Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.997
Filtrar
1.
Medicine (Baltimore) ; 99(45): e23051, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157959

RESUMO

BACKGROUND: During the last decade, a number of studies have evaluated the potential association between some genetic polymorphisms and childhood asthma risk, however, the results of published studies appear conflicts. The aim of the present study was to investigate association between genetic polymorphisms and pediatric asthma. METHODS: Relevant studies were searched in PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure), Wanfang, and Weipu database. Pooled odds ratios (OR) with 95% confidence interval (CI) were calculated to evaluate the strength of the associations. RESULTS: Fifty five case-control studies were finally included in this meta-analysis, including 17,971 pediatric asthma cases and 17,500 controls. Eighteen polymorphisms were identified, of which, 9 polymorphisms were found to be associated with asthma risk in overall populations: IL-13 +2044G/A, IL-4 -590C/T, ADAM33 F+1, ADAM33 T2, ADAM33 T1, ADAM33 ST+4,ORMDL3 rs7216389, VDR FokI, VDR TaqI. Furthermore, IL-13 +2044G/A, IL-4 -590C/T, ADAM33 T2, ADAM33 T1, VDR BsmI polymorphisms may cause an increased risk of asthma among Chinese children. CONCLUSIONS: This meta-analysis found that IL-13 +2044G/A, IL-4 -590C/T, ADAM33 F+1, ADAM33 T2, ADAM33 T1, ADAM33 ST+4,ORMDL3 rs7216389, VDR FokI, and VDR TaqI polymorphisms might be risk factors for childhood asthma. Further study with large population and more ethnicities is needed to estimate these associations.


Assuntos
Proteínas ADAM/genética , Asma/genética , Interleucina-13/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Gerenciamento de Dados , Feminino , Humanos , Lactente , Masculino , Polimorfismo Genético/genética , Fatores de Risco
2.
J Hum Genet ; 65(8): 657-665, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32277175

RESUMO

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.


Assuntos
Degeneração Macular/genética , Proteínas ADAM/genética , Proteínas da Fase Aguda/genética , Antígenos CD55/genética , Proteínas de Transporte/genética , Coenzima A Ligases/genética , Proteína de Ligação ao Complemento C4b/genética , Bases de Dados Genéticas , Proteínas do Olho/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Glicoproteínas de Membrana/genética , Subunidade p50 de NF-kappa B/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas Repressoras/genética , Retina/metabolismo , Retina/patologia
3.
PLoS One ; 15(3): e0229241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119686

RESUMO

While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10-05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10-08) (rs34631960 [OR 2.3±1.6-3.3] in thrombospondin type 1 domain-containing protein 4 (THSD4) and rs2328386 [OR 0.5±0.3-0.7] in human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.


Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Proteínas ADAM/genética , Administração por Inalação , Adolescente , Corticosteroides/uso terapêutico , Adulto , Fatores Etários , Idoso , Antiasmáticos/uso terapêutico , Asma/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Serviço Hospitalar de Emergência , Feminino , Estudo de Associação Genômica Ampla , Histona Desacetilases/genética , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Resultado do Tratamento , Adulto Jovem
4.
Arterioscler Thromb Vasc Biol ; 40(5): 1195-1206, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32212853

RESUMO

OBJECTIVE: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. CONCLUSIONS: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.


Assuntos
Células Endoteliais/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Pulmão/irrigação sanguínea , MicroRNAs/metabolismo , Microvasos/metabolismo , Neovascularização Fisiológica , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
Pharmacol Rep ; 72(2): 418-426, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048249

RESUMO

BACKGROUND: Anesthesia is a major component of surgery and recently considered an important regulator of cell phenotypes. Here we aimed to investigate propofol, an anesthesia drug, in suppressing pancreatic cancer (PDAC), focusing on A disintegrin and metalloprotease 8, (ADAM8) as a molecular mediator. METHODS: Quantitative real-time PCR and western blot were used to assess the change of ADAM8 expression in Panc1 PDAC cells treated with 5 or 10 µg/mL propofol, using cells treated with BB-94 inhibitor as controls. ADAM8 activity was measured through quantifying fluorescence release induced by PEPDAB013 decomposition. MTT assay, scratch wound assay and Matrigel invasion assay were used to investigate the proliferation, migration and invasion of the cells. Western blot and immunohistochemical analysis were used to quantify integrin ß1, ERK1/2, MMP2 and MMP9 expression. RESULTS: Propofol and BB-94 reduced ADAM8 expression, cell proliferation and migration of Panc1 cells. Tumor growth was inhibited by propofol and BB-94, concomitant with downregulation of integrin ß1, ERK1/2, MMP2 and MMP9. ADAM8 is downregulated by propofol, leading to inhibition of pancreatic cancer proliferation and migration. CONCLUSION: Pancreatic tumor growth is also inhibited by propofol and BB-94, which is attributed to suppression of ERK/MMPs signaling.


Assuntos
Proteínas ADAM/metabolismo , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/patologia , Propofol/farmacologia , Proteínas ADAM/genética , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/genética , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Propofol/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cell Mol Life Sci ; 77(2): 267-274, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432233

RESUMO

Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identified in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1-ADAM22.


Assuntos
Proteínas ADAM/genética , Epilepsia/genética , Epilepsia/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Animais , Autoanticorpos/metabolismo , Humanos , Mutação/genética
7.
Biosci Rep ; 39(12)2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31789346

RESUMO

The present study aimed to investigate the underlying mechanism of miR-126a-3p in the proliferation, migration and invasion of trophoblast cells in pre-eclampsia-like rats by targeting A Disintegrin and Metalloprotease 9 (ADAM9). First, the interaction between miR-126a-3p and ADAM9 was confirmed via biochemical assays. Placental tissues and trophoblast cells were then obtained. RNA in situ hybridization was performed in order to detect miR-126a-3p expression in the placenta. Subsequently, a series of biological assays, including reverse transcription-quantitative PCR (RT-qPCR), Western blotting, MTT assay, apoptosis assay, cell cycle assay, wound healing assay and transwell assay were adopted in order to determine the cell proliferation, cell cycle distribution, apoptotic rate, and migration and invasion of trophoblast cells in each group. The results revealed that miR-126a-3p was down-regulated in the placenta of pre-eclampsia-like rats. In vivo experiments' results indicated that miR-126a-3p could inhibit ADAM9 expression, and induce cyclin D1, Matrix metalloproteinase (MMP) 2 (MMP-2), MMP-9 expression. MTT, apoptosis and cell cycle assay results revealed that trophoblast cells transfected with miR-126a-3p mimic or si-ADAM9 exhibited higher proliferative activity and a lower apoptotic rate compared with the blank group (all P<0.05). The wound healing assay and transwell assay results confirmed that, compared with the blank group, the migration and invasion ability of trophoblast cells in the miR-126a-3p mimic group and small interfering RNA (siRNA)-ADAM9 group were significantly increased (all P<0.05). Conversely, miR-126a-3p inhibitor treatment revealed the opposite effect (all P<0.05). In conclusion, the present study demonstrated that miR-126a-3p could enhance proliferation, migration and invasion, but decrease the apoptosis rate of trophoblast cells in pre-eclampsia-like rats through targeting ADAM9.


Assuntos
Proteínas ADAM/genética , Metaloproteinase 9 da Matriz/genética , MicroRNAs/genética , Pré-Eclâmpsia/genética , Proteínas ADAM/antagonistas & inibidores , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Desintegrinas/genética , Feminino , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Ratos , Transfecção , Trofoblastos/metabolismo , Trofoblastos/patologia
8.
Indian J Med Res ; 150(3): 272-281, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31719298

RESUMO

Background & objectives: ADAM33 is implicated as a potentially strong candidate gene for asthma and bronchial hyper-responsiveness. Many polymorphisms of ADAM33 have been studied along with ADAM33 expression in various cells of the lungs. Haplotype analysis also showed association with asthma in different populations across the world. Therefore, the aim of this study was to perform a comprehensive screening of ADAM33 polymorphisms in adult patients with asthma. Methods: Thirty five polymorphisms of ADAM33 were genotyped in 55 patients with asthma and 53 controls. The association of single nucleotide polymorphisms (SNPs) and haplotypes with phenotypes of asthma was analysed. Results: The genotype, minor allele frequency, odds ratio and Hardy-Weinberg equilibrium did not show any significant difference among cases and controls. No association was found between SNPs of ADAM33 with the severity of asthma. Correlation analysis of ADAM33 SNPs to the phenotypes, based on clinical variables and allergen sensitization, did not show significant difference. Haplotype analysis showed that rs2280090 and rs2280091 were associated with asthma in the patient group. Interpretation & conclusions: Haplotype analysis showed an association of the two SNP variations with asthma. These SNPs lead to amino acid change and are prone to phosphorylation, which may affect expression levels and protein function of ADAM33 and asthma susceptibility.


Assuntos
Proteínas ADAM/genética , Asma/genética , Haplótipos , Adulto , Alelos , Brônquios/patologia , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Projetos Piloto , Polimorfismo de Nucleotídeo Único
9.
Clin Epigenetics ; 11(1): 154, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675985

RESUMO

BACKGROUND: Aberrant DNA methylation is involved in gastric carcinogenesis and may serve as a useful biomarker in the diagnosis and detection of gastric cancer (GC) recurrence. RESULTS: A total of 157 patients who received surgery for GC were enrolled in the present study. A genome-wide methylation analysis was performed in tumor and adjacent normal tissues for the discovery set of 16 GC patients; the top three hypermethylated CpG sites of DNA promoters were selected for validation in tissue and plasma samples for the validation set of 141 GC patients. The frequencies of the top three hypermethylated genes in available patient tissues (n = 141) and plasma samples (n = 106) were 41.8% and 38.7%, respectively, for ADAM19; 40.4% and 42.5%, respectively, for FLI1; and 56.7% and 50.9%, respectively, for MSC. In both tissue and plasma samples, FLI1 hypermethylation was associated with more advanced GC and liver and distant lymphatic metastasis, and ADAM19 hypermethylation was associated with more stage IV GC. In plasma samples, MSC hypermethylation was more common in non-superficial type GC than samples without MSC hypermethylation. In both tissue and plasma samples, patients with methylation of all the three genes had significantly more liver metastases, distant lymphatic metastases, and paraaortic lymph node metastases than patients with two or fewer hypermethylated genes. The survival analysis showed that only for stage III GC, patients with hypermethylation of two or three genes had a worse 5-year disease-free survival rate than those with hypermethylation of one or none of the three genes. Subgroup analysis showed that FLI1 hypermethylation in both tissue and plasma samples was associated with liver metastasis in MSI-/EBV- GC, and MSC hypermethylation in tissue samples was correlated with liver metastasis in MSI+ or EBV+ GC. Patients with FLI1 hypermethylation in plasma samples had a significantly worse 5-year disease-free survival rate than those without FLI1 hypermethylation in MSI-/EBV- GC. FLI1 hypermethylation was an independent prognostic factor affecting the overall survival and disease-free survival in both tissue and plasma samples. CONCLUSIONS: DNA methylation is a useful biomarker for predicting tumor recurrence patterns and GC patient survival.


Assuntos
Proteínas ADAM/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Proteína Proto-Oncogênica c-fli-1/genética , Neoplasias Gástricas/patologia , Proteínas ADAM/sangue , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/sangue , Neoplasias Gástricas/genética , Análise de Sobrevida
10.
Cell Rep ; 29(3): 603-616.e5, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618630

RESUMO

In higher vertebrates, cephalic neural crest cells (NCCs) form craniofacial skeleton by differentiating into chondrocytes and osteoblasts. A subpopulation of cephalic NCCs, cardiac NCCs (CNCCs), migrates to the heart. However, CNCCs mostly do not yield skeletogenic derivatives, and the molecular mechanisms of this fate restriction remain elusive. We identify a disintegrin and metalloprotease 19 (Adam19) as a position-specific fate regulator of NCCs. Adam19-depleted mice abnormally form NCC-derived cartilage in their hearts through the upregulation of Sox9 levels in CNCCs. Moreover, NCC-lineage-specific Sox9-overexpressing mice recapitulate CNCC chondrogenesis. In vitro experiments show that Adam19 mediates the cleavage of bone morphogenic protein (BMP) type I receptor Alk2 (Acvr1), whereas pharmacogenetic approaches reveal that Adam19 inhibits CNCC chondrogenesis by suppressing the BMP-Sox9 cascade, presumably through processing Alk2. These findings suggest a metalloprotease-dependent mechanism attenuating cellular responsiveness to BMP ligands, which is essential for both the positional restriction of NCC skeletogenesis and normal heart development.


Assuntos
Proteínas ADAM/metabolismo , Crista Neural/metabolismo , Transdução de Sinais , Proteínas ADAM/deficiência , Proteínas ADAM/genética , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Animais , Proteína Morfogenética Óssea 6/metabolismo , Cartilagem/crescimento & desenvolvimento , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular , Condrogênese , Embrião de Mamíferos/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Miocárdio/citologia , Miocárdio/metabolismo , Crista Neural/citologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Regulação para Cima
11.
Cell Commun Signal ; 17(1): 134, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640732

RESUMO

BACKGROUND: Osteoarthritis (OA) is one of the most prevalent joint disease, and there are still no effective therapeutic agents or clinical methods for the cure of this disease to date. The degradation of cartilage extracellular matrix (ECM) is a major cause of OA. METHOD: IL-1ß was used to induce chondrogenic degradation. Q-PCR and Western blotting were used to detect mRNA and protein level, respectively. ELISA was used to detect the secreted TNF-α and IL-6 level. Immunofluorescence was used to detect the protein level of Aggrecan, Collagen II and ki67. TUNEL and flow cytometry were used to examine cell apoptosis of chondrocytes. ChIP and luciferase assay were used to study molecular gene regulation. Osteoarthritic animal model and Safranin-O staining were used to determine the in vivo OA phenotype. RESULTS: The expression of ADAM8 was up-regulated in osteoarthritic chondrocytes. Knockdown of ADAM8 suppressed the OA phenotype in the in vitro OA cell model. ADAM8 regulated OA progression through the activation of EGFR/ERK/NF-κB signaling pathway. Inhibition of Notch signaling suppressed OA phenotype in the in vitro OA cell model. Notch signaling regulated the gene expression of ADAM8 directly via Hes1. Notch1-ADAM8 positive feedback loop promoted the progression of OA in vivo. CONCLUSION: Notch1-ADAM8 feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression.


Assuntos
Proteínas ADAM/metabolismo , Condrócitos/patologia , Progressão da Doença , Matriz Extracelular/metabolismo , Retroalimentação Fisiológica , Proteínas de Membrana/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Receptor Notch1/metabolismo , Proteínas ADAM/deficiência , Proteínas ADAM/genética , Animais , Linhagem Celular , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , NF-kappa B/metabolismo , Fenótipo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima
12.
Medicine (Baltimore) ; 98(42): e17327, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626088

RESUMO

To explore the association of a disintegrin and metalloprotease 33 (ADAM33) polymorphisms with childhood asthma susceptibility, we conducted this case-control study.In this case-control study, we selected 96 asthma children and 86 healthy children to conduct the genotyping of ADAM33 polymorphisms through polymerase chain reaction-direct sequencing (PCR-DS). Hardy-Weinberg equilibrium (HWE) status in the control group was detected adopting chi-square test. Frequency differences of genotypes, alleles, and haplotypes were compared by chi-square test between the case and control groups. Linkage disequilibrium (LD) between polymorphisms was checked using Haploview software. Association intensity of the polymorphisms with the disease risk was assessed by odds ratio (OR) and 95% confidence interval (95%CI).The frequency of rs678881 GA genotype was obviously higher in cases than in controls (P = .03) and the carriage of this genotype conferred higher risk of asthma among children than GG genotype (OR = 2.03, 95%CI = 1.05-3.91). However, neither rs2280089 nor rs2853209 polymorphism was significantly associated with the risk of childhood asthma. Strong LD was found among rs678881, rs2280089 and rs2853209, and haplotype GGT was distinctly associated with the risk of asthma in children (OR = 0.28, 95%CI = 0.13-0.57).ADAM33 rs678881 polymorphism is significantly correlated with increased susceptibility to asthma in Chinese Han children. Besides, haplotype GGT among the 3 polymorphisms was obviously associated with decreased risk of childhood asthma.


Assuntos
Proteínas ADAM/genética , Asma/genética , Alelos , Asma/sangue , Asma/etnologia , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Haplótipos , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
Hum Pathol ; 94: 92-97, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31493427

RESUMO

Conjunctival squamous cell carcinoma (cSCC) and its precursors are among the most frequent ocular surface neoplasms worldwide. Copy gain of 8p11.22 and ADAM3A overexpression have been recently identified in invasive cSCC. We sought to study copy number gains using fluorescent in situ hybridization (FISH) in cSCC and the spectrum of precursor lesions. A total of 54 cases conjunctival squamous intraepithelial neoplasia (CIN), carcinoma in situ (CIS), or cSCC were studied using FISH with an ADAM3A (8p11 locus) probe and a chromosome 8 (Chr 8) centromere reference probe. Eighty one percent (44/54) of the cases presented in men and 19% (10/54) in women. The age at presentation ranged from 12 to 94 years (mean 65.5 years). Severe CIN was diagnosed in 45% (24/54) of the cases, followed by CIS in 31% (17/54), moderate CIN in 15% (8/54), invasive cSCC in 7% (4/54), and mild CIN in 2% (1/54). Nine (of 54) (17%) cases harbored ADAM3A or Chr 8 gains, with one of these cases demonstrating high level amplification. All ADAM3A alterations were restricted to high-grade lesions, including 2/17 (12%) cCIS, 1/4 (24%) cSCC, 5/24 (20%) severe CIN and 1/8 (12%) moderate CIN. Monosomy 8 was detected in 2 (4%) cases. No ADAM3A alterations were detected in non-neoplastic controls. Gains of ADAM3A/chromosome 8 occur in a subset of cSCC and its precursors. Alterations were present in high-grade lesions, sparing non-neoplastic conjunctiva and absent in tested controls. Thus, the specificity of this alteration as a biomarker for ocular SCC deserves further study.


Assuntos
Proteínas ADAM/genética , Biomarcadores Tumorais/genética , Neoplasias da Túnica Conjuntiva/genética , Amplificação de Genes , Dosagem de Genes , Lesões Pré-Cancerosas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Lesões Intraepiteliais Escamosas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Neoplasias da Túnica Conjuntiva/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Lesões Pré-Cancerosas/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Lesões Intraepiteliais Escamosas/patologia , Adulto Jovem
14.
mBio ; 10(4)2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409686

RESUMO

Encephalomyocarditis virus (EMCV) is an animal pathogen and an important model organism, whose receptor requirements are poorly understood. Here, we employed a genome-wide haploid genetic screen to identify novel EMCV host factors. In addition to the previously described picornavirus receptors sialic acid and glycosaminoglycans, this screen unveiled important new host factors for EMCV. These factors include components of the fibroblast growth factor (FGF) signaling pathway, such as the potential receptors FGFR1 and ADAM9, a cell-surface metalloproteinase. By employing various knockout cells, we confirmed the importance of the identified host factors for EMCV infection. The largest reduction in infection efficiency was observed in cells lacking ADAM9. Pharmacological inhibition of the metalloproteinase activity of ADAM9 did not affect virus infection. Moreover, reconstitution of inactive ADAM9 in knockout cells restored susceptibility to EMCV, pointing to a proteinase-independent role of ADAM9 in mediating EMCV infection. Using neutralization assays with ADAM9-specific antiserum and soluble receptor proteins, we provided evidence for a role of ADAM9 in EMCV entry. Finally, binding assays showed that ADAM9 facilitates attachment of EMCV to the cell surface. Together, our findings reveal a role for ADAM9 as a novel receptor or cofactor for EMCV.IMPORTANCE EMCV is an animal pathogen that causes acute viral infections, usually myocarditis or encephalitis. It is thought to circulate mainly among rodents, from which it is occasionally transmitted to other animal species, including humans. EMCV causes fatal outbreaks of myocarditis and encephalitis in pig farms and zoos, making it an important veterinary pathogen. Although EMCV has been widely used as a model to study mechanisms of viral disease in mice, little is known about its entry mechanism. Here, we employ a haploid genetic screen for EMCV host factors and identify an essential role for ADAM9 in EMCV entry.


Assuntos
Proteínas ADAM/metabolismo , Infecções por Cardiovirus/virologia , Vírus da Encefalomiocardite/fisiologia , Proteínas de Membrana/metabolismo , Internalização do Vírus , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/genética , Animais , Infecções por Cardiovirus/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Vírus da Encefalomiocardite/metabolismo , Técnicas de Inativação de Genes , Genoma Humano/genética , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Ligação Viral , Replicação Viral
15.
Sci Rep ; 9(1): 11191, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371771

RESUMO

During vertebrate embryogenesis, the cranial neural crest (CNC) forms at the neural plate border and subsequently migrates and differentiates into many types of cells. The transcription factor Snai2, which is induced by canonical Wnt signaling to be expressed in the early CNC, is pivotal for CNC induction and migration in Xenopus. However, snai2 expression is silenced during CNC migration, and its roles at later developmental stages remain unclear. We generated a transgenic X. tropicalis line that expresses enhanced green fluorescent protein (eGFP) driven by the snai2 promoter/enhancer, and observed eGFP expression not only in the pre-migratory and migrating CNC, but also the differentiating CNC. This transgenic line can be used directly to detect deficiencies in CNC development at various stages, including subtle perturbation of CNC differentiation. In situ hybridization and immunohistochemistry confirm that Snai2 is re-expressed in the differentiating CNC. Using a separate transgenic Wnt reporter line, we show that canonical Wnt signaling is also active in the differentiating CNC. Blocking Wnt signaling shortly after CNC migration causes reduced snai2 expression and impaired differentiation of CNC-derived head cartilage structures. These results suggest that Wnt signaling is required for snai2 re-expression and CNC differentiation.


Assuntos
Encéfalo/embriologia , Crista Neural/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Wnt/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Animais , Animais Geneticamente Modificados , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas de Silenciamento de Genes , Genes Reporter/genética , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Imidas/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Crista Neural/citologia , Quinolinas/farmacologia , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/fisiologia , Proteínas de Xenopus/genética , Xenopus laevis/genética
16.
Sci Rep ; 9(1): 12540, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467400

RESUMO

A Disintegrin and Metalloproteinase-15 (ADAM15) is a transmembrane protein involved in protein ectodomain shedding, cell adhesion and signalling. We previously cloned and characterised alternatively spliced variants of ADAM15 that differ in their intracellular domains and demonstrated correlation of the expression of specific variants with breast cancer prognosis. In this study we have created isogenic cell panels (MDA-MB-231 and MCF-7) expressing five ADAM15 variants including wild-type and catalytically inactive forms. The expression of ADAM15 isoforms in MDA-MB-231 cells led to cell clustering to varying degree, without changes in EMT markers vimentin, slug and E-cadherin. Analysis of tight junction molecules revealed ADAM15 isoform specific, catalytic function dependent upregulation of Claudin-1. The expression of ADAM15A, and to a lesser degree of C and E isoforms led to an increase in Claudin-1 expression in MDA-MB-231 cells, while ADAM15B had no effect. In MCF-7 cells, ADAM15E was the principal variant inducing Claudin-1 expression. Sh-RNA mediated down-regulation of ADAM15 in ADAM15 over-expressing cells reduced Claudin-1 levels. Additionally, downregulation of endogenous ADAM15 expression in T47D cells by shRNA reduced endogenous Claudin-1 expression confirming a role for ADAM15 in regulating Claudin-1 expression. The PI3K/Akt/mTOR pathway was involved in regulating Claudin-1 expression downstream of ADAM15. Immunofluorescence analysis of MDA-MB-231 ADAM15A expressing cells showed Claudin-1 at cell-cell junctions, in the cytoplasm and nuclei. ADAM15 co-localised with Claudin-1 and ZO1 at cell-cell junctions. Immunoprecipitation analysis demonstrated complex formation between ADAM15 and ZO1/ZO2. These findings highlight the importance of ADAM15 Intra Cellular Domain-mediated interactions in regulating substrate selection and breast cancer cell phenotype.


Assuntos
Proteínas ADAM/metabolismo , Neoplasias da Mama/genética , Claudina-1/genética , Proteínas de Membrana/metabolismo , Proteínas ADAM/genética , Neoplasias da Mama/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Claudina-1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
17.
FASEB J ; 33(11): 11925-11940, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31381863

RESUMO

Meprin ß is a membrane-bound metalloprotease involved in extracellular matrix assembly and inflammatory processes in health and disease. A disintegrin and metalloproteinase (ADAM)10 and ADAM17 are physiologic relevant sheddases of inactive promeprin ß, which influences its substrate repertoire and subsequent biologic functions. Proteomic analysis also revealed several ADAMs as putative meprin ß substrates. Here, we demonstrate specific N-terminal processing of ADAM9, 10, and 17 by meprin ß and identify cleavage sites within their prodomains. Because ADAM prodomains can act as specific inhibitors, we postulate a role for meprin ß in the regulation of ADAM activities. Indeed, prodomain cleavage by meprin ß caused increased ADAM protease activities, as observed by peptide-based cleavage assays and demonstrated by increased ectodomain shedding activity. Direct interaction of meprin ß and ADAM proteases could be shown by immunofluorescence microscopy and immunoprecipitation experiments. As demonstrated by a bacterial activator of meprin ß and additional measurement of TNF-α shedding on bone marrow-derived macrophages, meprin ß/ADAM protease interactions likely influence inflammatory conditions. Thus, we identified a novel proteolytic pathway of meprin ß with ADAM proteases to control protease activities at the cell surface as part of the protease web.-Wichert, R., Scharfenberg, F., Colmorgen, C., Koudelka, T., Schwarz, J., Wetzel, S., Potempa, B., Potempa, J., Bartsch, J. W., Sagi, I., Tholey, A., Saftig, P., Rose-John, S., Becker-Pauly, C. Meprin ß induces activities of A disintegrin and metalloproteinases 9, 10, and 17 by specific prodomain cleavage.


Assuntos
Proteínas ADAM/metabolismo , Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Proteínas de Membrana/metabolismo , Metaloendopeptidases/metabolismo , Proteínas ADAM/química , Proteínas ADAM/genética , Proteína ADAM10/química , Proteína ADAM10/genética , Proteína ADAM17/química , Proteína ADAM17/genética , Animais , Membrana Celular/metabolismo , Células Cultivadas , Matriz Extracelular/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Camundongos Endogâmicos C57BL , Domínios Proteicos , Proteólise , Proteômica/métodos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
18.
Saudi Med J ; 40(8): 774-780, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423513

RESUMO

OBJECTIVES: To investigate the relationship of 3 single nucleotide polymorphism (SNP) variants of ADAM33 with asthma susceptibility in patients from Northern and Central Punjab, Punjab, Pakistan. Methods: In this case-control study, healthy and asthmatic participants were recruited between 2015 and 2017. The SNPs of ADAM33 gene, rs2280089, rs2280090, and rs2280091 were analyzed in 296 asthma patients and 343 healthy controls, as well as linkage disequilibrium and haplotype analysis. RESULTS: The non-significant differences were observed in allele and genotype frequencies of the SNPs in asthmatic and healthy persons even after population stratification based on age, caste, gender, family history, and environment. Although these SNPs were non-significant for disease susceptibility among children and adults, a fixed unique pattern of inheritance was nevertheless observed for the studied SNPs. Linkage disequilibrium analysis presented a very strong linkage between the SNP variants to predict their co-inheritance in study population. However, none of the haplotypes were found to be associated with asthma disease development. CONCLUSION: The studied SNPs of ADAM33 appeared to be non-significant for asthma susceptibility in  Northern and Central Punjabi population. The fixed allele combination inheritance pattern was a unique observation contrary to findings in other global populations.


Assuntos
Proteínas ADAM/genética , Asma/genética , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Paquistão , Polimorfismo de Nucleotídeo Único
19.
Arterioscler Thromb Vasc Biol ; 39(10): 2067-2081, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31366218

RESUMO

OBJECTIVE: Investigate the requirement of Aggrecan (Acan) cleavage during aortic wall development in a murine model with ADAMTS (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs) 5 deficiency and bicuspid aortic valves. APPROACH: Mice with altered extracellular matrix remodeling of proteoglycans will be examined for anomalies in ascending aortic wall development. Neo-epitope antibodies that recognize ADAMTS cleaved Acan fragments will be used to investigate the mechanistic requirement of Acan turnover, in aortic wall development. RESULTS: Adamts5-/-;Smad2+/- mice exhibited a high penetrance of aortic anomalies (n=17/17); Adamts5-/-;Smad2+/- mice with bicuspid aortic valves (7/17) showed a higher number of anomalies than Adamts5-/-;Smad2+/- mice with tricuspid aortic valves. Single mutant Adamts5-/- mice also displayed a high penetrance of aortic anomalies (n=19/19) compared with wild type (n=1/11). Aortic anomalies correlated with Acan accumulation that was apparent at the onset of elastogenesis in Adamts5-/- mice. Neo-epitope antibodies that recognize the initial amino acids in the Acan cleaved fragments neo-FREEE, neo-GLGS, and neo-SSELE were increased in the Adamts5-/- aortas compared with WT. Conversely, neo-TEGE, which recognizes highly digested Acan core fragments, was reduced in Adamts5-/- mice. However, mice containing a mutation in the TEGE373↓374ALGSV site, rendering it noncleavable, had low penetrance of aortic anomalies (n=2/4). Acan neo-DIPEN and neo-FFGVG fragments were observed in the aortic adventitia; Acan neo-FFGVG was increased abnormally in the medial layer and overlapped with smooth muscle cell loss in Adamts5-/- aortas. CONCLUSIONS: Disruption of ADAMTS5 Acan cleavage during development correlates with ascending aortic anomalies. These data indicate that the mechanism of ADAMTS5 Acan cleavage may be critical for normal aortic wall development.


Assuntos
Proteína ADAMTS5/genética , Agrecanas/genética , Aorta/anormalidades , Valva Aórtica/anormalidades , Regulação da Expressão Gênica no Desenvolvimento , Doenças das Valvas Cardíacas/patologia , Malformações Vasculares/genética , Proteínas ADAM/genética , Animais , Valva Aórtica/patologia , Biópsia por Agulha , Doenças das Valvas Cardíacas/genética , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Modelos Animais , Proteoglicanas/metabolismo , Sensibilidade e Especificidade , Proteína Smad2/metabolismo
20.
Anticancer Drugs ; 30(7): e0790, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31305294

RESUMO

ADAM8 is reported to promote extracellular matrix degradation to provide conditions for tumor metastasis. However, the underlying mechanism of ADAM8 in modulating chondrosarcoma (CHS) metastasis remains unclear. We used two human CHS cell lines SW1353 and HCS-2/8 to analyze the expression profiles of ADAM8 in CHS cells compared with the normal chondrocytes. An important proteolytic enzyme MMP-13 was detected as a marker for extracellular matrix degradation in chondrocytes. Then, by silencing or overexpressing ADAM8, the effects on cell migration and invasion in SW1353 and HCS-2/8, and the downstream signal transduction pathways were evaluated. ADAM8 and MMP-13 were highly expressed, and the NF-κB pathway was activated in SW1353 and HCS-2/8 cells. Silencing ADAM8 significantly reduced the ability of cell migration and invasion, and blocked the NF-κB signaling pathway through IκBα and p65 dephosphorylation, leading to reduced NF-κB transcription activity and decreased MMP-13 expression. ADAM8 overexpression promoted these processes, which, however, were reversed by an inhibitor Bay 11-7085. Our data showed a novel regulation mechanism for ADAM8 in promoting CHS migration and invasion by activating the NF-κB/MMP-13 signaling axis. Modulation of their levels may serve as potential targets in the treatment of CHS and even other cartilage diseases.


Assuntos
Proteínas ADAM/metabolismo , Neoplasias Ósseas/patologia , Movimento Celular , Condrossarcoma/patologia , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 13 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Proteínas ADAM/genética , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Proliferação de Células , Condrossarcoma/genética , Condrossarcoma/metabolismo , Humanos , Metaloproteinase 13 da Matriz/genética , Proteínas de Membrana/genética , NF-kappa B/genética , Invasividade Neoplásica , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...