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1.
Ann Clin Lab Sci ; 51(4): 470-486, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452885

RESUMO

OBJECTIVE: Epithelium-specific ETS protein 3 (Ese-3) is a member of the ETS family that is associated with tumor progression. However, there is little knowledge about Ese-3 in skin cancer. This study was conducted to explore the effects of Ese-3 on clinical prognosis in skin cancer and the functions of HaCaT cells. MATERIALS AND METHODS: Gene expression and clinical data were collected from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and three GSE datasets (GSE15605, GSE46517, and GSE114445). Comparison of data between groups was performed by Student's t-test and chi square test. Survival analysis was performed using log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models. Enrichment analysis was used to predict Ese-3 related functions. Cell proliferation assays, colony formation assays, and flow cytometry were used to assess cell proliferation, while Transwell assays analyzed cell migration and invasion. RESULTS: Compared with normal tissues, the Ese-3 mRNA in cutaneous malignant melanoma (CMM) patients was downregulated (P<0.0001). Ese-3 mRNA was associated with the T stage (χ 2=10.015, P=0.018), clinical stage (χ 2=4.122, P=0.042), and prognosis in CMM patients (P=0.0219) and was an independent prognostic predictor in CMM (HR=1.878, P=0.048). Enrichment analysis showed that differentially expressed proteins were associated with "protein kinase B (AKT) binding." CONCLUSION: Ese-3 inhibited the proliferation, migration, and invasion of HaCaT cells by downregulating PSIP1 and NUCKS1 expression levels to inactivate the phosphorylation of AKT.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/antagonistas & inibidores , Fosfoproteínas/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Células HaCaT , Humanos , Masculino , Invasividade Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Taxa de Sobrevida , Fatores de Transcrição/genética
2.
J Oral Pathol Med ; 49(9): 933-939, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449535

RESUMO

BACKGROUND: Synovitis is characterized by the infiltration of inflammatory cells and often accompanies the pathological progression of the clinical symptoms affecting the temporomandibular joint (TMJ), such as pain, snapping, and limited mouth opening. It has been suggested that the signal transduction pathway and resultant proinflammatory mediators play important roles in the pathogenesis of synovitis. Therefore, in this present research, we aimed to investigate the changes in the expressions of stromal cell-derived factor 1 (SDF-1) and interleukin (IL)-1ß in rats with occlusal interference. MATERIALS AND METHODS: We divided 36 male Wistar rats into the following groups: Group A (control group), Group B (occlusal interference group), and Group C (AMD3100 group). Synovial inflammation was induced in the rats in Groups B and C to establish the occlusal interference model. The inflammatory changes were detected, and the expressions of SDF-1 and IL-1ß in the synovium were assayed via immunostaining and a real-time quantitative polymerase chain reaction (PCR). RESULTS: In Group B, obvious inflammatory changes were observed in the synovial membranes; additionally, the SDF-1 and IL-1ß expression levels were significantly higher at the protein and mRNA levels. However, in Group C, these experimental results were inhibited by an injection with AMD3100. CONCLUSION: These results may indicate that SDF-1 regulates the expression level of inflammatory factors, such as IL-1ß, in the synovial membranes of rats with occlusal interference. Our findings suggest that the SDF-1 axis may contribute to the onset of synovitis during the development of TMJ joint disease.


Assuntos
Quimiocina CXCL12 , Articulação Temporomandibular , Animais , Secreções Corporais , Quimiocina CXCL12/genética , Inflamação , Interleucina-1beta , Masculino , Ratos , Ratos Wistar , Células Estromais , Membrana Sinovial
3.
J Chromatogr A ; 1622: 461098, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376014

RESUMO

In the current study, a novel covalent organic frameworks COF-SCU1 incorporated electrospun nanofibers (PAN@COF-SCU1 nanofibers) was fabricated via a facile electrospinning method and utilized as adsorbent in pipette tip solid-phase extraction (PT-SPE) of tetracycline antibiotics (TCs) from foods. The prepared PAN@COF-SCU1 nanofibers possessed both of the unique characteristics of electrospun nanofibers and COFS-CU1, and thus improving the adsorption capacity of the electrospun nanofibers and preventing the problems of leakage and high pressure caused by directly using the nanosize COFs as adsorbent in PT-SPE. The experiments affected the adsorption and desorption efficiencies, such as the loading ratios of COFS-CU1 in nanofibers, the amount of nanofibers, the matrix pH and desorption solvent, were studied in detail. Eventually, a new pipette tip solid-phase extraction-high performance liquid chromatography (PT-SPE/HPLC) method was proposed for the analysis of three TCs from food. Satisfied linearity for TCs was obtained in the range of 4-70 ng mL-1. The limits of detection and quantification were ranged from 0.6 to 3 ng mL-1 and from 2 to 10 ng mL-1, respectively. The interday and intraday precisions (RSD) were all lower than 9%. The proposed PT-SPE/HPLC method was used to determine TCs residues in grass carp and duck samples for the first time. The results could not only explore the availability of PT-SPE in the extraction of TCs in food samples, but also broadened the potential applications of COFs in sample preparation.


Assuntos
Carpas , Patos , Análise de Alimentos , Estruturas Metalorgânicas , Nanofibras , Extração em Fase Sólida , Tetraciclinas , Adsorção , Animais , Antibacterianos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Análise de Alimentos/métodos , Estruturas Metalorgânicas/síntese química , Nanofibras/química , Tetraciclinas/isolamento & purificação
4.
Aquat Toxicol ; 222: 105478, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32278258

RESUMO

This study was undertaken to systematically assess the utilities and performance of ontology-based semantic analysis in adverse outcome pathway (AOP) research. With an increasing number of AOPs developed by scientific domain experts to organize toxicity information and facilitate chemical risk assessment, there is a pressing need for objective approaches to evaluate the biological coherence and quality of these AOPs. Powered by ontologies covering a wide range of biological domains, abundant phenotypic data annotated ontologically, and some sophisticated knowledge computing tools, semantic analysis has great potential in this area of application. With the events in the AOP-Wiki first annotated into logical definitions and then grouped into phenotypic profiles by individual AOPs, the coherence and quality of AOPs were assessed at several levels: paired key event relationships (KER), all possible event pair combinations within AOPs, and the phenotypic profiles of AOPs, genes, biological pathways, human diseases, and selected chemicals. The semantic similarities were assessed at all these levels based on a unified cross-species vertebrate phenotype ontology encompassing the logical definitions of AOP events as well as many other domain ontologies. A substantial number of KERs and AOPs in the AOP-Wiki were found to be semantically coherent. These same coherent AOPs also mapped to many more genes, pathways, and diseases biologically aligned with the intended chain of events therein leading to their respective adverse outcomes. Significantly, these findings imply that semantic analysis should also have utilities in developing future AOPs by selecting candidate events from either the existing AOP-Wiki events or a broader collection of ontology terms semantically similar to the molecular initiating events or adverse outcomes of interest. In addition, semantic analysis enabled AOP networks to be constructed at the level of phenotypic profiles based on similarities, complementing those based on event sharing by bringing genes, pathways, diseases, and chemicals into the networks too-thus greatly expanding the biological scope and our understanding of AOPs.


Assuntos
Rotas de Resultados Adversos , Pesquisa Biomédica/métodos , Semântica , Toxicologia/métodos , Animais , Ontologias Biológicas , Humanos , Fenótipo , Medição de Risco
5.
Adv Exp Med Biol ; 1206: 435-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31776997

RESUMO

Protein homeostasis is essential for maintaining cell survival. Protein synthesis and degradation coordinately regulate protein homeostasis. Chaperone-mediated autophagy (CMA) was the first lysosomal process to be discovered by which intracellular components are selectively degraded. This process involves the recognition of the substrate, the unfolding and translocation of the substrate, and the degradation of the substrate. By degrading specific target proteins in a timely manner, CMA is involved in a variety of cellular activities. In the past few years, we have acquired a better understanding of how CMA is regulated. It has been reported that peroxide accumulation, aging and/or other pathological signals interfere with CMA function, which in turn induces neurodegenerative diseases, cancer, and other diseases. Combining results from the current research, we summarize the basic processes, regulatory mechanisms, and physiological functions of CMA and discuss its critical role in the development of diseases.


Assuntos
Autofagia , Chaperonas Moleculares , Humanos , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia
6.
Toxicology ; 412: 89-100, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30468866

RESUMO

This study was undertaken to evaluate the use of ontology-based semantic mapping (OS-Mapping) in chemical toxicity assessment. Nineteen chemical-species phenotypic profiles (CSPPs) were constructed by ontologically annotating the toxicity responses reported in more than seven hundred published studies of ten chemicals on six vertebrate species. The CSPPs were semantically compared to more than 29,000 publicly available phenotypic profiles of genes, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, and diseases based on a cross-species phenotype ontology. OS-Mapping was shown to differentiate chemical toxicities among themselves as well as within and across species. It also revealed cases of chemical by species interactions. In addition to confirming similar MOAs (mechanisms of action) for a few chemicals, OS-Mapping also generated novel insights into the MOAs underlying some seemingly different, yet phenotypically similar, classes of chemicals. The nature of a unified cross-species phenotype ontology and its representation of diverse knowledge domains allowed the construction of a complete phenotypic continuum for the 17α-ethynylestradiol_fathead minnow across the biological levels of organization, which complemented a similar one derived from the Comparative Toxicogenomics Database but based primarily on 17α-ethynylestradiol-induced molecular phenotypes. Overall, OS-Mapping has been demonstrated to offer a powerful approach to help bridge the gap between the molecular and non-molecular phenotypes of chemicals characterized by using high throughput or traditional omics methods and their apical endpoints of greater regulatory relevance, which are typically phenotypes found at the higher levels of biological organization. OS-Mapping also enables comparative toxicity assessment among chemicals, both within and across species. Furthermore, the semantic analysis of phenotypes can reveal additional novel MOAs for some well-known chemicals and discover candidate MOAs for chemicals that are less molecularly characterized. A full phenotypic continuum based on OS-Mapping will also be conducive to the future development of adverse outcome pathways. As phenomics continues to advance and the ontological annotation of literature becomes more automated, the power of OS-Mapping will be further enhanced.


Assuntos
Ontologias Biológicas , Substâncias Perigosas/toxicidade , Fenótipo , Medição de Risco , Animais , Peixes , Humanos , Camundongos , Ratos , Semântica
7.
Cell Death Dis ; 9(6): 693, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880811

RESUMO

MiRNAs, a group of powerful modulator of gene expression, participate in multiple cellular processes under physiological and pathological conditions. Emerging evidence shows that Drosha, which controls the initial step in canonical miRNA biogenesis, is involved in modulating cell survival and death in models of several diseases. However, the role of Drosha in Parkinson's disease (PD) has not been well established. Here, we show that the level of Drosha decreases in 6-OHDA-induced cellular and animal models of PD. 6-OHDA induced a p38 MAPK-dependent phosphorylation of Drosha. This triggered Drosha degradation. Enhancing the level of Drosha protected the dopaminergic (DA) neurons from 6-OHDA-induced toxicity in both in vitro and in vivo models of PD and alleviated the motor deficits of PD mice. These findings reveal that Drosha plays a critical role in the survival of DA neurons and suggest that stress-induced destabilization of Drosha may be part of the pathological process in PD.


Assuntos
Neurônios Dopaminérgicos/patologia , Doença de Parkinson/patologia , Ribonuclease III/deficiência , Animais , Linhagem Celular , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora , Oxidopamina , Doença de Parkinson/fisiopatologia , Fosforilação , Estabilidade Proteica , Proteólise , Ribonuclease III/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 2859-2870, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29842922

RESUMO

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.


Assuntos
Antioxidantes/farmacologia , GTP Fosfo-Hidrolases/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Animais , Antioxidantes/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Fosforilação , RNA Mensageiro/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Regulação para Cima
9.
PLoS One ; 12(10): e0186807, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29049393

RESUMO

Many organisms, including the fathead minnow (Pimephales promelas), a toxicological model organism, establish social hierarchies. The social rank of each male in a population is under the control of the hypothalamic-pituitary-gonadal (HPG) axis mainly through regulation of circulating androgen concentrations, which in turn drive the expression of secondary sex characteristics (SSCs). As dominant and subordinate males in an exposure study are initially under different physiological conditions (i.e., differing plasma androgen concentrations), we proposed that they belong to different subpopulations in the context of exposure to compounds that may interact with the HPG axis. Using a meta-analysis of our data from several previously published studies, we corroborated the hypothesis that social status, as indicated by SSCs, results in distinct clusters (eigenvalues >0.8 explaining >80% of variability) with differential expression of plasma vitellogenin, a commonly used biomarker of exposure to contaminants of emerging concern (CEC). Furthermore, we confirmed our predictions that exposure to estrogenic CECs would homogenize plasma vitellogenin response (E1: cluster mean SSC values decreased to 4.33 and 4.86 relative to those of control; E2: decreased to 4.8 and 5.37) across the social hierarchy. In contrast, serotonin-specific reuptake inhibitors expand this response range (cluster mean SSC increased to 5.21 and 6.5 relative to those of control). Our results demonstrated that social hierarchies in male fathead minnows result in heterogeneous responses to chemical exposure. These results represent a cautionary note for the experimental design of single-sex exposure studies. We anticipate our study to be a starting point for the re-evaluation of toxicological data analyses in single sex exposure experiments.


Assuntos
Estrogênios/toxicidade , Peixes , Inibidores de Captação de Serotonina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Masculino , Vitelogeninas/sangue
10.
Neurosci Bull ; 33(5): 552-560, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28791585

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease with a long preclinical phase. The continuous loss of dopaminergic (DA) neurons is one of the pathogenic hallmarks of PD. Diagnosis largely depends on clinical observation, but motor dysfunctions do not emerge until 70%-80% of the nigrostriatal nerve terminals have been destroyed. Therefore, a biomarker that indicates the degeneration of DA neurons is urgently needed. Transcription factors are sequence-specific DNA-binding proteins that regulate RNA synthesis from a DNA template. The precise control of gene expression plays a critical role in the development, maintenance, and survival of cells, including DA neurons. Deficiency of certain transcription factors has been associated with DA neuron loss and PD. In this review, we focus on some transcription factors and discuss their structure, function, mechanisms of neuroprotection, and their potential for use as biomarkers indicating the degeneration of DA neurons.


Assuntos
Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fatores de Transcrição/metabolismo , Biomarcadores/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Humanos , Degeneração Neural , Neuroproteção , Doença de Parkinson/genética
11.
Neuropsychiatr Dis Treat ; 13: 1805-1813, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744130

RESUMO

BACKGROUND: Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2) is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. METHODS: This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. RESULTS: By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251) compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan-Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt/ß-catenin signaling pathway. CONCLUSION: This study suggested that CASC2 may potentially serve as a valuable diagnostic and prognostic biomarker and a therapeutic target for glioma patients.

12.
J Neurochem ; 142(2): 272-285, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28444766

RESUMO

Sevoflurane, a typical inhaled anesthetic, is widely used in patients of all ages during surgery. The negative effects, such as inducing cell death and damaging spatial memory, of sevoflurane on neurodevelopment have raised increasing concerns in recent years. However, the molecular mechanism remains unclear. This study focused on the crucial role of endoplasmic reticulum (ER) stress in sevoflurane-induced hippocampal injury. Three-week-old rats were exposed to sevoflurane or control air for 5 h with or without ER stress inhibitor (4-phenylbutyric acid, 4-PBA) injection. The hippocampus was harvested to measure the ER stress sensors by western immunoblotting. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling staining was used to detect cell apoptosis and electrophysiology was used to measure the intrinsic excitability of neurons in hippocampus. We measured learning and memory ability by Morris water maze tests 5 weeks after sevoflurane exposure. Interestingly, persistent sevoflurane exposure significantly increased the levels of ER stress sensors in hippocampus. But it resulted in different effects in CA1 and dentate gyrus. Greatly increased caspase-12-mediated apoptotic cells, which were proved to be the neural stem cells, were detected in the dentate gyrus. Meanwhile, CA1 pyramidal neurons exhibited significantly reduced intrinsic excitability. Furthermore, the administration of ER stress inhibitor attenuated the above mentioned detrimental effects evidently and prevented the following relevant learning and memory deficits. In conclusion, sevoflurane-mediated ER stress performs distinct effects on the different subfields of the immature hippocampus and inhibiting ER stress during sevoflurane anesthesia will be a potential method to prevent the following learning and memory deficits in adulthood.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Éteres Metílicos/farmacologia , Memória Espacial/efeitos dos fármacos , Anestésicos Inalatórios/farmacologia , Animais , Animais Recém-Nascidos , Morte Celular/efeitos dos fármacos , Hipocampo/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenilbutiratos/farmacologia , Sevoflurano
13.
Environ Toxicol Chem ; 36(10): 2614-2623, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28316117

RESUMO

Fundamental questions remain about the application of omics in environmental risk assessments, such as the consistency of data across laboratories. The objective of the present study was to determine the congruence of transcript data across 6 independent laboratories. Male fathead minnows were exposed to a measured concentration of 15.8 ng/L 17α-ethinylestradiol (EE2) for 96 h. Livers were divided equally and sent to the participating laboratories for transcriptomic analysis using the same fathead minnow microarray. Each laboratory was free to apply bioinformatics pipelines of its choice. There were 12 491 transcripts that were identified by one or more of the laboratories as responsive to EE2. Of these, 587 transcripts (4.7%) were detected by all laboratories. Mean overlap for differentially expressed genes among laboratories was approximately 50%, which improved to approximately 59.0% using a standardized analysis pipeline. The dynamic range of fold change estimates was variable between laboratories, but ranking transcripts by their relative fold difference resulted in a positive relationship for comparisons between any 2 laboratories (mean R2 > 0.9, p < 0.001). Ten estrogen-responsive genes encompassing a fold change range from dramatic (>20-fold; e.g., vitellogenin) to subtle (∼2-fold; i.e., block of proliferation 1) were identified as differentially expressed, suggesting that laboratories can consistently identify transcripts that are known a priori to be perturbed by a chemical stressor. Thus, attention should turn toward identifying core transcriptional networks using focused arrays for specific chemicals. In addition, agreed-on bioinformatics pipelines and the ranking of genes based on fold change (as opposed to p value) should be considered in environmental risk assessment. These recommendations are expected to improve comparisons across laboratories and advance the use of omics in regulations. Environ Toxicol Chem 2017;36:2593-2601. © 2017 SETAC.


Assuntos
Cyprinidae/genética , Disruptores Endócrinos/toxicidade , Etinilestradiol/toxicidade , Laboratórios/normas , Fígado/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Cyprinidae/metabolismo , Ensaio de Imunoadsorção Enzimática , Fígado/efeitos dos fármacos , Masculino , Modelos Químicos , Análise de Sequência com Séries de Oligonucleotídeos , RNA/isolamento & purificação , RNA/metabolismo , Vitelogeninas/sangue
14.
Appl In Vitro Toxicol ; 3(4): 298-311, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30057931

RESUMO

Introduction: The Adverse Outcome Pathway framework is increasingly used to integrate data generated based on traditional and emerging toxicity testing paradigms. As the number of AOP descriptions has increased, so has the need to define the AOP in computable terms. Materials and Methods: Herein, we present a comprehensive annotation of 172 AOPs housed in the AOP-Wiki as of December 4, 2016 using terms from existing biological ontologies. Results: AOP Key Events (KEs) were assigned ontology terms using a concept called the Event Component, which consists of a Process, an Object, and an Action term, with each term originating from ontologies and other controlled vocabularies. Annotation of KEs with ontology classes from fourteen ontologies and controlled vocabularies resulted in a total of 685 KEs being annotated with a total of 809 Event Components. A set of seven conventions resulted, defining the annotation of KEs via Event Components. Discussion: This expanded annotation of AOPs allows computational reasoners to aid in both AOP development and applications. In addition, the incorporation of explicit biological objects will reduce the time required for converting a qualitative AOP description into a conceptual model that can support computational modeling. As high throughput genomics becomes a more important part of the high throughput toxicity testing landscape, the new approaches described here for annotating key events will also promote the visualization and analysis of genomics data in an AOP context.

15.
Cell Death Dis ; 7(12): e2563, 2016 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-28032867

RESUMO

Endoplasmic reticulum (ER) stress is involved in many cellular processes. Emerging evidence suggests that ER stress can trigger autophagy; however, the mechanisms by which ER stress regulates autophagy and its role in this condition are not fully understood. HIV Tat-interactive protein, 60 kDa (TIP60) is a newly discovered acetyltransferase that can modulate autophagy flux by activating ULK1 upon growth factor deprivation. In this study, we investigated the mechanisms by which ER stress induces autophagy. We showed that ER stress activates glycogen synthase kinase-3ß (GSK3ß). This led to a GSK3ß-dependent phosphorylation of TIP60, triggering a TIP60-mediated acetylation of ULK1 and activation of autophagy. Inhibition of either GSK3ß or TIP60 acetylation activities significantly attenuated ER stress-induced autophagy. Moreover, enhancing the level of TIP60 attenuated the level of CHOP after ER stress, and reduced the ER stress-induced cell death. In contrast, expression of TIP60 mutant that could not be phosphorylated by GSK3ß exacerbated the generation of CHOP and increased the ER stress-induced cell death. These findings reveal that ER stress engages the GSK3ß-TIP60-ULK1 pathway to increase autophagy. Attenuation of this pathway renders cells more sensitive to and increases the toxicity of ER stress.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Estresse do Retículo Endoplasmático , Glicogênio Sintase Quinase 3 beta/metabolismo , Histona Acetiltransferases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células HeLa , Humanos , Peróxido de Hidrogênio/toxicidade , Lisina Acetiltransferase 5 , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
16.
BMC Genomics ; 17: 84, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26822894

RESUMO

BACKGROUND: A very large and rapidly growing collection of transcriptomic profiles in public repositories is potentially of great value to developing data-driven bioinformatics applications for toxicology/ecotoxicology. Modeled on human connectivity mapping (Cmap) in biomedical research, this study was undertaken to investigate the utility of an analogous Cmap approach in ecotoxicology. Over 3500 zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) transcriptomic profiles, each associated with one of several dozen chemical treatment conditions, were compiled into three distinct collections of rank-ordered gene lists (ROGLs) by species and microarray platforms. Individual query signatures, each consisting of multiple gene probes differentially expressed in a chemical condition, were used to interrogate the reference ROGLs. RESULTS: Informative connections were established at high success rates within species when, as defined by their mechanisms of action (MOAs), both query signatures and ROGLs were associated with the same or similar chemicals. Thus, a simple query signature functioned effectively as an exposure biomarker without need for a time-consuming process of development and validation. More importantly, a large reference database of ROGLs also enabled a query signature to cross-interrogate other chemical conditions with overlapping MOAs, leading to novel groupings and subgroupings of seemingly unrelated chemicals at a finer resolution. This approach confirmed the identities of several estrogenic chemicals, as well as a polycyclic aromatic hydrocarbon and a neuro-toxin, in the largely uncharacterized water samples near several waste water treatment plants, and thus demonstrates its future potential utility in real world applications. CONCLUSIONS: The power of Cmap should grow as chemical coverages of ROGLs increase, making it a framework easily scalable in the future. The feasibility of toxicity extrapolation across fish species using Cmap needs more study, however, as more gene expression profiles linked to chemical conditions common to multiple fish species are needed.


Assuntos
Transcriptoma/genética , Animais , Cyprinidae/genética , Transcriptoma/efeitos dos fármacos , Transcriptoma/fisiologia , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/genética
17.
Oncol Lett ; 10(4): 2378-2384, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26622855

RESUMO

Oral cavity cancer is common worldwide. Furthermore, the epidermal growth factor receptor (EGFR) signaling pathway is considered to be constitutively activated in oral cancers. Paclitaxel is widely accepted as an antitumor drug as it effectively inhibits the cell cycle. This study predominantly explores the possible molecule mechanism of paclitaxel on oral cancer treatment. Cell viability was first detected using an MTT assay. Cell apoptosis was examined by Hoechst staining and flow cytometry using an annexin-V and propidium iodide kit. Specific EGFR signaling pathways were further explored through western blot analysis. Abnormal protein expression levels were determined via immunofluoresence. Additionally, the protein levels of matrix metalloproteinase (MMP)-2 and 9 were determined using ELISA. Paclitaxel significantly inhibited oral cancer cell viability in a time- and dose-dependent manner. Paclitaxel also enhanced oral cancer cell apoptosis via increased Bim and Bid protein expression. Furthermore, paclitaxel was observed to inhibit oral cancer cell proliferation through increased MMP-2 and MMP-9 protein levels. Paclitaxel inhibited the growth of the oral cancer cell line, tea8113 malignant proliferation and enhanced tea8113 cell apoptosis through inhibiting the EGFR signaling pathway.

18.
J BUON ; 20(3): 756-61, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26214627

RESUMO

PURPOSE: The aim of this study was to explore the treatment strategies for patients with obstructive colorectal cancer at different sites. METHODS: Treatment strategies were adopted according to the location of colorectal cancer and the condition of the patients when they were admitted to the hospital. Among a total of 134 patients, 29 patients were subjected to stent placement to relieve the obstruction before undergoing colorectal resection, 15 patients underwent per anum ileus catheterization to alleviate the symptoms of obstruction and waited for removal of the tumor within a limited time; 39 underwent intraoperative colonic lavage and colon resection with anastomosis and the remaining 51 patients were subjected to emergency surgery due to strangulation of the bowel, perforation, septic shock or other conditions before surgery. RESULTS: Stent placement was successfully performed on 23 patients, with a success rate of 79%. Ninety-five of 134 patients (71% had stage I anastomosis and only one case had anastomotic fistula. Infection of incision happened in 9 (7%) cases and 2 (1.5%) patients died of infection. CONCLUSIONS: Individualized treatment for patients with obstructive colorectal cancer can lead to tumor resection and stage I anastomosis, thereby avoiding the suffering of second-stage surgery or colostomy.


Assuntos
Cateterismo , Colectomia , Neoplasias Colorretais/terapia , Obstrução Intestinal/terapia , Stents , Irrigação Terapêutica , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo/efeitos adversos , Cateterismo/mortalidade , Colectomia/efeitos adversos , Colectomia/mortalidade , Neoplasias Colorretais/complicações , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/etiologia , Obstrução Intestinal/mortalidade , Obstrução Intestinal/cirurgia , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Fatores de Risco , Irrigação Terapêutica/efeitos adversos , Irrigação Terapêutica/mortalidade , Fatores de Tempo , Resultado do Tratamento
20.
PLoS One ; 9(12): e114178, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25493933

RESUMO

Fathead minnow and zebrafish are among the most intensively studied fish species in environmental toxicogenomics. To aid the assessment and interpretation of subtle transcriptomic effects from treatment conditions of interest, better characterization and understanding are needed for natural variation in gene expression among fish individuals from lab cultures. Leveraging the transcriptomics data from a number of our toxicogenomics studies conducted over the years, we conducted a meta-analysis of nearly 600 microarrays generated from the ovary tissue of untreated, reproductively mature fathead minnow and zebrafish samples. As expected, there was considerable batch-to-batch transcriptomic variation; this "batch-effect" appeared to differentially impact subsets of fish transcriptomes in a nonsystematic way. Temporally more closely spaced batches tended to share a greater transcriptomic similarity among one another. The overall level of within-batch variation was quite low in fish ovary tissue, making it a suitable system for studying chemical stressors with subtle biological effects. The observed differences in the within-batch variability of gene expression, at the levels of both individual genes and pathways, were probably both technical and biological. This suggests that biological interpretation and prioritization of genes and pathways targeted by experimental conditions should take into account both their intrinsic variability and the size of induced transcriptional changes. There was significant conservation of both the genomes and transcriptomes between fathead minnow and zebrafish. The high degree of conservation offers promising opportunities in not only studying fish molecular responses to environmental stressors by a comparative biology approach, but also effective sharing of a large amount of existing public transcriptomics data for developing toxicogenomics applications.


Assuntos
Cyprinidae/genética , Variação Genética , Transcriptoma , Peixe-Zebra/genética , Animais , Análise de Sequência com Séries de Oligonucleotídeos
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