in an oxaliplatin-resistant human cervical cancer cell line, S3. Further study demonstrated that the level of platinum-DNA adduct formation positively correlated with cell death in combination of desferal with platinums than that of each drug alone in S3 cells. Decrement of human copper transporter 1 (hCtr1) and transferrin receptor 1 (TfR1) expression involved in the development of platinum resistance in S3 cells. Moreover, desferal promoted the expression of hCtr1 through the upregulation of Sp1. The overexpression of Sp1 increased the expression of NF-κB and translocated it into the nucleus to bind to the TfR1 promoter region, which subsequently increased the expression of TfR1. Importantly, the cotreatment of oxaliplatin with desferal significantly potentiated the oxaliplatin-elicited antitumoral effect in the oxaliplatin-resistant xenograft animal model without any toxic effect observed. Taken together, these results demonstrated that the combination of desferal with oxaliplatin can overcome oxaliplatin resistance through the regulation of hCtr1 and TfR1, and may have beneficial effect for treatment of patient with oxaliplatin-refractory tumors.


Sujet(s)
Antigènes CD/métabolisme , Transporteurs de cations/métabolisme , Déferoxamine/administration et posologie , Composés organiques du platine/administration et posologie , Récepteurs à la transferrine/métabolisme , Facteur de transcription Sp1/métabolisme , Tumeurs du col de l'utérus/traitement médicamenteux , Transport nucléaire actif , Animaux , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Noyau de la cellule/métabolisme , Chélateurs/composition chimique , Transporteur-1 du cuivre , Adduits à l'ADN , Résistance aux médicaments antinéoplasiques , Femelle , Humains , Fer/composition chimique , Mâle , Souris , Souris nude , Transplantation tumorale , Oxaliplatine , Régions promotrices (génétique) , Régulation positive
16.
Environ Sci Pollut Res Int ; 23(9): 8518-28, 2016 May.
Article de Anglais | MEDLINE | ID: mdl-26791027

RÉSUMÉ

Estrogen-like endocrine disrupting compounds (EEDC) such as bisphenol A, nonylphenol, and phthalic acid esters are toxic compounds that may occur in both raw- and drinking water. The aim of this study was to combine chemical- and bioassay to evaluate the risk of EEDCs in the drinking water treatment plants (DWTPs). Fifty-six samples were collected from seven DWTPs located in northern-, central-, and southern Taiwan from 2011 to 2012 and subjected to chemical analyses and two bioassay methods for total estrogenic activity (E-Screen and T47D-KBluc assay). Among of the considered EEDCs, only dibutyl phthalate (DBP) and di (2-ethylhexyl) phthalate (DEHP) were detected in both drinking and raw water samples. DBP levels in drinking water ranged from

Sujet(s)
Eau de boisson/composition chimique , Exposition environnementale/statistiques et données numériques , Oestrogènes/analyse , Eaux usées/composition chimique , Polluants chimiques de l'eau/analyse , Purification de l'eau , Composés benzhydryliques/analyse , Dosage biologique , Phtalate de dibutyle/analyse , Perturbateurs endocriniens/analyse , Oestradiol/analyse , Femelle , Humains , Mâle , Phénols/analyse , Acides phtaliques/analyse , Taïwan
17.
Arch Toxicol ; 90(3): 589-601, 2016 Mar.
Article de Anglais | MEDLINE | ID: mdl-25543134

RÉSUMÉ

Phthalates are lipophilic and tend to accumulate in adipose tissue, an important regulator of energy balance and glucose homeostasis. The study aimed to determine whether cellular phthalate accumulation influenced fat cell energy metabolism. Following a 3-day treatment with adipogenesis-inducing medium and a 2-day treatment with adipogenesis-maintaining medium, 3T3-L1 cells differentiated into adipocytes in the presence of a phthalate at a clinically relevant concentration (30-300 µM) for another 6 days. Two phthalates, di(2-ethylhexyl)phthalate and di-n-butylphthalate, and their metabolites, mono(2-ethylhexyl)phthalate (MEHP) and mono-n-butylphthalate, were used here. The phthalate treatments caused no marked effect on cytotoxicity and adipogenesis. Only the MEHP-treated adipocytes were found having smaller lipid droplets; MEHP accumulated in cells in a dose- and time-dependent manner. The MEHP-treated adipocytes exhibited significant increases in lipolysis and glucose uptake; quantitative real-time polymerase chain reaction (qPCR) analysis revealed correlated changes in expression of marker genes involved in adipogenesis, lipid metabolism, and glucose uptake. Analysis of oxygen consumption rate (a mitochondrial respiration indicator) and extracellular acidification rate (a glycolysis indicator) indicated a higher energy metabolism in the adipocytes. qPCR analysis of critical genes involved in mitochondrial biogenesis and/or energy metabolism showed that expression of peroxisome proliferator-activated receptor γ coactivator-1α, sirtuin 3, and protein kinase A were significantly enhanced in the MEHP-treated adipocytes. In vitro evidence of MEHP impacts on lipolysis, glucose uptake/glycolysis, and mitochondrial respiration/biogenesis demonstrates that MEHP accumulation disturbs energy metabolism of fat cells.


Sujet(s)
Adipocytes/métabolisme , Phtalate de bis[2-éthylhexyle]/analogues et dérivés , Métabolisme énergétique/effets des médicaments et des substances chimiques , Cellules 3T3-L1/effets des médicaments et des substances chimiques , Cellules 3T3-L1/métabolisme , Adipocytes/effets des médicaments et des substances chimiques , Animaux , Phtalate de bis[2-éthylhexyle]/pharmacocinétique , Phtalate de bis[2-éthylhexyle]/toxicité , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Glucose/métabolisme , Gouttelettes lipidiques/effets des médicaments et des substances chimiques , Gouttelettes lipidiques/métabolisme , Lipolyse/effets des médicaments et des substances chimiques , Souris
18.
Biochem Pharmacol ; 95(1): 28-37, 2015 May 01.
Article de Anglais | MEDLINE | ID: mdl-25801007

RÉSUMÉ

The platinum-based regimen is the front-line treatment of chemotherapy. However, development of platinum resistance often causes therapeutic failure in this disease. We previously have generated an oxaliplatin-resistant subline, named S3, from human cervical carcinoma SiHa cells, and its resistant phenotype was well-characterized. In the present study, we aimed to identify the novel therapeutic strategy by combining copper chelator D-penicillamine with oxaliplatin, and to elucidate the underlying mechanisms for overcoming oxaliplatin resistance. As the result, D-penicillamine exerted synergistic killing effects only in S3 cells when combined with oxaliplatin and cisplatin by using Chou-Talalay method. Further study showed that the amounts of platinum DNA adduct formed were positively correlated to the percentage of cell death in S3 cells when co-treated D-penicillamine with oxaliplatin and cisplatin. D-penicillamine promoted copper influx transporter hCtr1 expression through upregulation of Sp1. Sp1 overexpression induced p53 translocation from nucleus to cytosol and caused p53 degradation through ubiquitination, which subsequently suppressed the expression of the copper efflux transporter ATP7A. Importantly, co-treatment of cisplatin with D-penicillamine enhanced oxaliplatin-elicited antitumor effect in the oxalipatin-resistant S3 xenograft tumors, but not found in SiHa xenograft model. Notably, Mice received D-penicillamine alone or in combination of D-penicillamine ad oxalipatin, increased hCtrl protein level in S3 xenograft tumor, however, the protein level of ATP7A was decreased. Taken together, this study provides insight into that the co-manipulation of hCtrl and ATP7A by D-penicillamine could increase the therapeutic efficacy of platinum drugs in oxaliplatin resistant tumors, especially in resistant phenotype with downexpression of hCtrl and overexpression of ATP7A.


Sujet(s)
Antinéoplasiques/administration et posologie , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Composés organiques du platine/administration et posologie , Pénicillamine/administration et posologie , Tumeurs du col de l'utérus/traitement médicamenteux , Animaux , Chélateurs/administration et posologie , Cisplatine/administration et posologie , Synergie des médicaments , Association de médicaments , Femelle , Humains , Mâle , Souris , Souris nude , Oxaliplatine , Tumeurs du col de l'utérus/anatomopathologie
19.
Int J Cancer ; 137(6): 1291-305, 2015 Sep 15.
Article de Anglais | MEDLINE | ID: mdl-25693518

RÉSUMÉ

Cisplatin (CDDP) is an important anti-cancer drug commonly used in various human cancers, including nasopharyngeal carcinoma (NPC). How to overcome the drug resistance of CDDP provides opportunities to improve clinical outcomes of NPC. O(6) -methylguanine-DNA methyltransferase (MGMT) has been well-characterized to be a therapeutic determinant of O(6) -alkylguanine alkylating drugs. However, the underlying mechanism and clinical relevance between MGMT and CDDP remain poorly defined in NPC. In this study, we showed that MGMT-proficient cells were highly resistant to the cytotoxic effects of CDDP as compared to MGMT-deficient cells. Further studies showed that the platinum level of DNA after CDDP exposure was significantly lower in MGMT-proficient cells than in MGMT-deficient cells. Host cell reactivation assay revealed that MGMT protected NPC cells from CDDP-induced DNA damage by enhancing DNA repair capacity. Importantly, we demonstrated for the first time that MGMT protein directly bound to CDDP-induced DNA damages. Subsequently, CDDP-bound MGMT protein became ubiquitinated and was degraded through ubiquitin-mediated proteasome system. We further analyzed the relationship between MGMT expression and clinical survivals in a cohort of 83 NPC patients. NPC patients who received CDDP-based concurrent chemoradiotherapy (CCRT), with high MGMT expression level, exhibited shorter progression-free survival (PFS; p = 0.022) and overall survival (OS; p = 0.015), than patients with low MGMT expression level. Furthermore, high MGMT expression level remained to be an independent prognostic factor for worse PFS (p = 0.01, hazard ratio 2.23) and OS (p = 0.018, hazard ratio 2.14). Our findings suggest that MGMT protein is important to determine the efficacy of CDDP in NPC.


Sujet(s)
Cisplatine/pharmacologie , Adduits à l'ADN/effets des médicaments et des substances chimiques , Réparation de l'ADN/effets des médicaments et des substances chimiques , Tumeurs du rhinopharynx/traitement médicamenteux , Tumeurs du rhinopharynx/génétique , O(6)-methylguanine-DNA methyltransferase/métabolisme , Composés organiques du platine/pharmacologie , Antinéoplasiques/pharmacologie , Carcinomes , Lignée cellulaire tumorale , Adduits à l'ADN/génétique , Réparation de l'ADN/génétique , Survie sans rechute , Humains , Cancer du nasopharynx , Tumeurs du rhinopharynx/métabolisme , Tumeurs du rhinopharynx/anatomopathologie , Pronostic
20.
Int J Environ Res Public Health ; 11(5): 4886-904, 2014 May 06.
Article de Anglais | MEDLINE | ID: mdl-24806195

RÉSUMÉ

Our goal was to determine dioxin levels in 800 soil samples collected from Taiwan. An in vitro DR-CALUX® assay was carried out with the help of an automated Soxhlet system and fast cleanup column. The mean dioxin level of 800 soil samples was 36.0 pg-bioanalytical equivalents (BEQs)/g dry weight (d.w.). Soil dioxin-BEQs were higher in northern Taiwan (61.8 pg-BEQ/g d.w.) than in central, southern, and eastern Taiwan (22.2, 24.9, and 7.80 pg-BEQ/g d.w., respectively). Analysis of multiple linear regression models identified four major predictors of dioxin-BEQs including soil sampling location (ß = 0.097, p < 0.001), land use (ß = 0.065, p < 0.001), soil brightness (ß = 0.170, p < 0.001), and soil moisture (ß = 0.051, p = 0.020), with adjusted R2 = 0.947 (p < 0.001) (n = 662). An univariate logistic regression analysis with the cut-off point of 33.4 pg-BEQ/g d.w. showed significant odds ratios (ORs) for soil sampling location (OR = 2.43, p < 0.001), land use (OR = 1.47, p < 0.001), and soil brightness (OR = 2.83, p = 0.009). In conclusion, four variables, including soil sampling location, land use, soil brightness, and soil moisture, may be related to soil-dioxin contamination. Soil samples collected in northern Taiwan, and especially in Bade City, soils near industrial areas, and soils with darker color may contain higher dioxin-BEQ levels.


Sujet(s)
Dioxines/analyse , Surveillance de l'environnement/méthodes , Assainissement et restauration de l'environnement , Polluants du sol/analyse , Sol/composition chimique , Dosage biologique , Chromatographie gazeuse-spectrométrie de masse , Analyse multifactorielle , Taïwan
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