RESUMO
Pneumoconiosis is one of the most serious occupational diseases worldwide. Silicosis due to prolonged inhalation of free silica dust during occupational activities is one of the main types. Cuproptosis is a newly discovered mode of programmed cell death characterized by the accumulation of free copper in the cell, which ultimately leads to cell death. Increased copper in the serum of silicosis patients, suggests that the development of silicosis is accompanied by changes in copper metabolism, but whether cuproptosis is involved in the progression of silicosis is actually to be determined. To test this hypothesis, we screened the genetic changes in patients with idiopathic fibrosis by bioinformatics methods and predicted and functionally annotated the cuproptosis-related genes among them. Subsequently, we established a mouse silicosis model and detected the concentration of copper ions and the activity of ceruloplasmin (CP) in serum, as well as changes of the concentration of copper and cuproptosis related genes in mouse lung tissues. We identified 9 cuproptosis-related genes among the differential genes in patients with IPF at different times and the tissue-specific expression levels of ferredoxin 1 (FDX1) and Lipoyl synthase (LIAS) proteins. Furthermore, serum CP activity and copper ion levels in silicosis mice were elevated on days 7th and 56th after silica exposure. The expression of CP in mouse lung tissue elevated at all stages after silica exposure. The mRNA level of FDX1 decreased on days 7th and 56th, and the protein level remained in accordance with the mRNA level on day 56th. LIAS and Dihydrolipoamide dehydrogenase (DLD) levels were downregulated at all times after silica exposure. In addition, Heatshockprotein70 (HSP70) expression was increased on day 56. In brief, our results demonstrate that there may be cellular cuproptosis during the development of experimental silicosis in mice and show synchronization with enhanced copper loading in mice.
Assuntos
Cobre , Silicose , Humanos , Animais , Camundongos , Cobre/toxicidade , Silicose/genética , Apoptose , Biologia Computacional , Modelos Animais de Doenças , RNA Mensageiro , Dióxido de Silício/toxicidadeRESUMO
Silicosis caused by long-term inhalation of crystalline silica during occupational activities seriously threatens the health of occupational populations. Imbalances in T helper 1(Th1), Th2, Th17, and regulatory T cells (Tregs) promote the development of pulmonary silicosis. Exosomes and their contents, especially microRNAs (miRNAs), represent a new type of intercellular signal transmission mediator related to various diseases including pulmonary fibrosis. However, whether exosomal miRNAs can affect the progression of silicosis by regulating T cell differentiation remains to be determined. To test this hypothesis, we established a miR-125a-5p antagomir mouse model and examined changes in miR-125a-5p levels and T cell subtypes. We found that miR-125a-5p levels were increased in lung tissues and serum exosomes in the silica group at 7 days and 28 days. Downregulation of miR-125a-5p attenuated α-smooth muscle actin (α-SMA), collagen I, fibronectin, p-p65, and p-inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK) protein expression, while tumor necrosis factor receptor-associated factor 6 (TRAF6) and p-inhibitor of κBα (IKBα) expression were increased. MiR-125a-5p anta-miR treatment contributes to the maintenance of Th1/Th2 balance during the progression of pulmonary fibrosis. Our findings indicated that knockdown miR-125a-5p could regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6.
Assuntos
Exossomos , MicroRNAs , Fibrose Pulmonar , Dióxido de Silício , Silicose , Animais , Camundongos , Proliferação de Células , MicroRNAs/genética , MicroRNAs/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Dióxido de Silício/toxicidade , Silicose/genética , Silicose/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Exossomos/genética , Exossomos/metabolismoRESUMO
Epithelial-mesenchymal transdifferentiation of alveolar type â ¡ epithelial cells is a vital source of pulmonary myofibroblasts, and myofibroblasts formation is recognized as an important phase in the pathological process of silicosis. miR-30c-5p has been determined to be relevant in the activation of the epithelial-mesenchymal transition (EMT) in numerous disease processes. However, elucidating the role played by miR-30c-5p in the silicosis-associated EMT process remains a great challenge. In this work, based on the establishment of mouse silicosis and A549 cells EMT models, miR-30c-5p was interfered with in vivo and in vitro models to reveal its effects on EMT and autophagy. Moreover, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), connective tissue growth factor (CTGF), autophagy-related gene 5 (ATG5), and autophagy were further interfered with in the A549 cells models to uncover the possible molecular mechanism through which miR-30c-5p inhibits silicosis associated EMT. The results demonstrated the targeted binding of miR-30c-5p to CTGF, ATG5, and MALAT1, and showed that miR-30c-5p could prevent EMT in lung epithelial cells by acting on CTGF and ATG5-associated autophagy, thereby inhibiting the silicosis fibrosis process. Furthermore, we also found that lncRNA MALAT1 might competitively absorb miR-30c-5p and affect the EMT of lung epithelial cells. In a word, interfering with miR-30c-5p and its related molecules (MALAT1, CTGF, and ATG5-associated autophagy) may provide a reference point for the application of silicosis intervention-related targets.
Assuntos
Células Epiteliais Alveolares , Proteína 5 Relacionada à Autofagia , Fator de Crescimento do Tecido Conjuntivo , Transição Epitelial-Mesenquimal , MicroRNAs , RNA Longo não Codificante , Silicose , Animais , Camundongos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Proteína 5 Relacionada à Autofagia/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Dióxido de Silício/toxicidade , Silicose/genética , Silicose/metabolismoRESUMO
Until now, the specific pathogenesis of silicosis is not clear. Exosomal miRNAs, as a newly discovered intercellular communication medium, play an important role in many diseases. Our previous research found that serum exosomal miR125a-5p was increased in silicosis patients by miRNAs high-throughput sequencing. TRAF6, is a target gene of miR125a-5p, which is involved in T-cell differentiation. Furthermore, results from animal study indicate that knockdown of miR-125a-5p can regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6. However, the level of serum exosomal miR125a-5p in silicosis patients has not been reported, the role of macrophages-secreted exosomal miR-125a-5p in regulating T cell differentiation to promote fibroblast transdifferentiation (FMT) remains unknown. In this study, the levels of serum exosomal miR125a-5p and serum TGF-ß1, IL-17A, IL-4 cytokines in silicosis patients were elevated, with the progression of silicosis, the level of serum exosomal miR125a-5p and serum IL-4 were increased; thus, the serum level of IFN-γ was negatively correlated with the progression of silicosis. In vitro, the levels of miR125a-5p in macrophages, exosomes, and T cells stimulated by silica were significantly increased. When the mimic was transfected into T cells, which directly suppressed TRAF6 and caused the imbalance of T cells differentiation, induced FMT. To sum up, these results indicate that exosomal miR-125a-5p may by targeting TRAF6 of T cells, induces the activation and apoptosis of T cells and the remodeling of Th1/Th2 and Th17/Tregs distribution, ultimately promotes FMT. Suggesting that exosomal miR-125a-5p may be a potential therapeutic target for silicosis.
Assuntos
MicroRNAs , Silicose , Animais , Humanos , Linfócitos T Reguladores , Dióxido de Silício/toxicidade , Transdiferenciação Celular , Interleucina-4 , Fator 6 Associado a Receptor de TNF , Células Th17 , Silicose/genética , MicroRNAs/genética , FibroblastosRESUMO
Using Born-Oppenheimer ab initio molecular dynamics (BOAIMD) simulations, the high-density water (HDW) and low-density water (LDW) structures based on SCAN meta-GGA are compared with those based on PBE GGA. Compared with Car-Parrinello ab initio molecular dynamics (CPAIMD) simulations, BOAIMD simulations can produce more accurate results because no fictitious electron mass is introduced. At each state point, our simulations continue for 100 ps after the system reached equilibrium, which is the longest ab initio simulations of liquid water reported so far and can ensure an accurate statistical average. The influence of the size effect and nuclear quantum effect on structure is not considered in the present work, but only that of two different functionals on the structure is discussed. It is found that, in HDW, just as shown using CPAIMD simulations, the SCAN-based hydrogen-bonds (HBs) are more flexible than the PBE-based ones, which makes the structure based on SCAN obviously closer to the experimental results than that based on PBE. However, it is not the case in LDW, and the difference between the results based on these two functionals is very small.
RESUMO
Based on the newly developed SCAN meta-GGA and the widely used PBE-GGA functionals, ab initio molecular dynamics are performed on water. It is proved that, although the SCAN meta-GGA is not as good as the TIP4P/2005 model potential in describing the equation of state of water, it is much better than the PBE-GGA, the ST2 model potential, and ab initio trained neural network potentials. Moreover, the SCAN meta-GGA predicts a first-order liquid-liquid transition from high- to low-density water at negative pressure, in which the structures are qualitatively consistent with experimental observations, and the spinodal point of high-density water is very close to Speedy's stability limit line.
RESUMO
Silicosis is a fatal fibrotic lung disease caused by long-term silica particle exposure, in which pulmonary macrophages play an important role. However, the relationship between macrophage polarization and silicosis remains unclear. We established an experimental silicosis mouse model to investigate macrophage polarization during silicosis development. C57BL/c mice were exposed to silica by intra-tracheal instillation and sacrificed at different time points. Lung tissues and bronchoalveolar lavage fluid were collected for flow cytometry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assays, western blotting, and histology examinations. The polarization of pulmonary macrophages was dysregulated during silicosis development. In the early stage of silicosis, M1 macrophages were induced and played a leading role in eliciting inflammatory; in the late stage, M2 macrophages were induced to promote tissue repair. Levels of several cytokines in lung tissue microenvironment changed with macrophage polarization. Inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-1ß and IL-6 were upregulated in the inflammation stage, while the anti-inflammatory cytokine IL-10 was upregulated in the fibrosis stage. Furthermore, we found that STAT (signal transducer and activator of transcription) and IRF (interferon regulatory factor) signaling pathway were involved in the regulation of macrophage polarization in silicosis. In summary, macrophage polarization is closely related to the occurrence and development of silicosis and may be a key point for further elucidating silicosis pathogenesis.
Assuntos
Macrófagos Alveolares/efeitos dos fármacos , Silicose/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Fatores Reguladores de Interferon/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/metabolismo , Fatores de Transcrição STAT/metabolismo , Dióxido de Silício , Silicose/metabolismo , Silicose/patologiaRESUMO
Telomere length was found to be associated with omethoate exposure and polymorphisms in certain genes among occupational workers. However, whether the polymorphisms in telomere-binding protein genes influence telomere length remains unclear. To explore the correlation between telomere length and polymorphisms in telomere-binding protein genes, telomere length in peripheral blood leukocytes was determined by real-time quantitative polymerase chain reaction in 180 omethoate-exposed workers and 115 healthy controls. Polymorphisms in 10 pairs of alleles were detected using flight mass spectrometry or polymerase chain reaction-restriction fragment length polymorphism technique. The results showed that individuals with GG genotype in TRF1 rs3863242 had longer telomere lengths than those with AG + AA genotype in the control group (p = 0.005). The multiple regression analysis suggested that both omethoate exposure (b = 0.526, p < 0.001) and TRF1 rs3863242 GG (b = 0.220, p = 0.002) were related to a longer telomere length. In conclusion, GG genotype in TRF1 rs3863242 is linked to prolongation of telomere length, and individuals with GG genotype are recommended to strengthen health protection in a Chinese occupational omethoate-exposed population.
Assuntos
Dimetoato/análogos & derivados , Exposição Ocupacional , Polimorfismo de Nucleotídeo Único , Telômero/efeitos dos fármacos , Proteína 1 de Ligação a Repetições Teloméricas/genética , Adulto , Povo Asiático , Estudos de Casos e Controles , Dimetoato/toxicidade , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Proteína 2 de Ligação a Repetições Teloméricas/genéticaRESUMO
Omethoate, an organophosphorous pesticide, causes a variety of health effects, especially the damage of chromosome DNA. The aim of the study was to assess the correlation between polymorphisms of encoding miRNA genes and telomere length in omethoate-exposure workers. 180 workers with more than 8 years omethoate-exposure and 115 healthy controls were recruited in the study. Genotyping for the selected single nucleotide polymorphisms loci were performed using the flight mass spectrometry. Real-time fluorescent quantitative polymerase chain reaction(PCR) method was applied to determine the relative telomere length(RTL) in human peripheral blood leukocytes DNA. After adjusting the covariate of affecting RTL, covariance analysis showed that the female was significantly longer than that of the male in control group(Pâ¯<â¯0.046). For the miR-145 rs353291 locus, this study showed that RTL of mutation homozygous AG+GG individuals was longer than that of wild homozygous AA in the exposure group (Pâ¯=â¯0.039). In the control group, RTL with wild homozygous TT genotype in miR-30a rs2222722 polymorphism locus was longer than that of the mutation homozygous CC genotype (Pâ¯=â¯0.038). After multiple linear regression analysis, the independent variables of entering into the model were omethoate-exposure (b = 0.562, Pâ¯<â¯0.001), miR-145 rs353291 (AG+GG) (b = 0.205, Pâ¯=â¯0.010). The prolongation of relative telomere length in omethoate exposed workers was associated with AG+GG genotypes in rs353291 polymorphism of encoding miR-145 gene.
Assuntos
Dimetoato/análogos & derivados , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero/efeitos dos fármacos , Telômero/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , DNA/genética , Dano ao DNA/efeitos dos fármacos , Dimetoato/toxicidade , Feminino , Loci Gênicos , Genótipo , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Omethoate is an organophosphorus pesticide that poses a major health hazard, especially DNA damage. The purpose of this study was to investigate the factors affecting telomere length in workers exposed to omethoate by analyzing the interaction between cell cycle gene polymorphism and environmental factors. The exposure group consisted of 118 workers exposed to omethoate for 8-10 years, the control group comprised 115 healthy people without occupational toxicant exposure history. The telomere length of genomic DNA from peripheral blood leucocyte was determined with real-time PCR. Polymerase chain reaction and restriction fragment length polymorphism was used to detect the polymorphisms in p53, p21 and MDM2 gene. The telomere length in the (CA + AA) genotypes for p21 rs1801270 polymorphism was longer than that in the CC genotype in control group (P = 0.015). The generalized linear model analysis indicated the interaction of the p21 rs1801270 polymorphic (CA + AA) genotypes and smoking has a significant effect on telomere length (ß = -0.258, P = 0.085). The prolongation of telomere length in omethoate-exposed workers was associated with genotypes (CA + AA) of p21 rs1801270, and interactions of (CA + AA) genotypes and smoking factor.
Assuntos
Dimetoato/análogos & derivados , Exposição Ocupacional/efeitos adversos , Praguicidas/toxicidade , Fumar/efeitos adversos , Telômero/metabolismo , Adulto , Dano ao DNA/efeitos dos fármacos , Dimetoato/toxicidade , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/genética , Telômero/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
It has been well documented that changes in ion fluxes across cellular membranes is fundamental in maintaining cellular homeostasis. Dysregulation and/or malfunction of ion channels are critical events in the pathogenesis of diverse diseases, including cancers. In this study, we focused on the study of K+ channels in hepatocellular carcinoma (HCC). By data mining TCGA cohort, the expression of 27 K+ channels was investigated and KCNJ11 was identified as a key dysregulated K+ channels in HCC. KCNJ11 was differentially expressed in HCC and predicted a poor prognosis in HCC patients. Inhibition of NFκB signaling suppressed KCNJ11 expression in HCC cells. Knockdown of KCNJ11 expression inhibited cell proliferation, promoted cell apoptosis, and reduced cell invasive capacity. Mechanistically, we found that KCNJ11 promotes tumor progression through interaction with LDHA and enhancing its enzymatic activity. Pharmacological inhibition of LDHA largely compromised the oncogenic function of KCNJ11 in cell proliferation, cell apoptosis, and cell invasion. Collectively, our data, as a proof of principle, demonstrate that KCNJ11 acts as an oncogene in HCC though forming a complex with LDHA and suggest that targeting KCNJ11 can be developed as a candidate tool to dampen HCC.
Assuntos
Carcinoma Hepatocelular/patologia , L-Lactato Desidrogenase/metabolismo , Neoplasias Hepáticas/patologia , Fígado/patologia , NF-kappa B/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Mapas de Interação de Proteínas , Apoptose , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Isoenzimas/metabolismo , Lactato Desidrogenase 5 , Fígado/metabolismo , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , PrognósticoRESUMO
Omethoate, an organophosphorous pesticide, can cause a variety of health effects, especially the decrease of cholinesterase activity. The aim of this study is to explore the association of genetic polymorphisms of telomere binding proteins with cholinesterase activity in omethoate-exposed population. Cholinesterase activities in whole blood, red blood cell and plasma were detected using acetylthiocholine and dithio-bis-(nitrobenzoic acid) method; Genetic Genotyping of POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242 and TERT rs2736098 were performed with PCR-RFLP. The cholinesterase activities of whole blood, red blood cells and plasma in exposure group are significantly lower than that of the control group (Pâ¯<â¯0.001). Multivariate analysis indicates that exposure group (bâ¯=â¯-â¯1.016, Pâ¯<â¯0.001), agender (bâ¯=â¯0.365, Pâ¯<â¯0.001), drinking (bâ¯=â¯0.271, Pâ¯=â¯0.004) and TERF1rs3863242 (bâ¯=â¯-â¯0.368, Pâ¯=â¯0.016) had an impact on cholinesterase activities. The results suggest that individual carrying AG+GG genotypes in TERF1 gene rs3863242 polymorphism were susceptible to damage in cholinesterase induced by omethoate.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Colinesterases/sangue , Dimetoato/análogos & derivados , Exposição Ocupacional/análise , Polimorfismo Genético , Proteínas de Ligação a Telômeros/genética , Adulto , China , Dimetoato/toxicidade , Eritrócitos/enzimologia , Genótipo , Humanos , Exposição Ocupacional/efeitos adversos , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Adulto JovemRESUMO
BACKGROUND: Cytochrome P4501A1 (CYP1A1) is a member of the cytochrome P450 gene family and plays an important role in the metabolism of exogenous and endogenous material. In recent research, it has been shown that its genetic polymorphisms are associated with many diseases. But the isoschizomers such as the BsrDI enzyme required for the detection of this polymorphism are expensive. METHODS: The study used an improved PCR-RFLP method with mismatched base for detection of the single-nucleotide polymorphism rs1048943. A new restriction enzyme cutting site was created by created restriction site PCR (CRS-PCR), and the restriction enzyme StyI for RFLP was cheaper than other enzymes. A total of 320 samples from Han Chinese were tested to evaluate this novel method. The PCR results were confirmed by DNA sequencing. RESULTS: After detecting 320 Chinese Han individuals, the genotype frequencies were 63.74% for AA, 31.54% for AG, and 4.72% for GG. The allelic frequencies were 75.48% for A and 24.52% for G. The x2 test showed the genotype and allele frequencies of CYP1A1 do not deviate from Hardy-Weinberg equilibrium, and the sequences of amplified products were consistent with the one published in GenBank with the exception of mismatched base. CONCLUSIONS: Based on PCR with mismatched primers we designed, the CYP1A1 polymorphism could be identified effectively with low cost.
Assuntos
Citocromo P-450 CYP1A1/genética , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único/genética , Povo Asiático/genética , China , DNA/análise , DNA/genética , Frequência do Gene/genética , Humanos , Fenótipo , Polimorfismo de Fragmento de RestriçãoRESUMO
Dendritic cells (DCs) are powerful antigen presentation cells and the initiator of adaptive immune response. Cimetidine, a widely used drug for gastric ulcers treatment, has significant immunomodulatory ability. However, the effects of cimetidine on DC-mediated T cell activation need to be further explored. In this study, we constructed the in vitro and in vivo model of cimetidine exposure, and our data showed that cimetidine stimulated the maturity of immature DCs, and further enhanced its T cell priming capacity. In vivo, the number of rat splenic CD103+ DC were not altered after cimetidine exposure, but the expression of surface markers CD54, CD11c, and MHC-II of which were up-regulated. Importantly, cimetidine interfered with DC-mediated T cell polarization, which was reflected in the up-regulation of Th1 and Th17 cells and the down-regulation of Th2 and Treg cells in vitro and in vivo. These results indicate that cimetidine can induce DC activation and promote DC mediated pro-inflammatory T cell response while weaken immunosuppressive T cell response.
Assuntos
Cimetidina , Células Th17 , Animais , Diferenciação Celular , Cimetidina/metabolismo , Cimetidina/farmacologia , Células Dendríticas/metabolismo , Ativação Linfocitária , RatosRESUMO
BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) exposure had been reported to be a risk factor of mtDNAcn in our early study. However, the effect of metabolic enzymes' genetic polymorphisms on mtDNAcn in PAHs-Exposure workers has not been fully evaluated. AIM: The aim of the study was to explore the effect of metabolic enzymes' genetic polymorphisms on mtDNAcn in PAHs-Exposure. METHODS AND RESULTS: We investigated the effects of metabolic enzymes' genetic polymorphisms on mtDNAcn among 544 coke oven workers and 238 office staffs. The mtDNAcn of peripheral blood leukocytes was measured using the Real-time quantitative polymerase chain reaction (PCR) method. PCR and restriction fragment length was used to detect five polymorphisms in GSTT1, GSTM1, GSTP1 rs1695, CYP2E1 rs6413432, and CYP2E1 rs3813867. The mtDNAcn in peripheral blood leukocytes was significantly lower in the exposure group than that in the control group (p < .001). The 1-OHPYR had an increasing trend with the genotypes AAâAG â GG of GSTP1 rs1695 in the control group. Generalized linear model indicated that the influencing factors of mtDNAcn were PAHs-exposure [ß (95% CI) = -0.420 (-0.469, -0.372), p < .001], male [ß (95% CI) = -0.058 (-0.103, -0.012), p = .013], and AA genotype for GSTP1 rs1695 [ß (95% CI) = -0.051 (-0.095, -0.008), p = .020]. CONCLUSION: The individuals carrying the AA genotype of GSTP1 rs1695 may have a lower mtDNAcn due to their weaker detoxification of PAHs.
Assuntos
Coque/efeitos adversos , Variações do Número de Cópias de DNA/efeitos dos fármacos , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Exposição Ocupacional/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Adolescente , Adulto , Estudos de Casos e Controles , China , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , DNA Mitocondrial/genética , Feminino , Glutationa S-Transferase pi/metabolismo , Glutationa Transferase/metabolismo , Voluntários Saudáveis , Humanos , Leucócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
There is a lot of abnormal information in the development of lung cancer, and how to extract useful knowledge is urgent from massive information. Data mining technology has become a popular tool for medical classification and prediction. However, each technology has its advantage and disadvantage, and several data mining methods will be applied to conduct the in-depth analysis step by step. And the prediction results of different models are compared. A total of 180 lung cancer patients and 243 lung benign individuals were collected from the First Affiliated Hospital of Zhengzhou University from October 2014 to March 2016, and the prediction models based on epidemiological data, clinical features and tumor markers were developed by artificial neural network (ANN), decision tree C5.0 and support vector machine (SVM). The results showed that there were significant differences between the lung cancer group and the lung benign group in terms of seven tumor markers and 10 epidemiological and clinical indicators. The accuracy rates of ANN, C5.0 and SVM were 76.47, 89.92 and 85.71%, respectively. The results of receiver operating characteristic curve (ROC) curve revealed the area under the ROC curve (AUC) of ANN was 0.811 (0.770-0.847), the AUC of C5.0 was 0.897 (0.864-0.924) and the AUC of SVM was 0.878 (0.843-0.908). It was shown that the decision tree C5.0 model has the least error rate and highest accuracy, and it could be used to diagnose lung cancer.
Assuntos
Mineração de Dados/métodos , Neoplasias Pulmonares/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Curva ROC , Máquina de Vetores de SuporteRESUMO
OBJECTIVE: The aim of this study was to explore the association between genetic variations in telomere pathway genes and the level of hydrogen peroxide (H2O2) in omethoate exposure workers. METHODS: A total of 180 omethoate exposure workers and 115 healthy controls were recruited. The level of H2O2 in plasma was determined with molybdenic acid colorimetry. Polymerase chain reaction and restriction fragment length was used to detect polymorphisms in POT1 rs1034794, POT1 rs10250202, TERF1 rs3863242, and TERT rs2736098. RESULTS: The level of H2O2 in exposure group (4.26 ± 0.71) was significantly higher than that in control group (3.29 ± 0.46). Generalized linear models indicated that risk factors for the increase H2O2 level were exposure [ß(95 % CI) = 0.951 (0.806, 1.096), P < 0.001] and AA + AT genotype in POT1 rs034794 [ß(95 % CI) = 0.397 (0.049, 0.745), P = 0.025]. CONCLUSION: The increase H2O2 level was associated with omethoate exposure and AA + AT genotypes in POT1 gene rs1034794. It provided a new idea that polymorphisms in telomere pathway genes may indirectly regulate telomere length by influencing oxidative stress.
Assuntos
Dimetoato/análogos & derivados , Peróxido de Hidrogênio/sangue , Inseticidas/toxicidade , Exposição Ocupacional/efeitos adversos , Proteínas de Ligação a Telômeros/genética , Adulto , Dimetoato/toxicidade , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Complexo Shelterina , Telomerase/genética , Telômero/genéticaRESUMO
Identification of hub genes and key pathways of gastric cancer was recognized to be essential to elucidate the tumorigenesis of GC. This study was aimed to identify the differentially expressed genes (DEGs) in GC via bioinformatics methods and their related pathways involved in the pathological process of GC. Gene expression profile datasets acquired by microarray chips or RNA-seq were downloaded from GEO dataset and TCGA, and 298 differentially expressed genes was identified. The Gene Ontology (GO) and Kyoto Gene and Genomic Encyclopedia (KEGG) pathways of DEGs were then analyzed by the DAVID database to elucidate the potential molecular functions of DEGs. The protein-protein interaction (PPI) network of DEGs was further analyzed with the STRING database and PHTF2 was identified as a hub gene in the PPI network. Subsequently, PHTF2 was found to be highly expressed in different subtypes of gastric cancer tissues obtained from TCGA database or clinical patients, resulting with a poor prognosis. By GSEA, PHTF2 was found to significantly enrich the fatty acid metabolism pathway in gastric cancer. Moreover, PHTF2-regulated lipids metabolism significantly affected the tumorigenesis of GC cells. In summary, this work identified a new mechanism by which PHTF2 precipitated in the pathological process of GC by regulating cellular lipid metabolism.
Assuntos
Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Neoplasias Gástricas/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Mapas de Interação de Proteínas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
Improvements in science and technology have led to the increasing threats of new chemicals to the public health. It is crucial to evaluate the toxicity, especially immunotoxicology. Dendritic cells (DCs) are believed to be more favorable choices in immunotoxicity evaluations. To obtain and evaluate the value of human monocyte-derived immature DCs (imDCs) in vitro applications in immunotoxicology, compared the results in vitro. DCs were obtained from enriched leukocytes of peripheral blood by using magnetic cell sorting and cytokine (rhGM-CSF + rhIL-4) co-induction. imDCs function in vitro and the surface antigens changes both in imDCs and THP-1 after 24 h of 2,4-dinitrochlorobenzene (DNCB) exposure were determined. The results were compared with those of DNCB-induced rats. The feasibility of imDCs applications in immunotoxicology was evaluated. In vivo, the splenic nodules, lymphocytes, and CD103+DC surface antigen expression were altered in the spleen of DNCB-induced rats. Moreover, DNCB exposure increased CD8+ T cell numbers both in peripheral blood and in the spleen of DNCB-induced rats. In vitro, DNCB exposure reduced the antigen uptake capacity and enhanced the T cell proliferative capacity of imDCs. The results are consistent with in vivo, but superior to that of the THP-1. Our results suggest that human monocyte-derived DCs may have potential applications as an attractive in vitro alternative cell model to evaluate the sensitization of DNCB.
RESUMO
Silicosis, a severe and irreversible form of pulmonary fibrosis (PF) caused by long-term exposure to dust particles in production environments, is the biggest occupational health concern in China and most low-income countries. The transdifferentiation of pulmonary fibroblasts is the terminal event in silicosis, and specific transcription factors (TFs) play a crucial role in this condition. However, the relationship between TF-mediated regulation and silicosis remains unknown. We performed a transcriptomic analysis to elucidate this relationship, and our results revealed that two TFs, EGR2 and BHLHE40, were upregulated and five, i.e., TBX2, NR1H3 (LXRα), NR2F1, PPARG (PPARγ), and EPAS1, were downregulated in activated fibroblasts. Notably, PPARγ and LXRα expression was also decreased in an experimental mouse model of silicosis. The mechanism underlying these changes may involve TGF-ß1 secretion from silica-exposed alveolar macrophages, causing PPARγ and LXRα downregulation, which in turn would result in aberrant α-SMA transcription. Our results suggest that LXRα is a potential target for the prevention of silicosis and PF.