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1.
Mol Immunol ; 171: 47-55, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38795684

RESUMO

Myopia is regarded as a worldwide epidemic ocular disease, has been proved related to inflammation. CD55, also known as decay-accelerating factor (DAF) can modulate the activation of complement through inhibiting the formation of complement 3 convertase and its dysregulation is involved in various inflammatory diseases. To investigate the association between CD55 and myopia, and to test whether CD55 can inhibit myopia development by suppressing inflammation in the eye, we use three different animal models including monocular form-deprivation myopia, myopia induced by TNF-α administration and allergic conjunctivitis animal model to reveal the CD55 in myopia development. The tears of thirty-eight participants with different spherical equivalents were collected and CD55 in the tears were also analyzed. Complement 3 and complement 5 levels increased while CD55 levels decreased in allergic conjunctivitis and myopic eyes. After anti-inflammatory drugs administration, CD55 expression was increased in monocular form-deprivation myopia model. We also found inflammatory cytokines TGF-ß, IL-6, TNF-α, and IL-1ß may enhance complement 3 and complement 5 activation while CD55 level was suppressed contrary. Moreover, lower CD55 levels were found in the tears of patients with myopia with decreased diopter values. Finally, CD55-Fc administration on the eyelids can inhibit the elongation of axial length and change of refractive error. CD55-Fc application also suppress myopia development subsequent to complement 3 and complement 5 reduction and can lower myopia-specific (MMP-2 and TGF-ß) cytokine expression in TNF-α induced myopia animal model. This suggests that CD55 can inhibit myopia development by suppression of complement activation and eventual down-regulation of inflammation.


Assuntos
Antígenos CD55 , Modelos Animais de Doenças , Inflamação , Miopia , Adolescente , Animais , Feminino , Humanos , Masculino , Adulto Jovem , Antígenos CD55/metabolismo , Ativação do Complemento/efeitos dos fármacos , Complemento C3/metabolismo , Conjuntivite Alérgica/imunologia , Conjuntivite Alérgica/metabolismo , Citocinas/metabolismo , Miopia/metabolismo , Lágrimas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Complemento C5/metabolismo
2.
Biomaterials ; 305: 122443, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38160627

RESUMO

The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.


Assuntos
Neoplasias Pulmonares , Humanos , Porosidade , Linfócitos T Citotóxicos , Imunoterapia , Antígenos de Neoplasias , Células Dendríticas , Catecóis
3.
iScience ; 24(8): 102888, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34401669

RESUMO

Lymphoma is a group of blood cancers that develop from the immune system, and one of the main risk factors is associated with exposure to environmental chemicals. Bisphenol A (BPA) is a common chemical used in the manufacture of materials in polycarbonate and epoxy plastic products and can interfere with the immune system. BPA is considered to possibly induce lymphoma development by affecting the immune system, but its potential mechanisms have not been well established. This study performed a gene-network analysis of microarray data sets in human lymphoma tissues as well as in human cells with BPA exposure to explore module genes and construct the potential pathway for lymphomagenesis in response to BPA. This study provided evidence that BPA exposure resulted in disrupted cell cycle and DNA damage by activating CTNNB1, the initiator of the aberrant constructed CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway, which may potentially lead to lymphomagenesis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33625709

RESUMO

Bisphenol A (BPA) is a plasticizer used in the manufacture of polycarbonate and epoxy resins. It was found that higher urinary BPA levels are more likely to be associated with coronary artery disease (CVD). In recent years, the increasing incidence of CVD among young people is observed, which may be related with inflammation rather than the traditional triple-H risk factors. BPA is an endocrine-disrupting chemical, and can induce oxidative stress and chronic inflammation since its estrogenic effect. Inflammatory responses could come from the stimulation of IκB kinases (IKKs) by estrogen receptors (ERs). Therefore, this study investigated the association of BPA exposure with the gene expression of pro-inflammatory response (ERs and IKKs), an inflammation biomarker of CVD (C-reactive protein, CRP), and physiologic index potency of CVD development symptoms in young adults. This study divided BPA exposure levels into high and low groups based on the median plasma BPA level (4.34 ng/mL), and found that the high BPA group obviously had higher BMI, blood pressure, plasma CRP levels, and gene expression of ERß and IKKß. BMI and gene expression of IKKß were also positively correlated with plasma CRP secretion. Furthermore, the study subjects with potential CVD development symptoms had the increased levels of BPA (OR 2.10, 95% CI 0.83-5.39), CRP (OR 2.61, 95% CI 1.03-10.6) and IKKß (OR 4.29, 95% CI 1.51-15.6). These results indicated that exposure to BPA is potentially associated with expression of pro-inflammatory genes related to CRP secretion, which may promote the risk of CVD development symptoms in young adults. This study highlighted the possible connection between BPA exposure and CVD development but the mechanism between them needs to be further explored.

5.
Nanomaterials (Basel) ; 10(7)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629933

RESUMO

Soluble amyloid-ß oligomers (oAß42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer's disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAß42 into magnetic plaques (mpAß42) and activation of microglia on cellular plaque clearance was developed. With oAß42 being effectively converted into mpAß42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the good preservation of neurite outgrowth through the diminished uptake of oAß42, neurons treated with oAß42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAß42. The phagocytic uptake of mpAß42 by microglia was enhanced significantly as compared to the counterpart of oAß42, and the M1 polarization of microglia often occurring after the uptake of oAß42 restricted to an appreciable extent. As a result, the inflammation induced by pro-inflammatory cytokines was greatly alleviated.

6.
In Vitro Cell Dev Biol Anim ; 54(8): 589-599, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30083841

RESUMO

Application of high-dosage UVB irradiation in phototherapeutic dermatological treatments present health concerns attributed to UV-exposure. In assessing UV-induced photobiological damage, we investigated dose-dependent effects of UVB irradiation on human keratinocyte cells (HaCaT). Our study implemented survival and apoptosis assays and revealed an unexpected dose response wherein higher UVB-dosage induced higher viability. Established inhibitors, such as AKT- (LY294002), PKC- (Gö6976, and Rottlerin), ERK- (PD98059), P38 MAPK- (SB203580), and JNK- (SP600125), were assessed to investigate UV-induced apoptotic pathways. Despite unobvious contributions of known signaling pathways in dose-response mediation, microarray analysis identified transcriptional expression of UVB-response genes related to the respiratory-chain. Observed correlation of ROS-production with UVB irradiation potentiated ROS as the underlying mechanism for observed dose responses. Inability of established pathways to explain such responses suggests the complex nature underlying UVB-phototherapy response.


Assuntos
Queratinócitos/efeitos da radiação , Raios Ultravioleta , Acetofenonas/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzopiranos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Transporte de Elétrons/efeitos da radiação , Flavonoides/farmacologia , Perfilação da Expressão Gênica , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/efeitos da radiação , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/efeitos da radiação
7.
Toxicol Sci ; 158(1): 151-163, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28460142

RESUMO

Silver nanoparticles (AgNPs) enter the central nervous system through the blood-brain barrier (BBB). AgNP exposure can increase amyloid beta (Aß) deposition in neuronal cells to potentially induce Alzheimer's disease (AD) progression. However, the mechanism through which AgNPs alter BBB permeability in endothelial cells and subsequently lead to AD progression remains unclear. This study investigated whether AgNPs disrupt the tight junction proteins of brain endothelial cells, and alter the proteomic metabolism of neuronal cells underlying AD progression in a triple cell coculture model constructed using mouse brain endothelial (bEnd.3) cells, mouse brain astrocytes (ALT), and mouse neuroblastoma neuro-2a (N2a) cells. The results showed that AgNPs accumulated in ALT and N2a cells because of the disruption of tight junction proteins, claudin-5 and ZO-1, in bEnd.3 cells. The proteomic profiling of N2a cells after AgNP exposure identified 298 differentially expressed proteins related to fatty acid metabolism. Particularly, AgNP-induced palmitic acid production was observed in N2a cells, which might promote Aß generation. Moreover, AgNP exposure increased the protein expression of amyloid precursor protein (APP) and Aß generation-related secretases, PSEN1, PSEN2, and ß-site APP cleaving enzyme for APP cleavage in ALT and N2a cells, stimulated Aß40 and Aß42 secretion in the culture medium, and attenuated the gene expression of Aß clearance-related receptors, P-gp and LRP-1, in bEnd.3 cells. Increased Aß might further aggregate on the neuronal cell surface to enhance the secretion of inflammatory cytokines, MCP-1 and IL-6, thus inducing apoptosis in N2a cells. This study suggested that AgNP exposure might cause Aß deposition and inflammation for subsequent neuronal cell apoptosis to potentially induce AD progression.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Ácidos Graxos/metabolismo , Nanopartículas Metálicas/toxicidade , Modelos Biológicos , Neurônios/metabolismo , Proteômica , Prata/química , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Técnicas de Cocultura , Citocinas/metabolismo , Azul Evans/metabolismo , Mediadores da Inflamação/metabolismo , Nanopartículas Metálicas/química , Camundongos , Neurônios/citologia , Proteínas de Junções Íntimas/metabolismo
8.
Toxicol In Vitro ; 41: 133-142, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28238728

RESUMO

Bisphenol A (BPA) are commonly used in the manufacture of polycarbonate plastics. Higher BPA exposure levels have been found in patients with endometrial hyperplasia that is one of risk factors of endometrial cancer (EC). Aberrant microRNAs (miRNAs) regulation has been observed in the development of cancer. Thus, this study investigated whether BPA exposure can disrupt miRNA regulation and its gene expression regarding to EC carcinogenic progress. Microarray experiments of miRNA and mRNA were performed in human endometrial cancer RL95-2 cells with treatment of low-to-moderate (10, 103 and 105nM) BPA to explore the aberrant genes corresponding to human EC progression. According to the analysis of KEGG pathway and Cytoscape gene network, this study identified that BPA exposure reduced miR-149 expression to down-regulate DNA repair gene ARF6 (ADP-ribosylation factor 6) and tumor protein p53 (TP53), and up-regulate CCNE2 (cyclin E2) potentially to interrupt cell cycle. BPA also increased miR-107 to suppress hedgehog signaling factors, suppressor of fused homolog (SUFU) and GLI family zinc finger 3 (GLI3) to activate hedgehog signaling for cell proliferation underlying carcinogenesis. Furthermore, the BPA-induced cell proliferation was attenuated by transfection with miR-149 mimic and miR-107 inhibitor. These findings provided an insight into potential epigenetic mechanism of BPA exposure on the risk of endometrial carcinogenesis.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Fenóis/toxicidade , Fator 6 de Ribosilação do ADP , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Humanos , RNA Mensageiro/genética
9.
Environ Toxicol ; 32(6): 1742-1753, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28181394

RESUMO

Silver nanoparticles (AgNPs) are commonly used nanomaterials in consumer products. Previous studies focused on its effects on neurons; however, little is known about their effects and uptake mechanisms on glial cells under normal or activated states. Here, ALT astrocyte-like, BV-2 microglia and differentiated N2a neuroblastoma cells were directly or indirectly exposed to 10 nm AgNPs using mono- and co-culture system. A lipopolysaccharide (LPS) was pretreated to activate glial cells before AgNP treatment for mimicking NP exposure under brain inflammation. From mono-culture, ALT took up the most AgNPs and had the lowest cell viability within three cells. Moreover, AgNPs induced H2 O2 and NO from ALT/activated ALT and BV-2, respectively. However, AgNPs did not induce cytokines release (IL-6, TNF-α, MCP-1). LPS-activated BV-2 took up more AgNPs than normal BV-2, while the induction of ROS and cytokines from activated cells were diminished. Ca2+ -regulated clathrin- and caveolae-independent endocytosis and phagocytosis were involved in the AgNP uptake in ALT, which caused more rapid NP translocation to lysosome than in macropinocytosis and clathrin-dependent endocytosis-involved BV-2. AgNPs directly caused apoptosis and necrosis in N2a cells, while by indirect NP exposure to bottom chamber ALT or BV-2 in Transwell, more apoptotic upper chamber N2a cells were observed. Cell viability of BV-2 also decreased in an ALT-BV-2 co-culturing study. The damaged cells correlated to NP-mediated H2 O2 release from ALT or NO from BV-2, which indicates that toxic response of AgNPs to neurons is not direct, but indirectly arises from AgNP-induced soluble factors from other glial cells.


Assuntos
Astrócitos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Lisossomos/metabolismo , Nanopartículas Metálicas/toxicidade , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Prata/toxicidade , Animais , Apoptose/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/imunologia , Microglia/metabolismo , Necrose , Neurônios/imunologia , Neurônios/metabolismo , Fagocitose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
10.
Front Pharmacol ; 8: 902, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29326587

RESUMO

Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

11.
Sci Total Environ ; 572: 734-741, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27515016

RESUMO

Elementary school classroom dust is an important source of exposure to polybrominated dibenzo-p-dioxins/furans and diphenyl ethers (PBDD/DF/DEs) for school-age children. Our goal is thus to investigate concentrations of PBDD/DF/DEs in elementary school classroom dust to further assess the impact on school-age children via ingestion. The dust from classrooms, including both normal (NR) and computer classrooms (CR), was collected from six urban and four rural schools. Fourteen PBDEs and twelve PBDD/Fs were measured using high-resolution gas-chromatography/high-resolution mass-spectrometry. The mean levels of Σ14PBDEs in NR and CR dust from the urban classrooms were 370 and 2510ng/g and those whose dust from the rural classrooms were 464 and 1780ng/g. The means of ΣPBDD/Fs were 0.0401ng-WHO2005-TEQ/g (concentration: 4.72ng/g) in urban NR dust, 0.0636ng-WHO2005-TEQ/g (7.51ng/g) in urban CR dust, 0.0281ng-WHO2005TEQ/g (3.60ng/g) in rural NR dust, and 0.0474ng-WHO2005TEQ/g (6.28ng/g) in rural CR dust. The PBDEs pattern in NR dust was quite different from that in CR dust, but the PBDD/Fs patterns in NR and CR dust were similar. A linearly significant correlation coefficient (n=20, r=0.862, p<0.001) was found between ΣPBDEs and ΣPBDD/Fs in NR and CR dust, indicating that the PBDEs and PBDD/Fs in the dust may be from the same sources in the elementary school classrooms. This study assessed the risks (daily intake and cancer and non-cancer risks) of PBDEs and PBDD/Fs for the children from the classroom dust, and the calculated risk values did not exceed the related thresholds. With regard to the exposure scenarios for school-age children in an indoor environment, the results suggest that they might ingest more dust PBDD/DF/DEs in their homes than in the schools. In conclusion, the exposure of Taiwanese elementary school children to PBDD/DF/DEs via indoor dust was with a safe range based on our findings.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Dibenzofuranos Policlorados/análise , Éteres Difenil Halogenados/análise , Dibenzodioxinas Policloradas/análise , Poluentes Atmosféricos/toxicidade , Computadores , Dibenzofuranos Policlorados/toxicidade , Poeira/análise , Exposição Ambiental/efeitos adversos , Éteres Difenil Halogenados/toxicidade , Humanos , Dibenzodioxinas Policloradas/toxicidade , Medição de Risco , Instituições Acadêmicas , Taiwan
12.
Chem Biol Interact ; 254: 34-44, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27216632

RESUMO

Although, titanium dioxide nanoparticles (TiO2NPs) are nanomaterials commonly used in consumer products, little is known about their hazardous effects, especially on central nervous systems. To examine this issue, ALT astrocyte-like, BV-2 microglia and differentiated N2a neuroblastoma cells were exposed to 6 nm of 100% anatase TiO2NPs. A lipopolysaccharide (LPS) was pre-treated to activate glial cells before NP treatment for mimicking NP exposure under brain injury. We found that ALT and BV-2 cells took up more NPs than N2a cells and caused lower cell viability. TiO2NPs induced IL-1ß in the three cell lines and IL-6 in N2a. LPS-activated BV-2 took up more TiO2NPs than normal BV-2 and released more intra/extracellular reactive oxygen species (ROS), IL-1ß, IL-6 and MCP-1 than did activated BV-2. Involvement of clathrin- and caveolae-dependent endocytosis in ALT and clathrin-dependent endocytosis and phagocytosis in BV-2 both had a slow NP translocation rate to lysosome, which may cause slow ROS production (after 24 h). Although TiO2NPs did not directly cause N2a viability loss, by indirect NP exposure to the bottom chamber of LPS-activated BV-2 in the Transwell system, they caused late apoptosis and loss of cell viability in the upper N2a chamber due to H2O2 and/or TNF-α release from BV-2. However, none of the adverse effects in N2a or BV-2 cells was observed when TiO2NPs were exposed to ALT-N2a or ALT-BV-2 co-culture. These results demonstrate that neuron damage can result from TiO2NP-mediated ROS and/or cytokines release from microglia, but not from astrocytes.


Assuntos
Apoptose/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Titânio/química , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Endocitose/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Lipopolissacarídeos/toxicidade , Lisossomos/metabolismo , Nanopartículas Metálicas/química , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Toxicol In Vitro ; 34: 289-299, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27131904

RESUMO

Silver nanoparticles (AgNPs) are commonly used in daily living products. AgNPs can induce inflammatory response in neuronal cells, and potentially develop neurological disorders. The gene networks in response to AgNPs-induced neurodegenerative progression have not been clarified in various brain neural cells. This study found that 3-5nm AgNPs were detectable to enter the nuclei of mouse neuronal cells after 24-h of exposure. The differentially expressed genes in mouse brain neural cells exposure to AgNPs were further identified using Phalanx Mouse OneArray® chip, and permitted to explore the gene network pathway regulating in neurodegenerative progression according to Cytoscape analysis. In focal adhesion pathway of ALT astrocytes, AgNPs induced the gene expression of RasGRF1 and reduced its downstream BCL2 gene for apoptosis. In cytosolic DNA sensing pathway of microglial BV2 cells, AgNPs reduced the gene expression of TREX1 and decreased IRF7 to release pro-inflammatory cytokines for inflammation and cellular activation. In MAPK pathway of neuronal N2a cells, AgNPs elevated GADD45α gene expression, and attenuated its downstream PTPRR gene to interfere with neuron growth and differentiation. Moreover, AgNPs induced beta amyloid deposition in N2a cells, and decreased PSEN1 and PSEN2, which may disrupt calcium homeostasis and presynaptic dysfunction for Alzheimer's disease development. These findings suggested that AgNPs exposure reveals the potency to induce the progression of neurodegenerative disorder.


Assuntos
Astrócitos/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Prata/toxicidade , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/citologia , Linhagem Celular , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Camundongos , Microglia/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/metabolismo , Presenilina-1/genética , Presenilina-2/genética
14.
Environ Sci Pollut Res Int ; 23(9): 8518-28, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26791027

RESUMO

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

Assuntos
Água Potável/química , Exposição Ambiental/estatística & dados numéricos , Estrogênios/análise , Águas Residuárias/química , Poluentes Químicos da Água/análise , Purificação da Água , Compostos Benzidrílicos/análise , Bioensaio , Dibutilftalato/análise , Disruptores Endócrinos/análise , Estradiol/análise , Feminino , Humanos , Masculino , Fenóis/análise , Ácidos Ftálicos/análise , Taiwan
15.
Bull Environ Contam Toxicol ; 96(2): 192-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26564202

RESUMO

Our goal was to develop a fast-screening method for measuring dioxin levels in soils. The adenovirus (Ad)-dioxin-responsive (DR) bioassay system (AdEasy-6XDRE-TATA-Luc) combined with a fast-cleanup system was examined under conventional conditions (i.e., with incubation at 37°C) and three alternative conditions [incubation at 37°C with addition of phorbol-12-myristate-13-acetate (PMA), incubation at 33°C, and incubation at 33°C with addition of PMA]. The best conditions for carrying out the Ad-DR bioassay was 33°C and no addition of PMA. The background level of soil dioxins determined by the chemical assay [6.49 ng I-TEQ/kg dry weight (dw)] was well correlated (Pearson's r = 0.873, p < 0.001) with that by the Ad-DR bioassay [expressed in ng bioanalytical equivalents (BEQ) 81.1 ng BEQ/kg dw] (n = 17). When surveyed in contaminated soil samples (n = 114) from industrial areas by the Ad-DR bioassay, dioxin levels were 117, 102, 98.5, and 112 ng BEQ/kg dw, respectively, in northern, central, southern, and eastern Taiwan.


Assuntos
Bioensaio/métodos , Dioxinas/análise , Monitoramento Ambiental/métodos , Poluentes do Solo/análise , Solo/química , Adenoviridae/genética , Animais , Dioxinas/química , Genes Reporter , Luciferases/química , Ratos , Poluentes do Solo/química , Taiwan
16.
PLoS One ; 9(11): e113424, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25409520

RESUMO

Following an increase in the use of electric appliances that can generate 50 or 60 Hz electromagnetic fields, concerns have intensified regarding the biological effects of extremely low-frequency electromagnetic fields (ELF-EMFs) on human health. Previous epidemiological studies have suggested the carcinogenic potential of environmental exposure to ELF-EMFs, specifically at 50 or 60 Hz. However, the biological mechanism facilitating the effects of ELF-EMFs remains unclear. Cellular studies have yielded inconsistent results regarding the biological effects of ELF-EMFs. The inconsistent results might have been due to diverse cell types. In our previous study, we indicated that 1.5 mT, 60 Hz ELF-EMFs will cause G1 arrest through the activation of the ATM-Chk2-p21 pathway in human keratinocyte HaCaT cells. The aim of the current study was to investigate whether ELF-EMFs cause similar effects in a distinct epidermal keratinocyte, primary normal human epidermal keratinocytes (NHEK), by using the same ELF-EMF exposure system and experimental design. We observed that ELF-EMFs exerted no effects on cell growth, cell proliferation, cell cycle distribution, and the activation of ATM signaling pathway in NHEK cells. We demonstrated that the 2 epidermal keratinocytes responded to ELF-EMFs differently. To further validate this finding, we simultaneously exposed the NHEK and HaCaT cells to ELF-EMFs in the same incubator for 168 h and observed the cell growths. The simultaneous exposure of the two cell types results showed that the NHEK and HaCaT cells exhibited distinct responses to ELF-EMFs. Thus, we confirmed that the biological effects of ELF-EMFs in epidermal keratinocytes are cell type specific. Our findings may partially explain the inconsistent results of previous studies when comparing results across various experimental models.


Assuntos
Campos Eletromagnéticos , Queratinócitos/efeitos da radiação , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proliferação de Células/efeitos da radiação , Células Cultivadas , Quinase do Ponto de Checagem 2/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Epidérmicas , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Humanos , Peróxido de Hidrogênio/toxicidade , Queratinócitos/citologia , Queratinócitos/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Raios Ultravioleta
17.
PLoS One ; 9(8): e104732, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25111195

RESUMO

In daily life, humans are exposed to the extremely low-frequency electromagnetic fields (ELF-EMFs) generated by electric appliances, and public concern is increasing regarding the biological effects of such exposure. Numerous studies have yielded inconsistent results regarding the biological effects of ELF-EMF exposure. Here we show that ELF-EMFs activate the ATM-Chk2-p21 pathway in HaCaT cells, inhibiting cell proliferation. To present well-founded results, we comprehensively evaluated the biological effects of ELF-EMFs at the transcriptional, protein, and cellular levels. Human HaCaT cells from an immortalized epidermal keratinocyte cell line were exposed to a 1.5 mT, 60 Hz ELF-EMF for 144 h. The ELF-EMF could cause G1 arrest and decrease colony formation. Protein expression experiments revealed that ELF-EMFs induced the activation of the ATM/Chk2 signaling cascades. In addition, the p21 protein, a regulator of cell cycle progression at G1 and G2/M, exhibited a higher level of expression in exposed HaCaT cells compared with the expression of sham-exposed cells. The ELF-EMF-induced G1 arrest was diminished when the CHK2 gene expression (which encodes checkpoint kinase 2; Chk2) was suppressed by specific small interfering RNA (siRNA). These findings indicate that ELF-EMFs activate the ATM-Chk2-p21 pathway in HaCaT cells, resulting in cell cycle arrest at the G1 phase. Based on the precise control of the ELF-EMF exposure and rigorous sham-exposure experiments, all transcriptional, protein, and cellular level experiments consistently supported the conclusion. This is the first study to confirm that a specific pathway is triggered by ELF-EMF exposure.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Campos Eletromagnéticos/efeitos adversos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Linhagem Celular , Proliferação de Células/efeitos da radiação , Humanos , Transcriptoma/efeitos da radiação
18.
BMC Genomics ; 15: 300, 2014 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-24758163

RESUMO

BACKGROUND: Endometrial cancers (ECs) are the most common form of gynecologic malignancy. Recent studies have reported that ECs reveal distinct markers for molecular pathogenesis, which in turn is linked to the various histological types of ECs. To understand further the molecular events contributing to ECs and endometrial tumorigenesis in general, a more precise identification of cancer-associated molecules and signaling networks would be useful for the detection and monitoring of malignancy, improving clinical cancer therapy, and personalization of treatments. RESULTS: ECs-specific gene co-expression networks were constructed by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Important pathways and putative cancer hub genes contribution to tumorigenesis of ECs were identified. An elastic-net regularized classification model was built using the cancer hub gene signatures to predict the phenotypic characteristics of ECs. The 19 cancer hub gene signatures had high predictive power to distinguish among three key principal features of ECs: grade, type, and stage. Intriguingly, these hub gene networks seem to contribute to ECs progression and malignancy via cell-cycle regulation, antigen processing and the citric acid (TCA) cycle. CONCLUSIONS: The results of this study provide a powerful biomarker discovery platform to better understand the progression of ECs and to uncover potential therapeutic targets in the treatment of ECs. This information might lead to improved monitoring of ECs and resulting improvement of treatment of ECs, the 4th most common of cancer in women.


Assuntos
Neoplasias do Endométrio/genética , Redes Reguladoras de Genes , Ciclo do Ácido Cítrico , Feminino , Humanos
19.
Int J Environ Res Public Health ; 11(1): 337-54, 2013 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-24368426

RESUMO

The composting procedure in food waste plants generates airborne bioaerosols that have the potential to damage human airway epithelial cells. Persistent inflammation and repair responses induce airway remodeling and damage to the respiratory system. This study elucidated the expression changes of airway remodeling genes in human lung mucoepidermoid NCI-H292 cells exposed to bioaerosols from a composting plant. Different types of microorganisms were detectable in the composting plant, using the agar culture method. Real-time polymerase chain reaction was used to quantify the level of Aspergillus fumigatus and the profile of remodeling genes. The real-time PCR results indicated that the amount of A. fumigatus in the composting hall was less than 10(2) conidia. The endotoxins in the field bioaerosols were determined using a limulus amebocyte lysate test. The endotoxin levels depended on the type of particulate matter (PM), with coarse particles (2.5-10 µm) having higher endotoxin levels than did fine particles (0.5-2.5 µm). After exposure to the conditioned medium of field bioaerosol samples, NCI-H292 cells showed increased pro-inflammatory interleukin (IL)-6 release and activated epidermal growth factor receptor (EGFR), transforming growth factor (TGF)-ß1 and cyclin-dependent kinase inhibitor 1 (p21 WAF1/CIP1) gene expression, but not of matrix metallopeptidase (MMP)-9. Airborne endotoxin levels were higher inside the composting hall than they were in other areas, and they were associated with PM. This suggested that airborne bioaerosols in the composting plant contained endotoxins and microorganisms besides A. fumigatus that cause the inflammatory cytokine secretion and augment the expression of remodeling genes in NCI-H292 cells. It is thus necessary to monitor potentially hazardous materials from bioaerosols in food composting plants, which could affect the health of workers.


Assuntos
Microbiologia do Ar , Remodelação das Vias Aéreas , Endotoxinas/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Resíduos de Alimentos , Aerossóis/efeitos adversos , Remodelação das Vias Aéreas/genética , Aspergillus fumigatus/isolamento & purificação , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Endotoxinas/análise , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Interleucina-6/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Material Particulado/efeitos adversos , Material Particulado/análise , Reciclagem , Mucosa Respiratória/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
20.
PLoS One ; 7(5): e37935, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22655084

RESUMO

BACKGROUND: Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvß3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvß3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)](2)) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. PRINCIPAL FINDINGS: Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvß3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK)](2) peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvß3 was correlated with the enhanced apoptosis in U87MG cells. CONCLUSIONS: This study provides a novel concept of targeting integrin-αvß3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioblastoma/tratamento farmacológico , Paclitaxel/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Humanos , Integrina alfaVbeta3/metabolismo , Paclitaxel/administração & dosagem , Peptídeos Cíclicos/administração & dosagem
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