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1.
J Pediatr Ophthalmol Strabismus ; 56: e45-e48, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31282960

RESUMO

Ectopia lentis is displacement of the lens from its original position. It can be inherited or acquired with isolated or systemic findings. The authors describe a 4-year-old girl with isolated ectopia lentis et pupillae caused by pathogenic variants in the ADAMTSL4 gene and discuss the molecular genetic work-up of individuals with ectopia lentis. [J Pediatr Ophthalmol Strabismus. 2019;56:e45-e48.].


Assuntos
Proteínas ADAMTS/genética , Algoritmos , DNA/genética , Ectopia do Cristalino/genética , Cristalino/diagnóstico por imagem , Mutação , Distúrbios Pupilares/genética , Proteínas ADAMTS/metabolismo , Pré-Escolar , Análise Mutacional de DNA , Ectopia do Cristalino/diagnóstico , Ectopia do Cristalino/metabolismo , Feminino , Humanos , Linhagem , Distúrbios Pupilares/diagnóstico , Distúrbios Pupilares/metabolismo , Tomografia de Coerência Óptica
2.
Cell Physiol Biochem ; 52(5): 1003-1016, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977985

RESUMO

BACKGROUND/AIMS: The composition of the extracellular matrix (ECM) in the central nervous system (CNS) has several features that make it unique. For instance, it is remarkable for the presence of proteoglycans such as versican, brevican, and neurocan, some of which have been identified as substrates of different members of the ADAMTS family of secreted metalloproteases. Previous studies have associated ADAMTSs with the repair of the CNS, including recovery following degradation of glial scar tissue and the stimulation of axonal growth after brain injury. However, the involvement of ADAMTSs in diseases of the CNS is complex and not understood fully, and a current challenge is unraveling the precise roles of these metalloproteases in the brain. METHODS: ADAMTS12 and neurocan gene expression was examined by quantitative PCR. Western blot analysis was employed to detect ADAMTS12 and neurocan protein expression in cell lines, and immunostaining techniques were used to detect neurocan in mouse brain tissues. Neurocan cleavage using recombinant ADAMTS1, ADAMTS4, ADAMTS5, and ADAMTS12 metalloproteases was evaluated by western blotting. Cell adhesion and migration were assessed using uncoated culture dishes or dishes coated with Matrigel or ECM components. RESULTS: We identified neurocan as a novel component of brain ECM that can be cleaved by ADAMTS12. In addition, we showed that neurocan cleavage by ADAMTS12 altered the adhesive properties of the human neuroglioma H4 cell line. Moreover, immunohistochemical analysis of Adamts12-deficient mice revealed the significant accumulation of neurocan in the brain of neonatal mice. CONCLUSION: Overall, our results suggest that ADAMTS12 could be involved in the repair of the CNS through its ability to degrade neurocan. Moreover, it can be inferred that alterations in neurocan degradation processes could be associated with the pathogenesis of neurological disorders.


Assuntos
Proteínas ADAMTS/biossíntese , Proteínas ADAMTS/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Doenças dos Nervos Cranianos/metabolismo , Lectinas Tipo C/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteoglicanas/metabolismo , Proteólise , Proteínas ADAMTS/genética , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proteoglicanas de Sulfatos de Condroitina/genética , Doenças dos Nervos Cranianos/genética , Doenças dos Nervos Cranianos/patologia , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Proteoglicanas/genética
3.
Biol Pharm Bull ; 42(3): 354-356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828067

RESUMO

Reelin is a secreted protein that antagonizes the deposition and toxicity of amyloid ß peptide (Aß). Therefore, augmentation of Reelin activity may ameliorate Alzheimer's disease (AD). We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS-3) cleaves and inactivates Reelin in the mouse brain. In the present study, we investigated the effect of reducing ADAMTS-3 on deposition of Aß by crossbreeding drug-inducible ADAMTS-3 conditional knock-out (cKO) mice with "next-generation" AD model mice. We found that reducing ADAMTS-3 inhibited deposition of Aß significantly in AppNL-F mice, which produce human wild-type Aß. On the other hand, reducing ADAMTS-3 had no effect in AppNL-G-F mice, which produce the Arctic mutant Aß (E22G) that forms protofibrils more efficiently than does wild-type Aß. Thus, the findings suggest that the administration of an inhibitor against ADAMTS-3 will prevent the progression of AD pathology caused by deposition of wild-type Aß.


Assuntos
Proteínas ADAMTS/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas ADAMTS/antagonistas & inibidores , Proteínas ADAMTS/genética , Doença de Alzheimer , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
4.
Int J Mol Med ; 43(5): 2241-2251, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896805

RESUMO

Osteoarthritis (OA) is the most common type of degenerative joint disease and secreted inflammatory molecules serve a pivotal role in it. Peimine has been reported to have anti­inflammatory activity. In order to investigate the potential therapeutic role of Peimine in OA, mouse articular chondrocytes were treated with IL­1ß and different doses of Peimine in vitro. The data revealed that Peimine not only suppressed IL­1ß­induced production of nitric oxide (NO) and prostaglandin E2, but also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase­2 (COX­2). In addition, Peimine inhibited the IL­1ß­induced mRNA expression of matrix metalloproteinase (MMP)­1, MMP­3, MMP­9, MMP­13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)­4 and ADAMTS­5. Furthermore, Peimine inhibited IL­1ß­induced activation of the mitogen­activated protein kinase (MAPK) pathway. The protective effect of Peimine on IL­1ß­treated chondrocytes was attenuated following activation of the MAPK pathway, as demonstrated by the increased expression levels of MMP­3, MMP­13, ADAMTS­5, iNOS and COX­2 compared with the Peimine group. The in vivo data suggested that Peimine limited the development of OA in the mouse model. In general, the data indicate that Peimine suppresses IL­1ß­induced inflammation in mouse chondrocytes by inhibiting the MAPK pathway, suggesting a promising therapeutic role for Peimine in the treatment of OA.


Assuntos
Cevanas/uso terapêutico , Condrócitos/enzimologia , Condrócitos/patologia , Regulação para Baixo , Inflamação/enzimologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas ADAMTS/metabolismo , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Sobrevivência Celular/efeitos dos fármacos , Cevanas/farmacologia , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inflamação/patologia , Interleucina-1beta , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/patologia
5.
Nat Commun ; 10(1): 953, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814516

RESUMO

Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis.


Assuntos
Proteínas ADAMTS/metabolismo , Proteína ADAMTS9/metabolismo , Cílios/metabolismo , Cílios/ultraestrutura , Proteínas ADAMTS/deficiência , Proteínas ADAMTS/genética , Proteína ADAMTS9/deficiência , Proteína ADAMTS9/genética , Animais , Linhagem Celular , Endocitose , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Modelos Biológicos , Mutação , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Proteólise , Transdução de Sinais , Versicanas/genética , Versicanas/metabolismo , Saco Vitelino/embriologia , Saco Vitelino/metabolismo
6.
Dis Markers ; 2019: 1802620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728876

RESUMO

Background: Researches on immunotherapy of glioblastoma multiforme (GBM, WHO grade IV) have increased exponentially in recent years. As a targeted therapy, a series of biomarkers have been identified in local tumor tissue, while circulating marker which could be detected in the body fluids is still lacking. ADAMTSL4, a secreted glycoprotein, was earlier found to play a critical role in a prognostic signature for primary GBM (pGBM). We aimed to investigate the role of ADAMTSL4 at transcriptome level and its relationship with clinical practice in pGBM. Methods: A cohort of 88 pGBM patients with RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) was analyzed, and 168 pGBM patients from TCGA were included as validation. Several bioinformatic methods and predictive tools were applied to investigate the ADAMTSL4-associated immune microenvironment status. Results: We found that ADAMTSL4 was enriched in GBM (WHO grade IV), especially for those with IDH1/2 wild-type and MGMT unmethylated groups. According to the TCGA classification scheme, ADAMTSL4 can act as a potential marker for subtypes with poorer prognosis. Bioinformatic analyses revealed that ADAMTSL4 was significantly correlated to the immune-related processes in GBM (WHO grade IV), especially representing the infiltration of immune cells and complicated tumor microenvironment. Clinically, high expression of ADAMTSL4 was an independent indicator for poor prognosis. Conclusion: The expression of ADAMTSL4 is closely related to the clinicopathologic characteristics of pGBM. Meanwhile, it may play a critical role in immune-related processes. As a secreted glycoprotein, ADAMTSL4 is a promising circulating biomarker for pGBM, deserving further investigations.


Assuntos
Proteínas ADAMTS/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas ADAMTS/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Encéfalo/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioblastoma/sangue , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade
8.
Biomed Pharmacother ; 106: 1169-1174, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119184

RESUMO

Osteoarthritis (OA) is a degenerative joint disease that is commonly accompanied by inflammation. Scoparone is a biologically active constituent isolated from Artemisia capillaris and possesses anti-inflammatory activity. However, the effect of scoparone on inflammatory response in OA has not been authenticated. The aim of this study was to evaluate the role of scoparone in OA in vitro. Our results showed that IL-1ß treatment significantly inhibited the cell viability of chondrocytes, whereas the inhibition effect was attenuated by scoparone in a dose-dependent manner. IL-1ß also efficiently induced the production of nitric oxide (NO), prostaglandin E2 (PGE2), MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in chondrocytes. However, scoparone dose-dependently suppressed the induction. In addition, scoparone repressed IL-1ß-induced the expression of iNOS and COX-2 in chondrocytes. Furthermore, the activation of the PI3K/Akt/NF-κB pathway induced by IL-1ß was diminished by scoparone treatment. Taken together, these findings indicated that scoparone inhibited the expression of inflammatory mediators in IL-1ß-induced chondrocytes via regulating the PI3K/Akt/NF-κB pathway. Thus, scoparone may be used as a new therapeutic agent for the treatment of OA.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Cumarínicos/farmacologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/farmacologia , NF-kappa B/metabolismo , Osteoartrite do Joelho/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas ADAMTS/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/enzimologia , Condrócitos/patologia , Relação Dose-Resposta a Droga , Humanos , Metaloproteinases da Matriz Secretadas/metabolismo , Pessoa de Meia-Idade , Osteoartrite do Joelho/enzimologia , Osteoartrite do Joelho/patologia , Fosforilação , Transdução de Sinais/efeitos dos fármacos
9.
Nat Commun ; 9(1): 1864, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29760442

RESUMO

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.


Assuntos
Córnea/metabolismo , Genoma Humano , Glaucoma de Ângulo Aberto/genética , Ceratocone/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Grupo com Ancestrais do Continente Asiático , Córnea/anormalidades , Córnea/patologia , Doenças da Córnea/etnologia , Doenças da Córnea/genética , Doenças da Córnea/metabolismo , Doenças da Córnea/patologia , Distrofias Hereditárias da Córnea/etnologia , Distrofias Hereditárias da Córnea/genética , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Decorina/genética , Decorina/metabolismo , Síndrome de Ehlers-Danlos/etnologia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/patologia , Grupo com Ancestrais do Continente Europeu , Oftalmopatias Hereditárias/etnologia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Fibrilina-1/genética , Fibrilina-1/metabolismo , Expressão Gênica , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/metabolismo , Glaucoma de Ângulo Aberto/patologia , Humanos , Ceratocone/etnologia , Ceratocone/metabolismo , Ceratocone/patologia , Síndrome de Loeys-Dietz/etnologia , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/metabolismo , Síndrome de Loeys-Dietz/patologia , Lumicana/genética , Lumicana/metabolismo , Síndrome de Marfan/etnologia , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Análise da Randomização Mendeliana , Miopia/etnologia , Miopia/genética , Miopia/metabolismo , Miopia/patologia
10.
Biomed Pharmacother ; 102: 1099-1104, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29710527

RESUMO

Excessive expression of matrix metalloproteinases (MMPs) induced by pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) has been associated with destruction of the articular cartilage matrix in chondrocytes from patients with osteoarthritis (OA). Among the MMPs, MMP-1, MMP-3 and MMP-13 participate in the degradation of type II collagen, the main component of the extracellular matrix in articular cartilage. Sodium butyrate is a bacterial metabolite used in the treatment of inflammatory diseases. However, the effects of sodium butyrate on the expression of MMPs and degradation of type II collagen has not been explored. In the current study, for the first time, we aimed to determine whether sodium butyrate influences IL-1ß-induced degradation of type II collagen in human chondrocytes in the articular cartilage matrix. Our results indicate that sodium butyrate significantly abrogated IL-1ß-induced up-regulation of MMP-1, MMP-3, and MMP-13 at both the gene and protein levels. In addition, treatment with sodium butyrate suppressed expression of the endogenous tissue inhibitors TIMP-1 and TIMP-2. Notably, sodium butyrate attenuated IL-1ß-induced degradation of type II collagen. Mechanistically, we found that sodium butyrate abolished the activation of NF-κB by inhibiting phosphorylation of IKK, IκBα, and NF-κB p65. Based on these observations, we conclude that butyrate may have potential as a therapeutic agent for OA.


Assuntos
Ácido Butírico/farmacologia , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Proteólise/efeitos dos fármacos , Proteínas ADAMTS/metabolismo , Células Cultivadas , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/enzimologia , Humanos , Interleucina-1beta/farmacologia , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Invest Ophthalmol Vis Sci ; 59(3): 1167-1177, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29625437

RESUMO

Purpose: Coloboma is a sight-threatening congenital eye disease caused by a failure in optic fissure (OF) closure. The aim of this study was to investigate the role of Adamts16, a metalloproteinase, in OF closure. Methods: RNA in situ hybridization was used to examine the expression of Adamts16 in developing mouse and zebrafish eyes. Morpholino knockdowns were performed to study adamts16 function during zebrafish eye development. Additionally, immunofluorescent staining, RNA in situ hybridization, bromodeoxyuridine (BrdU) labeling, TUNEL assays, and high-throughput sequencing were used to examine altered cellular and molecular events in adamts16-morphant optic cups (OCs). Results: Adamts16 is expressed at the edges of the closing OF in both mice and zebrafish eyes. Zebrafish adamts16 knockdown resulted in coloboma formation. In adamts16-morphant eyes, the basement membrane failed to disassemble at the closing OF edges, OC cells exhibited decreased proliferation and increased apoptosis, and fibroblast growth factor 8 (fgf8) was ectopically upregulated in the OC. Conclusions: adamts16 is required for proper OF closure in zebrafish eyes. adamts16 controls OF closure possibly through the combined functions of degrading the basement membrane at the closing OF edges, promoting cell proliferation and survival, and restricting fgf8 expression. Our study linked a metalloproteinase to OF closure, which may facilitate future etiologic studies on human coloboma cases.


Assuntos
Proteínas ADAMTS/fisiologia , Coloboma/embriologia , Disco Óptico/anormalidades , Disco Óptico/embriologia , Proteínas ADAMTS/metabolismo , Animais , Membrana Basal/patologia , Coloboma/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Disco Óptico/metabolismo , Peixe-Zebra
12.
Gene ; 659: 1-10, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29518549

RESUMO

ADAMTS3 is a member of procollagen N-proteinase subfamily of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family. It has an important function in the procollagen maturation process. The removal of N-peptidases is required for the accurate processing of fibrillar collagens. Otherwise, several disorders can occur that is related with the collagenous tissues. ADAMTS3 mainly maturates type II collagen molecule which is the main component of the bone and cartilage. There are several expression studies about ADAMTS3 gene however its transcriptional regulation has not been lightened up, yet. Here we first time cloned and functionally analyzed the promoter region of ADAMTS3 gene, approximately 1380 bp upstream of the transcription start site. Transient transfection experiments showed that all truncated promoter constructs are active and 171 bp fragment is sufficient to activate gene expression in both Saos-2 and MG63 cells. In silico analysis showed that ADAMTS3 has a TATA-less promoter and contains several SP1/GC box binding motifs and a CpG island. Therefore we mainly investigated the SP1 dependent regulation of ADAMTS3 promoter. SP1 downregulated ADAMTS3 transcriptional activity. As consistent with the transcriptional activity, mRNA, and protein expression levels were also decreased by SP1. On the other hand, functional binding of the SP1 on multiple regions of ADAMTS3 promoter was confirmed by EMSA studies. As ADAMTS3 is responsible for the collagen maturation and biosynthesis, further we investigated the effect of SP1 on type I-II and III collagen gene expressions. We point out that SP1 increased type II and III collagen expression and in contrast decreased type I collagen expression levels in Saos-2 cells. mRNA expression level was decreased for all collagen types in MG63 model. Decrease in the type II collagen expression was also demonstrated at the protein level by SP1. Collectively these results provide first findings for the SP1-related transcriptional regulation of ADAMTS3 and collagen genes in osteosarcoma cell lines.


Assuntos
Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Neoplasias Ósseas/genética , Osteossarcoma/genética , Pró-Colágeno N-Endopeptidase/genética , Pró-Colágeno N-Endopeptidase/metabolismo , Fator de Transcrição Sp1/metabolismo , Proteínas ADAMTS/química , Sítios de Ligação , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Clonagem Molecular , Colágeno/genética , Simulação por Computador , Ilhas de CpG , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Osteossarcoma/metabolismo , Pró-Colágeno N-Endopeptidase/química , Regiões Promotoras Genéticas
13.
Exp Mol Pathol ; 104(2): 134-139, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29475036

RESUMO

BACKGROUND: A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) enzymes play important roles in cell functions including adhesion, invasion, migration, and proliferation. ADAMTS-6 is a member of the ADAMTS family; reports of its relationship with esophageal squamous cell carcinoma (ESCC) progression are rare. It is unclear whether ADAMTS-6 could be an independent ESCC biomarker. METHODS: ADAMTS-6 expression was detected by immunohistochemistry (IHC) in 171 paraffin-embedded ESCC specimens; relationships with patients' clinicopathological features and Twist-1 expression were analyzed by the Pearson Chi-square method, respectively. Overall survival (OS) and disease-free survival (DFS) were determined using the Kaplan-Meier method and compared using the long-rank test. RESULTS: ADAMTS-6 was expressed mainly in the cytoplasm and nucleus; the expression was significantly higher in tumor tissues. Increased expression of ADAMTS-6 correlated with clinical stage (P = 0.009), pT stage (P = 0.042), lymph node metastasis (P = 0.014) and recurrence (P = 0.033). There were no significant correlations between ADAMTS-6 expression and other clinicopathological parameters including age, sex, tumor size, distant metastasis, differentiation, …chemotherapy, radiotherapy, CD68 expression and epithelial mesenchymal transition (EMT) status. Kaplan-Meier survival curves revealed that upregulated expression of ADAMTS-6 indicated short OS (P = 0.001) and DFS (P = 0.002). Multivariate analysis confirmed that high ADAMTS-6 expression was an independent factor for ESCC prognosis. ADAMTS-6 expression was significantly correlated with Twist-1 expression in ESCC cancer cells (P = 0.007) and stromal cells (P < 0.001). Patients with ESCC revealing expression of both ADAMTS-6 and Twist-1 exhibited significantly reduced OS and DFS rates than other patients. CONCLUSIONS: High ADAMTS-6 expression is a useful marker of poor prognosis in patients with ESCC.


Assuntos
Proteínas ADAMTS/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Prognóstico , Proteína 1 Relacionada a Twist/metabolismo
14.
Int J Mol Sci ; 19(2)2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29393911

RESUMO

Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients.


Assuntos
Proteínas ADAMTS/genética , Regulação Neoplásica da Expressão Gênica , Metaloproteinases da Matriz/genética , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/genética , Inibidores Teciduais de Metaloproteinases/genética , Proteínas ADAMTS/metabolismo , Antineoplásicos/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Metaloproteinases da Matriz/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Transdução de Sinais , Análise de Sobrevida , Inibidores Teciduais de Metaloproteinases/metabolismo
15.
Biochem Biophys Res Commun ; 496(4): 1362-1368, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29421655

RESUMO

ADAMTS18 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) that are known for their crucial role in development, angiogenesis, inflammation and coagulation. It was previously reported that ADAMTS18 cleaved by thrombin induced platelet fragmentation, through which thrombus were dissolved. However, it remains unclear whether this represents a dominant physiologic mechanism controlling thrombus growth in vivo. Here, we used an established Adamts18 knockout (KO) mouse model to determine its function in thrombus formation. ADAMTS18 deficiency accelerated FeCl3-induced carotid artery thrombosis and aggravated postischemic cerebral infarction in mice. However, this accelerated thrombus phenotype in Adamts18 KO mice was not due to the lack of ADAMTS18-mediated-platelet fragmentation. Moreover, Adamts18 deficiency exerted little effects on mouse platelet functions. The underlying molecular mechanisms could be attributed in part to the abnormal vascular remodeling, including deficiency of carotid body (glomus) and aberrant carotid basal lamina. These results indicate a novel function of ADAMTS18 in vascular remodeling and associated thrombus formation.


Assuntos
Proteínas ADAMTS/metabolismo , Trombose das Artérias Carótidas/metabolismo , Infarto Cerebral/metabolismo , Trombose/metabolismo , Trombose/patologia , Proteínas ADAMTS/genética , Animais , Trombose das Artérias Carótidas/patologia , Infarto Cerebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Nucl Med Commun ; 39(2): 110-117, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29194287

RESUMO

OBJECTIVE: The aim of this study was to investigate the presence of ADAMTS2 and ADAMTS5 in the salivary gland (SG) of rats after high-dose radioiodine therapy. METHODS: A total of 36 male Wistar albino rats were used for this study. Thirty-six male rats were divided randomly into six groups: control and five radioactive iodine (RAI) treatment groups of six rats each. All animals were killed. The evaluation of biodistribution and histopathological studies were carried out on the SGs removed. Real-time PCR and immunohistochemical analysis were carried out to determine mRNA and protein expression levels of ADAMTS genes. Differences between the groups were evaluated statistically. RESULTS: In RAI-treated groups, ADAMTS2 and ADAMTS5 gene expression was observed to increase, whereas there was no mRNA or protein expression in the control group. There were statistically significant increases in the mRNA expression of ADAMTS2 (all RAI-administered groups in parathyroid gland and at 4, 24, and 48 h in submandibular gland) and ADAMTS5 (all RAI-administered groups, except on the 30th day in the parathyroid gland and all RAI groups in submandibular gland). Through immunohistochemical analysis, the staining pattern in the extracellular source was also observed in the overexpressed ADAMTS2 and ADAMTS5 groups. Nuclear coarsening and partial focal subnuclei vacuolization were determined in all RAI-administered groups with histopathological examinations. CONCLUSION: An increase in the mRNA expression levels of ADAMTS2 and ADAMTS5 genes was detected in the RAI-administered groups. These results suggested that ADAMTS2 and ADAMTS5 genes might play a role in radiation exposure and radioiodine-induced SG changes.


Assuntos
Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Radioisótopos do Iodo/uso terapêutico , Glândulas Salivares/metabolismo , Glândulas Salivares/efeitos da radiação , Animais , Radioisótopos do Iodo/farmacocinética , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Dosagem Radioterapêutica , Ratos , Distribuição Tecidual
17.
Gene ; 638: 26-35, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28943345

RESUMO

The present study was conducted to clarify the involvement of the basement membrane (BM) in insect metamorphosis through analysis of the expression profile of two types of metalloproteinase (MMP and ADAMTS) genes in several organs, their ecdysone involvement, and the histological change of BM. BM was observed around wing sac and in the wing cavity and around fat bodies at the W0 stage but disappeared after the W3 stage, and wing discs evaginated and fat body cells scattered after the W3 stage. The disappearance of the BM of midgut and silk glands was not observed after the W3 stage, but degenerated epithelium cells in the midgut and shrunken cells in the silk gland were observed after the W3 stage. BmMMP1 showed a peak at P0 in the wing discs, fat bodies, midgut, and silk gland. BmMMP2 showed a broad peak around pupation in the wing discs, fat bodies, midgut, and silk gland. BmADAMTS-1 showed enhanced expression at W2 in the wing discs, fat bodies, midgut, and hemocyte, while BmADAMTS-L showed enhanced expression at W3 in the fat bodies, midgut, silk gland, and hemocyte. After pupation, they showed a different expression in different organs. All of four genes were induced by 20-hydroxyecdysone in wing discs in vitro. The present results suggested the involvement of MMPs and ADAMTS in the BM digestion and the morphogenesis of organs during Bombyx metamorphosis.


Assuntos
Bombyx/crescimento & desenvolvimento , Bombyx/genética , Metaloproteinases da Matriz/genética , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Animais , Membrana Basal/metabolismo , Bombyx/enzimologia , Bombyx/metabolismo , Ecdisona/metabolismo , Larva/crescimento & desenvolvimento , Larva/metabolismo , Metamorfose Biológica , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
18.
Hypertens Pregnancy ; 37(1): 9-17, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29135310

RESUMO

The aim of this study is to compare ADAMTS (A Disintegrin and Metalloprotease Domains with Thrombospondins motifs) 1, 4, 12, and 13 levels in maternal and cord blood and placental tissue between preeclampsia and uncomplicated pregnancies. The enzyme-linked immunosorbent assay (ELISA) results showed that ADAMTS 1, 4, 12, and 13 levels in the maternal and cord blood were lower in the preeclampsia group than in the control group. Based on the immunohistochemistry (IHC) results, ADAMTS 1, 4, and 12 levels in placental tissues were higher in the preeclampsia group. According to the polymerase chain reaction (PCR) results, ADAMTS 1, 4, and 12 were higher, whereas ADAMTS 13 was lower in the preeclampsia group than in the control group.


Assuntos
Proteínas ADAMTS/metabolismo , Proteína ADAMTS1/metabolismo , Proteína ADAMTS13/metabolismo , Proteína ADAMTS4/metabolismo , Sangue Fetal/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Proteínas ADAMTS/sangue , Proteína ADAMTS1/sangue , Proteína ADAMTS13/sangue , Proteína ADAMTS4/sangue , Adulto , Feminino , Humanos , Pré-Eclâmpsia/sangue , Gravidez
19.
Nat Commun ; 8(1): 1632, 2017 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-29158497

RESUMO

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged ≤ 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 × 10-5) and rs10963755 (P meta = 3.91 × 10-4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP <0.2) and approaches genome-wide significance in multivariable analysis (P multivariable = 5.37 × 10-8). Expression quantitative trait analysis provides tentative evidence that rs715212 may influence AREG expression (P eQTL = 0.035), although further functional studies are needed to confirm this association and determine a mechanism.


Assuntos
Proteínas ADAMTS/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteínas da Matriz Extracelular/genética , Mutação em Linhagem Germinativa , Proteínas ADAMTS/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfirregulina/genética , Antineoplásicos/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Proteínas da Matriz Extracelular/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Resultado do Tratamento , Adulto Jovem
20.
Hum Mol Genet ; 26(21): 4095-4104, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28985353

RESUMO

Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features. We discovered bi-allelic missense mutations in ADAMTS3. Both were predicted to be highly damaging. These amino acid substitutions affect well-conserved residues in the prodomain and in the peptidase domain of ADAMTS3. In vitro, the mutant proteins were abnormally processed and sequestered within cells, which abolished proteolytic activation of pro-VEGFC. VEGFC processing is also affected by CCBE1 mutations that cause the Hennekam lymphangiectasia-lymphedema syndrome syndrome type1. Our data identifies ADAMTS3 as a novel gene that can be mutated in individuals affected by the Hennekam syndrome. These patients have distinctive facial features similar to those with mutations in CCBE1. Our results corroborate the recent in vitro and murine data that suggest a close functional interaction between ADAMTS3 and CCBE1 in triggering VEGFR3 signaling, a cornerstone for the differentiation and function of lymphatic endothelial cells.


Assuntos
Proteínas ADAMTS/deficiência , Proteínas ADAMTS/genética , Anormalidades Craniofaciais/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Pró-Colágeno N-Endopeptidase/deficiência , Pró-Colágeno N-Endopeptidase/genética , Proteínas ADAMTS/metabolismo , Adulto , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , Sequência Conservada , Anormalidades Craniofaciais/metabolismo , Células Endoteliais/metabolismo , Feminino , Células HEK293 , Humanos , Linfangiectasia Intestinal/metabolismo , Linfedema/metabolismo , Masculino , Mutação de Sentido Incorreto , Linhagem , Pró-Colágeno N-Endopeptidase/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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