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1.
Gene ; 730: 144320, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31887330

RESUMO

PURPOSE: The goal of this study is to evaluate the association between MMP-2, 3, TIMP-2, 3 polymorphisms and risk of colorectal cancer (CRC) in a Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNP) were genotyped in 505 CRC patients and 510 controls. The association between candidate SNPs and risk of CRC were evaluated using odds ratio (OR), 95% confidence interval (95% CI). RESULTS: The minor allele frequency of rs1053605 in cases was significantly lower than controls (p = 0.005). The CT genotype frequency of rs1053605 in cases was significantly lower than those in controls, while the frequencies of rs4789936-CT and rs715572-AG genotype of in cases were significantly higher than those in controls (p < 0.05). Genetic model analysis showed that rs522616 was associated with decreased risk of CRC under recessive model (p = 0.041); rs1053605 was correlated with decreased risk of CRC under dominant (p = 0.012) and additive (p = 0.009) models; rs4789936 also has association with decreased risk of CRC under recessive model (p = 0.021); while rs715572 was associated with increased risk of CRC under dominant (p = 0.007) and additive (p = 0.011) models. CONCLUSION: Our results shed new light on association between MMP and TIMP polymorphisms and CRC risk.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Colorretais/genética , Alelos , Estudos de Casos e Controles , Neoplasias do Colo/genética , Grupos Étnicos/genética , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/genética
2.
Food Funct ; 10(9): 6121-6134, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497829

RESUMO

Collagen hydrolysate has been widely used as a nutraceutical agent against skin aging and has gained increasing attention. Previous research has suggested that oral administration of antioxidant collagen peptides (ACPs) exerted beneficial effects on the photoaging skin structure and collagen. However, the bioactive components in ACP metabolites that are responsible for the repair effects have not been elucidated. In this study, serum containing collagen peptides (CPS) after oral administration and collagen peptides isolated from serum metabolites (SCP) were collected and their effects on cell proliferation, hyaluronic acid secretion and the collagen synthesis pathway in UVA-induced skin fibroblasts (ESF) were evaluated. Furthermore, hydroxyproline (Hyp)-containing collagen peptides from SCP were analyzed and their repair effects were examined. The repair effects of ACP metabolites in serum differed depending on the preparation method and SCP were the active components responsible for the repair effects. SCP displayed repair effects by activating the TGF-ß/Smad pathway to promote procollagen synthesis and suppressing AP-1, MMP-1 and MMP-3 protein expression to prevent collagen degradation, in which SHCP exhibited the strongest bioactivity. In addition, SCP showed repair effects by reactive oxygen species (ROS) scavenging activity and preserving the endogenous antioxidant defense systems. Furthermore, IO (Ile-Hyp) and AOG (Ala-Hyp-Gly) were identified as the active peptides promoting procollagen synthesis by activating the TGF-ß/Smad3 pathway. These results may be useful in screening of anti-photoaging factors in metabolites and producing highly efficient collagen peptide products.


Assuntos
Colágeno/química , Colágeno/metabolismo , Proteínas de Peixes/química , Peptídeos/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Carpas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Peptídeos/química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Raios Ultravioleta/efeitos adversos
3.
Artif Cells Nanomed Biotechnol ; 47(1): 3259-3264, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31368822

RESUMO

Impairment of type II collagen caused by MMPs in response to overproduction of IL-1ß is an important step in the pathological progression of osteoarthritis (OA). Lunasin, a well-known peptide present in the soybean, has displayed a positive impact on numerous physiological functions. Little information in the effects of lunasin on cartilage degradation has been sought in clinical research before. Here, we report that lunasin suppressed the increase in MMP-3 and MMP-13 caused by IL-1ß. In addition, we found that lunasin could prevent the decrease in TIMP-1 and TIMP-2 expressions caused by IL-1ß. Notably, lunasin suppressed reduction of type II collagen, the basis for articular cartilage. Lunasin also attenuated activation of the JAK2/STAT1/IRF-1 pathway. These effects of lunasin suggest that it might become a promising therapeutic agent for chondro-protective therapy.


Assuntos
Colágeno Tipo II/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Proteínas de Plantas/farmacologia , Cartilagem Articular/citologia , Proliferação de Células/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Interleucina-1beta/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
4.
Mol Biol Rep ; 46(5): 4699-4707, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31218540

RESUMO

Matrix metalloproteinases (MMPs) are implicated in atherosclerosis evolution into a coronary artery disease (CAD). They could be used as biomarkers for a predictive approach when they are studied simultaneously. We aim in our study to demonstrate prospectively in patients with history of CAD that MMPs level is linked to clinical cardiovascular outcomes. Two hundred and eighteen patients diagnosed with CAD were followed prospectively for 5 years in the Cardiology Department of la Rabta Hospital University. Clinical cardiovascular outcomes during the period of the cohort were recorded. Measures were performed for biological and matrix markers at baseline. MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2 were measured by ELISA in Sandwich assay. Fifty-nine cardiovascular outcomes occurred during the cohort period. By multivariate analysis, only MMP-3 persisted as a predictor for cardiovascular events even after adjustment. This metalloproteinase have been shown to be an independent predictor for cardiovascular outcomes (HR = 3.01; CI (1.3-6.95). The found cut-off value by receiver operating curve (ROC) was used for Kaplan-Meier analysis and revealed that patients with MMP-3 level higher than 9.3 ng/mL had a lower survival rate (p = 0.03). MMP-3 baseline level in patients with history of CAD is a potential predictor for cardiovascular outcomes.


Assuntos
Biomarcadores , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/mortalidade , Metaloproteinase 3 da Matriz/metabolismo , Adulto , Idoso , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaloproteinase 3 da Matriz/genética , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC
5.
J Sci Med Sport ; 22(10): 1074-1078, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31208828

RESUMO

OBJECTIVES: To systematically evaluate the effects of matrix metalloproteinase-3 (MMP3) and tissue inhibitor of metalloproteinase-2 (TIMP2) on chronic Achilles tendinopathy (AT) susceptibility. Chronic AT is one of the most prevalent and severe injuries in athletes. Early studies suggested that tendon extracellular matrix (ECM) may be involved in the pathogenesis of chronic AT. MMP3 is an important member of the MMP family and is important to ECM integrity. In addition, tissue inhibitor of metalloproteinase-2 (TIMP2) can indirectly limit the activity of MMP3 activity. DESIGN: Case-control genetic association study. METHODS: A total of 1084 chronic AT patients and 2188 controls with Chinese Han ancestry were recruited. Twenty-one SNPs, 4 mapped to MMP3 and 17 mapped to TIMP2, were selected and genotyped. Genetic association analyses and eQTL analyses were performed. In addition, we also examined the potential effects of epistasis using a case-only study design. RESULTS: Two SNPs, rs679620 (OR=0.82, P=0.0006, MMP3) and rs4789932 (OR=1.2, P=0.0002, TIMP2) were identified to be significantly associated with chronic AT risk. No significant results were obtained from epistasis analyses. SNP rs4789932 was identified to be strongly associated with the gene expression level of TIMP2 in two types of human tissues: atrial appendage (P=0.0003) and tibial artery (P=0.0009). CONCLUSIONS: We have identified genetic polymorphisms in MMP3 and TIMP2 to be significantly associated with chronic AT risk. Further eQTL analyses indicated that SNP rs4789932 of TIMP2 was related to the gene expression levels of TIMP2. These results suggest important roles for MMP3 and TIMP2 in the pathophysiology of chronic AT.


Assuntos
Tendão do Calcâneo/fisiopatologia , Metaloproteinase 3 da Matriz/genética , Tendinopatia/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
6.
Mol Med Rep ; 20(2): 915-930, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173206

RESUMO

Osteosarcoma is the most common type of malignant bone cancer, which often affects teenagers and young adults. The present study aimed to screen for critical genes and microRNAs (miRNAs/miRs) involved in osteosarcoma. A total of four microarray datasets (accession numbers GSE32981, GSE21257, GSE14827 and GSE14359) were downloaded from the Gene Expression Omnibus database. Following data preprocessing, module analysis was performed to identify the stable modules using the weighted gene co­expression network analysis (WGCNA) package. The differentially expressed genes (DEGs) between metastatic samples and non­metastatic samples were screened, followed by gene co­expression network construction, and Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Subsequently, prognosis­associated genes were screened and a miRNA­target gene regulatory network was constructed. Finally, the data for critical genes were validated. WGCNA analysis identified six modules; blue and yellow modules were significantly positively associated with osteosarcoma metastasis. A total of 1,613 DEGs were screened between primary tissue samples and metastatic samples. Following comparison of the genes in the two (blue and yellow) modules, a total of 166 DEGs were identified (metastatic samples vs. non­metastatic samples). Functional enrichment analysis demonstrated that these DEGs were mainly involved in 'defense response', 'p53 signaling pathway' and 'lysosome'. By utilizing the clinical information in GSE21257, 10 critical genes associated with osteosarcoma prognosis were obtained, including CTP synthase 2 (CTPS2), tumor protein p53 inducible protein 3 (TP53I3) and solute carrier family 1 member 1 (SLC1A1). In addition, hsa­miR­422a and hsa­miR­194 were highlighted in the miRNA­target gene network. Finally, matrix metallopeptidase 3 (MMP3) and vascular endothelial growth factor B (VEGFB) were predicted as critical genes in osteosarcoma metastasis. CTPS2, TP53I3 and SLC1A1 may serve major roles in osteosarcoma development, and hsa­miR­422a, hsa­miR­194, MMP3 and VEGFB may be associated with osteosarcoma metastasis.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Carbono-Nitrogênio Ligases/genética , Carbono-Nitrogênio Ligases/metabolismo , Bases de Dados Genéticas , Transportador 3 de Aminoácido Excitatório/genética , Transportador 3 de Aminoácido Excitatório/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Metástase Neoplásica , Proteínas de Neoplasias/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Análise de Sobrevida , Fator B de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/metabolismo
7.
Appl Biochem Biotechnol ; 189(3): 729-744, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31111375

RESUMO

Vina-ginsenoside R7 (R7) has been exhibited to engage in multiple pharmacological activities, such as antioxidant and anti-inflammatory activities. However, no photoaging-related studies have been performed on R7. Research is being conducted with the aim of assessing whether treatment with R7 has a protective effect on UVB-induced photoaging skin. Our results show that UVB exposure directly reduces matrix metalloproteinase (MMP) secretion through R7 by restraining the AP-1/MAPK pathway and blocks extracellular matrix (ECM) expression degradation. In addition, R7 improves the expression of transforming growth factor beta 1 (TGF-ß1), and type I procollagen also facilitates the synthesis of collagen by the TGF-ß/Smad signal transduction pathway. Finally, R7 valid blocks nuclear factor-κB (NF-κB) activation and enhances antioxidative stress capacity through activated nuclear factor (erythroid derived 2)-like 2 (Nrf2). In particular, the application of R7 restrains pro-inflammatory cytokines (TNF-α, IL-6, iNOS), which trigger ECM, degrade enzyme production, and suppress vascular endothelial growth factor (VEGF) secretion. In conclusion, R7 may constitute a promising cosmetic ingredient that can protect against skin photodamage resulting from detrimental UVB irradiation.


Assuntos
Anti-Inflamatórios/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Ginsenosídeos/farmacologia , Proteínas Luminescentes/farmacologia , Pele/citologia , Raios Ultravioleta/efeitos adversos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Colágeno Tipo I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Humanos , Interleucina-6/metabolismo , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Espaço Intracelular/efeitos da radiação , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteólise/efeitos dos fármacos , Proteólise/efeitos da radiação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese
8.
Med Sci Monit ; 25: 3815-3824, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31116709

RESUMO

BACKGROUND Pelvic organ prolapse (POP) is due to age-related atrophy and the weakening of the tissues of the pelvic floor, with degradation of collagen and extracellular matrix (ECM) by metalloproteinases (MMPs). This study aimed to investigates the role of the age-related enzyme klotho, encoded by the KL gene, in cultured fibroblasts obtained from patients with POP and the levels of reactive oxygen species (ROS), interleukin-6 (IL-6), and MMPs. MATERIAL AND METHODS Pelvic floor fibroblasts were obtained from connective tissue from three patients with POP and three normal subjects. Cell proliferation and ROS production were measured using a cell counting kit-8 (CCK-8) assay and flow cytometry. Levels of interleukin-6 (IL-6), klotho, metalloproteinase-1 (MMP-1), MMP-3, extracellular signal-regulated kinases 1/2 (ERK1/2), and p-ERK1/2 were measured by enzyme-linked immunoassay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. RESULTS In cultured pelvic floor fibroblasts from patients with POP, the expression of klotho protein and klotho mRNA were significantly down-regulated in fibroblasts from patients with POP compared with normal fibroblasts. Klotho supplementation in cultured fibroblasts for patients with POP included increased cell growth, reduced expression of ROS reduction, and reduced the secretion of IL-6. Using qRT-PCR and Western blot, klotho supplementation of fibroblasts from patients with POP increased cell growth and reduced the levels of IL-6 and ROS in a dose-dependent way. CONCLUSIONS Klotho protein reduced the expression of MMP-1 and MMP-3 in fibroblasts from patients with POP by down-regulating the phosphorylation of ERK1/2.


Assuntos
Glucuronidase/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Prolapso de Órgão Pélvico/metabolismo , Adulto , Idoso , Células Cultivadas , China , Colágeno/metabolismo , Regulação para Baixo , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Glucuronidase/genética , Humanos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Pessoa de Meia-Idade , Diafragma da Pelve , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
9.
J Orthop Res ; 37(9): 2043-2052, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31095777

RESUMO

Anterior cruciate ligament reconstructive surgery can restore biomechanical stability, however, such surgery cannot reliably prevent the onset of post-traumatic osteoarthritis. The aim of this study was to elucidate the molecular response that occurs within the menisci following a surgical injury that allows bleeding into the joint space, and then to investigate the effect of dexamethasone (DEX) on this molecular response. Cell viability studies following acute controlled exposure to blood and blood plus DEX were also conducted. Forty-eight New Zealand white rabbits were randomly allocated into control, sham, surgical, and surgical + DEX groups (each group n = 6). Animals were sacrificed at 48 h and 9 weeks, and menisci were harvested. The messenger RNA (mRNA) expression levels for key inflammatory, and degradative proteins, as well as mRNA levels for autophagy pathway molecules were quantified, and statistically significant changes were described. Meniscal cell viability was calculated by incubating groups of medial and lateral menisci in autologous blood, or autologous blood plus DEX for 48 h (each group n = 4; total of eight medial and eight lateral menisci), and then conducting a histological live/dead assay. Results indicated a significant reduction in only medial meniscal cell viability when the tissue was exposed to blood in combination with DEX. A single administration of DEX following surgery significantly suppresses the elevated molecular expression for key inflammatory and degradative markers within menisci at 48 h and 9 weeks post-surgery. In vitro, autologous blood did not affect cell viability, but addition of DEX uniquely impacted the medial menisci. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2043-2052, 2019.


Assuntos
Dexametasona/administração & dosagem , Hemartrose/metabolismo , Meniscos Tibiais/metabolismo , Animais , Autofagia , Sobrevivência Celular/efeitos dos fármacos , Feminino , Hemartrose/patologia , Injeções Intra-Articulares , Metaloproteinase 3 da Matriz/genética , Meniscos Tibiais/patologia , RNA Mensageiro/análise , Coelhos
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 645-648, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055827

RESUMO

OBJECTIVE: To assess the association of 5A/6A polymorphism in the promoter region of MMP3 gene with the stability of extracellular matrix of atherosclerotic plaque. METHODS: Clinical data of 776 consecutive patients undergoing percutaneous coronary intervention (PCI) was reviewed. MMP3 gene polymorphisms and serum level of MMP3 for the second admission were collected. The target gene fragment containing MMP3 promoter region was transfected into HepG2 vector cells. The influence of the polymorphism on the expression of the MMP3 gene was determined in vitro. RESULTS: Compared with the first admission data, the proportion of mutant MMP3 genotypes (5A/5A+5A/6A) was significantly higher in patients with acute myocardial infarction (AMI) compared with the control group (37.6% vs. 24.9%, P<0.01). 64.1% of the patients carrying the 5A allele had AMI, whereas only 50.11% of those carrying the 6A allele had AMI (P<0.01). The proportion of wild-type MMP3 genotype (6A/6A) was significantly higher in the stenotic group compared with the non-restenosis group (79.5% vs. 66.5%, P<0.01). Restenosis has occurred in 9.5% of patients harboring the 5A allele compared with 16.2% in those carrying the 6A allele (P<0.01). In addition, serum level of MMP3 in the restenosis group was significantly lower than that of the non-restenosis group (P<0.01). In vitro studies confirmed that the expression of pGL2-Basic/6A was significantly lower than that of pGL2-Basic/5A. CONCLUSION: The 5A/6A polymorphism in the promoter region of the MMP3 gene may influence its transcriptional activity and impact on the degradation or push-up of extracellular matrix, resulting in a difference in the stability of atherosclerosis plaques, which in turn may induce different pathological processes in AMI or restenosis after stenting.


Assuntos
Metaloproteinase 3 da Matriz/genética , Intervenção Coronária Percutânea , Placa Aterosclerótica , Regiões Promotoras Genéticas , Estudos de Casos e Controles , Matriz Extracelular , Predisposição Genética para Doença , Genótipo , Humanos , Placa Aterosclerótica/genética , Polimorfismo Genético
11.
J Biol Chem ; 294(24): 9476-9488, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31040180

RESUMO

Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs), enzymes that contribute to cancer and many inflammatory and degenerative diseases. The TIMP N-terminal domain binds and inhibits an MMP catalytic domain, but the role of the TIMP C-terminal domain in MMP inhibition is poorly understood. Here, we employed yeast surface display for directed evolution of full-length human TIMP-1 to develop MMP-3-targeting ultrabinders. By simultaneously incorporating diversity into both domains, we identified TIMP-1 variants that were up to 10-fold improved in binding MMP-3 compared with WT TIMP-1, with inhibition constants (Ki ) in the low picomolar range. Analysis of individual and paired mutations from the selected TIMP-1 variants revealed cooperative effects between distant residues located on the N- and C-terminal TIMP domains, positioned on opposite sides of the interaction interface with MMP-3. Crystal structures of MMP-3 complexes with TIMP-1 variants revealed conformational changes in TIMP-1 near the cooperative mutation sites. Affinity was strengthened by cinching of a reciprocal "tyrosine clasp" formed between the N-terminal domain of TIMP-1 and proximal MMP-3 interface and by changes in secondary structure within the TIMP-1 C-terminal domain that stabilize interdomain interactions and improve complementarity to MMP-3. Our protein engineering and structural studies provide critical insight into the cooperative function of TIMP domains and the significance of peripheral TIMP epitopes in MMP recognition. Our findings suggest new strategies to engineer TIMP proteins for therapeutic applications, and our directed evolution approach may also enable exploration of functional domain interactions in other protein systems.


Assuntos
Evolução Molecular Direcionada , Metaloproteinase 3 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Humanos , Metaloproteinase 3 da Matriz/química , Metaloproteinase 3 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/química , Mutação , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Inibidor Tecidual de Metaloproteinase-1/química , Inibidor Tecidual de Metaloproteinase-1/genética , Técnicas do Sistema de Duplo-Híbrido
12.
Drug Dev Res ; 80(5): 637-645, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31032997

RESUMO

Osteoarthritis (OA) is one of the most chronic degenerative arthritic diseases, which gradually results in chondrocyte changes, articular cartilage degeneration, subchondral bone sclerosis, joint pain, swelling, and dysfunction. Berberine (BBR) has various confirmed biological activities, such as anti-inflammatory and antioxidant activities. However, the effect of BBR on the production of inflammation-associated proteins, including inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, metalloproteinases (MMPs), Collagen II, TNF-α, and IL-6 via the MAPK (mitogen-activated protein kinases) pathway in IL-1ß-stimulated rat chondrocytes, has not yet been studied. Thus, the purpose of this study was to evaluate whether BBR would decrease the production of inflammation-associated proteins through the MAPK signal pathway. Rat chondrocytes were cultured and pretreated with BBR at different concentrations (0, 25, 50, and 100 µM) and then stimulated with or without IL-1ß (10 ng/mL). The mRNA expression of iNOS, COX-2, MMP-3, MMP-13, TNF-α, and IL-6 was measured by real-time polymerase chain reaction (RT-PCR), and the protein expression of iNOS, COX-2, Collagen II, MMP-3,MMP-13, and MAPKs were measured by Western blotting. The results showed that the expression of iNOS, COX-2, MMP-3, MMP-13, TNF-α, and IL-6 increased in the IL-1ß-treated group and BBR showed an ability to inhibit the elevated expression under the pretreatment. Furthermore, the IL-1ß-induced downregulation of Collagen II could be ameliorated by BBR. Moreover, the expression of MAPKs was significantly decreased by BBR. These results demonstrated that BBR had the anti-catabolic and anti-inflammation abilities that were through the MAPKs in IL-1ß-induced rat chondrocytes. These findings may provide a novel therapeutic choice for treatment of OA using BBR.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Condrócitos/citologia , Interleucina-1beta/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Interleucina-6/genética , Interleucina-6/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945680

RESUMO

Chronic periodontitis (CP) is the common form of inflammatory oral disease. Matrix metalloproteinases (MMPs) play a pivotal role in the progression of CP by degrading gingival tissue and its remodelling. Here, we conducted a case-control study to investigate a possible association of single-nucleotide polymorphism of MMP genes and their interaction with CP in the Indian population. A total of 357 DNA samples of venous blood was isolated, of which 157 were identified as CP patients and 200 were healthy individuals. Genotyping of six MMP genes (MMP1, MMP3, MMP7, MMP8, MMP12 and MMP13) was done using polymerase chain reaction following Sanger's method of sequencing. Statistical analyses were performed by SPSS v16.0, R package (SNPassoc). Gene-gene interactions were evaluated by MDR 3.0.2. The frequency of 6A allele of MMP3 -11715A-6A gene polymorphisms (36%) and G allele of MMP8 +17G-C gene polymorphisms (34%) were higher in the CP population compared with the healthy population (19% and 24%, respectively). A significant association of T allele of MMP8 -799C-T gene promoter polymorphism was found with CP (OR = 2.95, 95%CI = 2.16 - 4.04, P < 0.0001). Genotypic frequency of MMP12 -82A-G polymorphism is associated with CP risk while its allelic distribution is not (OR = 1.32, 95%CI = 0.93 - 1.88, P = 0.129). Gene-gene interactions show the best cross validation consistency model, i.e. MMP1 -519A-G X MMP7 -181A-G X MMP8 -799C-T polymorphismswith a value of 9/10. This gene-gene interaction shows that the significant association of MMP8 -799C-T polymorphism with CP increased susceptibility. Allelic distribution of MMP8+17G-C and MMP3-11715A-6A polymorphisms revealed their protective role towards decreased risk of CP. MMP1 -519A-G and MMP7 -181A-G polymorphisms show combinatorial synergistic effect on CP risk.


Assuntos
Periodontite Crônica/genética , Predisposição Genética para Doença , Metaloproteinases da Matriz/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Periodontite Crônica/epidemiologia , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Incidência , Índia/epidemiologia , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 8 da Matriz/genética , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
14.
Theriogenology ; 131: 123-132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959438

RESUMO

This study was designed to examine changes in target transcript abundance in endometrial explants exposed to pregnancy-associated glycoproteins (PAGs). Endometrial explants from pregnant and non-pregnant heifers collected on day18 (day 0: day of insemination) were incubated in the absence or presence of PAGs (15 µg/ml). The PAGs represented a mixture comprised of approximately equal amounts of bovine PAGs 4, 6, and 9. Samples were harvested for RNA extraction after 24 h or 96 h of incubation. Transcript abundance for target genes related to prostaglandin synthesis (PTGES), a chemokine (CXCL5) and tissue remodeling (EMMPRIN; MMPs 1, 2, 3, 7, 8, and 9; PLAU; SPP1; TIMP1 and TIMP2) were analyzed by quantitative PCR. Changes in relative transcript abundance for MMP1, MMP3, MMP7, PLAU, EMMPRIN and SPP1 were observed after PAG exposure in both non-pregnant and pregnant endometrium (P < 0.05). However, some of the transcripts associated with tissue remodeling were altered only at certain time points (either 24 h or 96 h). The transcript for bovine CXCL5 was increased in non-pregnant endometrium four- and six-fold at 24 h and 96 h of PAG exposure, respectively (P < 0.05); in pregnant endometrium, only the 24 h incubation period exhibited an elevation in CXCL5 (P < 0.05). In non-pregnant endometrium, both PTGES and MMP9 were elevated after exposure to PAGs for 24 h (P < 0.05) but not in the other samples. Some interferon-responsive transcripts (IFI6, ISG15) were found to be more abundant (P < 0.05) in pregnant endometrium after 96 h exposure to PAGs compared to endometrium that had not been exposed to the PAGs. Likewise, ISG15 message was elevated (P = 0.06) in non-pregnant endometrium after 24 h incubation with PAGs. These results indicate that the PAGs used in this experiment were able to induce changes in endometrial transcripts encoding for proteins associated with matrix remodeling as well as chemokine production and prostaglandin release.


Assuntos
Bovinos , Endométrio/metabolismo , Glicoproteínas/farmacologia , Animais , Basigina/genética , Basigina/metabolismo , Feminino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Gravidez , RNA Mensageiro/metabolismo
15.
Genet Test Mol Biomarkers ; 23(5): 304-309, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30969151

RESUMO

Aims: Metastasis is a significant obstacle to curing esophageal squamous cell carcinoma (ESCC). The CCAAT/enhancer binding protein ß (C/EBPß) and matrix metalloproteinase 3 (MMP3) are thought to play key roles in cancer invasion and metastasis. In this study, we aimed to detect whether C/EBPß-mediated tumor invasion was dependent on MMP3. In addition, we determined whether C/EBPß upregulation was associated with MMP3 levels and metastatic status in patients with ESCC. Materials and Methods: A total of 126 patients with ESCC were recruited for this study. The mRNA and protein levels of C/EBPß and MMP3 in ESCC cell lines and specimens from ESCC patient were determined by reverse transcription-polymerase chain reaction and western blot, respectively. Tumor cell invasion was analyzed using an in vitro Matrigel Invasion Assay. The correlation between C/EBPß and MMP3 expression was determined by Pearson's correlation analysis. Results: Both mRNA and protein levels of MMP3 were upregulated by C/EBPß overexpression and downregulated by C/EBPß siRNA in KYSE150 cell cultures. The promotion of ESCC cell invasion through C/EBPß was inhibited by MMP3 siRNA. The level of C/EBPß was correlated with MMP3 and metastatic status in patients with ESCC. Conclusions: C/EBPß upregulation promoted tumor cell invasion in an MMP3-dependent manner in vitro and was associated with metastatic status in ESCC.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Carcinoma de Células Escamosas do Esôfago/genética , Metaloproteinase 3 da Matriz/fisiologia , Idoso , Proteína beta Intensificadora de Ligação a CCAAT/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , China , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/fisiopatologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Regulação para Cima
16.
Int Immunopharmacol ; 71: 259-266, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30927736

RESUMO

BACKGROUND AND AIM: Taraxasterol, a pentacyclic-triterpene, has been reported to exert potent anti-inflammatory activity. However, the molecular mechanisms by which taraxasterol attenuates acute experimental colitis (AEC) remain undocumented. METHODS: A network pharmacology approach was used to identify the candidate and collective targets of taraxasterol and acute colitis, and an AEC model was established by oral administration of dextran sulfate sodium (DSS) in mice. Body weight and colon lengths were then examined, the pathological scoring was assessed by using hematoxylin and eosin staining, and the expression levels of target genes were further confirmed by qRT-PCR and immunohistochemistry (IHC) analysis in taraxasterol treated AEC models. RESULTS: 14 collective targets of taraxasterol and acute colitis were identified by a network pharmacology analysis, including PPARG, JAK2, MMP3, NR1I2 and PTPN11. Further investigations in an AEC model showed that, taraxasterol alleviated the unfavorable clinical symptoms and attenuated the intestinal inflammation response by reducing the cytokines TNF-α, IL-1ß and IL-6 levels. qRT-PCR and IHC analysis evidenced that, taraxasterol decreased MMP3 expression levels, but increased PPARG expression levels in AEC models as compared with the DSS group. CONCLUSIONS: Our findings demonstrated that taraxasterol improved DSS-induced AEC through regulating MMP3 and PPARG expression, providing a new insight into the potential therapeutic strategies for acute colitis.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Colo/patologia , Esteróis/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo , Mapas de Interação de Proteínas , Esteróis/uso terapêutico , Taraxacum/imunologia , Triterpenos/uso terapêutico
17.
Gene ; 698: 1-8, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30825594

RESUMO

Although articular cartilage degeneration in osteoarthritis represents a major public health problem, there is still no molecular approach to prevent this pathology by blocking specific molecules. We have previously applied genome-wide expression analyses with porcine samples to identify specific markers of either growth plate or articular cartilage. Since the molecular differences were also found in cultured chondrocytes derived from both sites, we utilized primary porcine articular chondrocytes (PPACs) for the present study and analyzed, if and how they respond to synoviocyte-derived molecules. PPACs were treated by conditioned medium from porcine synovial fibroblasts (SF-CM) for 2, 6 and 24 h. Gene expression was subsequently monitored by qRT-PCR and microarray analysis. We found that short-term administration of SF-CM to PPACs significantly reduced expression of chondrocyte markers, while it induced expression of SDC4, encoding syndecan-4, a positive regulator of articular cartilage breakdown. Consistently, expression of MMP3, a putative downstream effector of syndecan-4 was strongly induced by SF-CM in PPACs. We identified an MMP3-inducing fraction in the range of 40 kDa after gel filtration, and we confirmed our findings in three-dimensional PPAC cultures, where SF-CM also reduced the glycosaminoglycan content. Taken together, our data suggest that synovial fibroblasts secrete one or more molecule(s) that activate specific signaling events in articular chondrocytes. Identifying a responsible ligand receptor pair(s) might pave the way to develop molecular therapies to reduce the severity of osteoarthritis.


Assuntos
Condrócitos/metabolismo , Fibroblastos/metabolismo , Líquido Sinovial/metabolismo , Animais , Cartilagem Articular/metabolismo , Condrócitos/fisiologia , Fibroblastos/fisiologia , Expressão Gênica , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Lâmina de Crescimento , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite , Cultura Primária de Células , Suínos , Sindecana-4/genética , Sindecana-4/metabolismo , Membrana Sinovial
18.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1516-1524, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30876808

RESUMO

Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-α phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFRα activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFRα phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFRα-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFRα, indicating a direct interaction between cadherin-11 and PDGFRα extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFRα and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion.


Assuntos
Artrite Reumatoide/genética , Caderinas/genética , Fibroblastos/metabolismo , Osteoartrite/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transdução de Sinais/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Caderinas/metabolismo , Adesão Celular , Proliferação de Células , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Cultura Primária de Células , Ligação Proteica , Domínios Proteicos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
19.
J Sci Med Sport ; 22(7): 753-757, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30755371

RESUMO

OBJECTIVES: Anterior cruciate ligament rupture (ACLR) is a common and severe knee injury which typically occurs as a result of sports participation, primarily via a non-contact mechanism. A number of extrinsic and intrinsic risk factors, including genetics, have been identified thus far. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) play a crucial role in extracellular matrix remodeling of ligaments and therefore the genes encoding MMPs and TIMPs are plausible candidates for investigation with ACL rupture risk. DESIGN: A case-control genetic association study was conducted on 229 (158 male) individuals with surgically diagnosed primary ACLR, ruptured through non-contact mechanisms and 192 (107 male) apparently healthy participants (CON) without any history of ACLR. All participants were physically active, unrelated, self-reported Caucasians. METHODS: All participants were genotyped for four single nucleotide polymorphisms (SNP): MMP3 (rs591058C/T, rs679620 G/A), MMP8 (rs11225395C/T), and TIMP2 (rs4789932 G/A) using standard PCR assays. Gene-gene interactions were inferred. Single-locus association analysis was conducted using the Chi-square test. SNP-SNP interaction effects were analysed using multifactor dimensionality reduction (MDR) method. RESULTS: Genotype frequencies did not significantly differ between cases and controls, however, the MMP3 rs679620 G and rs591058C alleles were significantly overrepresented in cases compared to controls (p=0.021, OR=1.38, 95% CI: 1.05-1.81). CONCLUSIONS: These results support the hypothesis that genetic variation within MMP3 contributes to inter-individual susceptibility to non-contact ACLR. However, these results need to be explored further in larger, independent sample sets.


Assuntos
Lesões do Ligamento Cruzado Anterior/genética , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 8 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Inibidor Tecidual de Metaloproteinase-2/genética , Adulto , Traumatismos em Atletas/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Ruptura/genética
20.
J Neuroinflammation ; 16(1): 4, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616691

RESUMO

BACKGROUND: Microglia/macrophages (M/Ms) with multiple functions derived from distinct activation states are key surveillants maintaining brain homeostasis. However, their activation status and role during the brain metastasis of malignant tumors have been poorly characterized. METHODS: Heterozygous CX3CR1-GFP transgenic mice were used to visualize the dynamic changes of M/Ms during the development of experimental brain metastasis through long-term intravital imaging equipped with redesigned bilateral cranial windows. The occurrence of experimental brain metastasis was evaluated after M/Ms were depleted with PLX3397, a CSF-1R inhibitor. The possible mediators of M/Ms in facilitating the brain metastasis were determined using reverse transcription-PCR, immunofluorescence, correlational analysis, and MMP inhibition. RESULTS: Here, we showed that M/Ms were persistently activated and facilitated the formation of melanoma brain metastasis in vivo. We observed that M/Ms gradually and massively accumulated in the metastasis, with a 2.89-fold increase. To precisely depict the dynamic changes in the activation state of M/Ms, we defined the branching parameter to quantify their morphological alterations. The quantitative data showed that the extent of activation of M/Ms in metastatic foci was enhanced, with a 2.27-fold increase from day 1 to day 21. Along with the activation, the M/Ms increased their moving velocity (4.15-fold) and established a rapid, confined, and discontinuous motility behavior. The occurrence of melanoma brain metastasis was significantly hindered under M/M elimination, indicating the key role of M/Ms in the experimental brain metastasis. Interestingly, we found that M/Ms highly expressed matrix metalloproteinase 3 (MMP3), which were strongly correlated with M/M activation and the decrease of tight junction protein zonula occludens-1 (ZO-1). An MMP inhibitor moderately decreased the occurrence of melanoma brain metastasis, suggesting that MMP3 secreted by M/Ms may facilitate melanoma cell growth. CONCLUSIONS: Our results indicated that the activated M/Ms were essential in the development of melanoma brain metastasis, suggesting that M/Ms are a potential therapeutic target for tumor brain metastasis.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Encéfalo/diagnóstico por imagem , Regulação Neoplásica da Expressão Gênica/fisiologia , Macrófagos/patologia , Microglia/patologia , Aminopiridinas/administração & dosagem , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/secundário , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Lateralidade Funcional , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Microscopia Intravital/métodos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Pirróis/administração & dosagem , Fatores de Tempo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
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