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1.
Anticancer Res ; 40(2): 703-707, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014911

RESUMO

BACKGROUND/AIM: Few studies have examined the contribution of matrix metalloproteinases (MMP) to either diagnosis or prognosis of pterygium. The aim of this study was to investigate the contribution of MMP-1 genotypes to pterygium risk. PATIENTS AND METHODS: A total of 134 cases and 268 controls were included and their MMP-1 -1607 (rs1799705) genotypes were examined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for rs1799705 genotypes were 48.5, 36.6 and 14.9% among patients and 33.9, 44.8, and 21.3% among controls (p trend=0.0167). The odds ratios (ORs) after adjusting for age and gender for 1G/2G and 1G/1G genotypes at rs1799705 were 0.54 (95%CI=0.33-0.89, p=0.0168) and 0.46 (95%CI=0.27-0.88, p=0.0192), respectively. Consistently, the adjusted OR for those carrying the 1G allele at MMP-1 -1607 was 0.61 (95%CI=0.41-0.78, p=0.0167), compared with the wild-type 2G allele. CONCLUSION: The genotypes at rs1799705 play a role in determining personal susceptibility to pterygium.


Assuntos
Metaloproteinase 1 da Matriz/genética , Pterígio/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Pterígio/enzimologia , Pterígio/epidemiologia , Taiwan/epidemiologia
2.
DNA Cell Biol ; 39(2): 255-272, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31977248

RESUMO

Cervical squamous cell carcinoma (CESC) is a human papillomavirus-driven tumor that the underlying molecular mechanisms are unclear. This study aimed to elucidate the key candidate genes and potential mechanism in CESC by bioinformatics analysis. A total of 132 common differentially expressed genes (DEGs) were identified based on three expression profile data sets. A multivariate Cox proportional regression model was used to develop a four-gene prognostic signature. Mechanistically, the correlationship between MMP1 and tumor-infiltrating lymphocytes was further analyzed. Furthermore, annotations were investigated by Gene Ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, potential drugs for CESC treatment were predicted by Connectivity Map. We profiled four genes (EFNA1, ANLN, MMP1, and ZWINT) with significant prognostic values for CESC. Multiple public available data sets were used for mRNA expression and prognostic characterization. Subsequently, GO and KEGG pathway analyses showed DEGs were mainly enriched in cell cycle, immunity, and metabolic-related pathway. We then conducted an integrated analysis of MMP1, and the expression of MMP1 showed significantly inverse association with the amount of CD8+ T cells, CD4+ T cells, and macrophages infiltration. Our findings suggest the four-gene signature may be associated with prognosis. We further revealed that MMP1 may be a novel biomarker for immunotherapy, and prognostic judgment of patients with cervical cancer.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 1 da Matriz/genética , Neoplasias do Colo do Útero/genética , Carcinoma de Células Escamosas/diagnóstico , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/genética , Humanos , Prognóstico , Mapas de Interação de Proteínas/genética , Neoplasias do Colo do Útero/diagnóstico
3.
J Orthop Res ; 38(1): 150-159, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254408

RESUMO

Tendon cells, tenocytes, are constantly subjected to mechanical stress in vivo, which maintains a level of cellular tension. When a tendon is subjected to overloading, local rupture of collagen fibers are induced, which deprives tenocytes of mechanical stress, lowers their cellular tension level and upregulates their catabolism. In addition, leukocytes are attracted to the rupture sites and produce interleukin-1ß (IL-1ß), and this exogenous IL-1ß also stimulates tenocyte catabolism. We tested a hypothesis that catabolic tenocytes with low cellular tension at the rupture sites excessively respond to the exogenous IL-1ß and further upregulate matrix metalloproteinase 1 (MMP-1) gene expression. Tenocytes from rabbit Achilles tendon were cultured on the following substrates: glass or polydimethylsiloxane micropillar substrates with a height of 2, 4, or 8 µm. Following a 3-day IL-1ß stimulation at a concentration of 0, 1, 10, or 100 pM, the effects of IL-1ß stimulation on cell morphology and MMP-1 gene expression was analysed with fluorescent microscopy and fluorescence in situ hybridization, respectively. In addition, the effects of IL-1ß stimulation on cell membrane fluidity were examined. It was demonstrated that the cells on 8-µm-height micropillars exhibited a greater response than those on rigid substrates with flat (glass) and topologically the same surface (2-µm-height micropillars) to IL-1ß when supplied at the same concentration. Besides this, membrane fluidity was lower in the cells on micropillars. Therefore, it appears that cellular attachment to softer substrates lowers the cellular actin cortex tension, reducing the membrane fluidity and possibly elevating the sensitivity of IL-1 receptors to ligand binding. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:150-159, 2020.


Assuntos
Interleucina-1beta/farmacologia , Metaloproteinase 1 da Matriz/genética , Tenócitos/patologia , Animais , Células Cultivadas , Expressão Gênica , Hibridização in Situ Fluorescente , Masculino , Fluidez de Membrana , Coelhos , Estresse Mecânico , Tenócitos/efeitos dos fármacos , Tenócitos/enzimologia
4.
Yonsei Med J ; 61(1): 85-93, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31887804

RESUMO

PURPOSE: The aim of this study was to investigate the effect of FST gene on the inhibition of fibrosis in fibroblastic cells from scar tissue around repaired zone II flexor tendons. MATERIALS AND METHODS: Immunohistochemistry was conducted on fibroblast cells transfected with adenovirus-LacZ (Ad-LacZ) as a marker gene (control), or with adenovirus-FST (Ad-FST) as a therapeutic gene. Fibroblast cultures without adenoviral exposure served as controls. RESULTS: Fibroblastic cells transfected with Ad-FST demonstrated significant decrease in collagen type I, MMP-1, MMP2, and α-SMA mRNA expressions compared to those transfected with Ad-LacZ. In addition, fibroblastic cells transfected with Ad-FST exhibited significant decrease in MMP-1, TIMP-1, fibronectin, PAI-1, TRPV4, α-SMA, desmin, and PAX7 protein expressions. CONCLUSION: Based on these findings, we conclude that FST may be a novel therapeutic strategy for preventing scar adhesions around repaired tendons by inhibiting fibroblasts from differentiating into myofibroblasts, in addition to producing type I collagen and regulating extracellular matrix turnover via the downregulation of MMP-1 and TIMP-1. FST may also decrease contracture of the scar by inhibiting Ca2+-dependent cell contraction.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Cicatriz/metabolismo , Cicatriz/patologia , Colágeno Tipo I/biossíntese , Fibroblastos/metabolismo , Folistatina/metabolismo , Miofibroblastos/patologia , Traumatismos dos Tendões/patologia , Actinas/metabolismo , Animais , Células Cultivadas , Desmina/metabolismo , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Regulação da Expressão Gênica , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Tendões/patologia
5.
Arch Oral Biol ; 108: 104547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525531

RESUMO

OBJECTIVE: This study investigated the risk and prognostic value of single nucleotide polymorphisms (SNP) inIL-8, MMP-1 and MMP-13 in oral and oropharyngeal squamous cell carcinomas (SCCs). DESIGN: SNPs rs2227532 and rs4073 inIL-8, rs2071230 and rs470558 in MMP-1, and rs2252070 in MMP-13 were genotyped in 125 oral and oropharyngeal SCC patients and 130 healthy controls, using TaqMan allelic discrimination assays. Multiple logistic regression models were used to explore the association between SNPs and cancer development, as well as SNP-SNP interaction and gene-environmental factor (GxE) interaction. Univariate and multivariate methods were applied for survival analyses. RESULTS: With exception of rs2227532, all the SNPs were in Hardy-Weinberg equilibrium in the control. No associations between rs4073 in IL-8 and rs2071230 and rs470558 in MMP-1 were observed, but rs2252070 in MMP-13, in the dominant model, was associated in a protective manner to oral and oropharyngeal SCC (OR: 0.20, 95% CI: 0.06-0.71, p = 0.007). All SNPs interact significantly with cigarette smoking and alcohol consumption on susceptibility to oral and oropharyngeal SCC, but they showed no influence on survival of the patients. CONCLUSIONS: Our results show that rs2252070 inMMP-13 may confer protection effect against oral and oropharyngeal SCC. In addition, the combined effects of IL-8 (rs4073), MMP-1 (rs2071230 and rs470558) and MMP-13 (rs2252070) with environmental carcinogens, such as tobacco and alcohol, are related to increased risk for oral and oropharyngeal SCC development.


Assuntos
Carcinoma de Células Escamosas , Interleucina-8 , Metaloproteinase 13 da Matriz , Metaloproteinase 1 da Matriz , Neoplasias Bucais , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Humanos , Interleucina-8/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 13 da Matriz/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único , Prognóstico
6.
Chem Biodivers ; 16(12): e1900467, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556199

RESUMO

Pulmonary fibrosis (PF) is a chronic obstructive pulmonary disease without effective clinical drug treatment. Qing-Xuan Granule (QX) as a traditional Chinese patent medicine is clinically used to cure children's cough. This study was designed to investigate the effects of QX and possible molecular mechanisms for bleomycin-induced PF. The work used Western blotting and Q-PCR to explore the vitro and vivo mechanisms of QX treatment, while using HPLC-TOF/MS to explore the composition of QX. QX was given daily orally for two weeks after bleomycin intratracheal instillation. The protective effects of QX on lung function, inflammation, growth factors, hydroxyproline content and deposition of extracellular matrix were investigated. QX decreased expression of Col I and α-SMA in lung tissues by down-regulating TGF-ß1-Smad2/3 signaling and suppressed epithelial-mesenchymal transition and effectively reversed abnormal mRNA levels of MMP-1and TIMP-1 as well as LOXL-2 in lung tissues. HPLC-TOF/MS indicate that six substances could be the main active components, which were reported to protect against experimental lung disease.


Assuntos
Substâncias Protetoras/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Bleomicina/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
7.
BMC Med Genet ; 20(1): 149, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477042

RESUMO

BACKGROUND: Rotator cuff disease is a widespread musculoskeletal pathology and a major cause of shoulder pain. Studies on familial predisposition suggest that genetic plays a role in the pathogenesis of rotator cuff disease. Several genes are responsible for rotator cuff disease. The aim of this study was to perform a systematic review on genetic association between rotator cuff disease and genes variations. METHODS: A systematic review of the literature was performed, in accordance with the PRISMA guidelines. PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases were searched comprehensively using the keywords: "Rotator cuff", "Gene", "Genetic", "Predisposition", "Single-nucleotide polymorphism" and "Genome-wide association". RESULTS: 8 studies investigating genes variations associated with rotator cuff tears were included in this review. 6 studies were case-control studies on candidate genes and 2 studies were GWASs. A significant association between SNPs and rotator cuff disease was found for DEFB1, FGFR1, FGFR3, ESRRB, FGF10, MMP-1, TNC, FCRL3, SASH1, SAP30BP, rs71404070 located next to cadherin8. Contradictory results were reported for MMP-3. CONCLUSION: Further investigations are warranted to identify complete genetic profiles of rotator cuff disease and to clarify the complex interaction between genes, encoded proteins and environment. This may lead to individualized strategies for prevention and treatment of rotator cuff disease. LEVEL OF EVIDENCE: Level IV, Systematic Review.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Lesões do Manguito Rotador/genética , Caderinas/genética , Bases de Dados Factuais , Fator 10 de Crescimento de Fibroblastos/genética , Humanos , Metaloproteinase 1 da Matriz/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores Estrogênicos/genética , Receptores Imunológicos/genética , Manguito Rotador , Tenascina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , beta-Defensinas/genética
8.
BMC Cancer ; 19(1): 784, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391080

RESUMO

BACKGROUND: Many patients diagnosed with oesophageal adenocarcinoma (OAC) present with advanced disease and approximately half present with metastatic disease. Patients with localised disease, who are managed with curative intent, frequently undergo neoadjuvant chemoradiotherapy. Unfortunately, ~ 70% of patients have little or no response to chemoradiotherapy. We previously identified miR-330-5p as being the most significantly downregulated microRNA in the pre-treatment OAC tumours of non-responders to treatment, but that loss of miR-330-5p had a limited impact on sensitivity to chemotherapy and radiation in vitro. Here, we further examined the impact of miR-330-5p loss on OAC biology. METHODS: miR-330-5p was suppressed in OE33 OAC cells following stable transfection of a vector-driven anti-sense RNA. Whole transcriptome digital RNA-Seq was employed to identify miR-330-5p regulated genes, and qPCR was used for validation. Protein expression was assessed by protein array, Western blotting and zymography. Invasive potential was measured using a transwell assay system. Tumour xenograft growth profile studies were performed in immunocompromised CD1 mice. RESULTS: In OE33 cells, suppression of miR-330-5p significantly altered expression of 42 genes, and several secreted proteases. MMP1 gene expression and protein secretion was significantly enhanced with miR-330-5p suppression. This corresponded to enhanced collagen invasion in vitro. In vivo, OE33-derived tumour xenografts with miR-330-5p suppression grew faster than controls. CONCLUSIONS: Loss of miR-330-5p expression in OAC tumours may influence tumour cell invasive capacity, tumour growth and therapeutic sensitivity via alterations to the tumour microenvironment.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Metaloproteinase 1 da Matriz/genética , MicroRNAs/genética , Fenótipo , Adenocarcinoma/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias Esofágicas/metabolismo , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Interferência de RNA , Transcriptoma , Microambiente Tumoral/genética
9.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383744

RESUMO

Reproductive tract pathology caused by Chlamydia trachomatis infection is an important global cause of human infertility. To better understand the mechanisms associated with Chlamydia-induced genital tract pathogenesis in humans, we used CRISPR genome editing to disrupt Toll-like receptor 3 (TLR3) function in the human oviduct epithelial (hOE) cell line OE-E6/E7 in order to investigate the possible role(s) of TLR3 signaling in the immune response to Chlamydia Disruption of TLR3 function in these cells significantly diminished the Chlamydia-induced synthesis of several inflammation biomarkers, including interferon beta (IFN-ß), interleukin-6 (IL-6), interleukin-6 receptor alpha (IL-6Rα), soluble interleukin-6 receptor beta (sIL-6Rß, or gp130), IL-8, IL-20, IL-26, IL-34, soluble tumor necrosis factor receptor 1 (sTNF-R1), tumor necrosis factor ligand superfamily member 13B (TNFSF13B), matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-3. In contrast, the Chlamydia-induced synthesis of CCL5, IL-29 (IFN-λ1), and IL-28A (IFN-λ2) was significantly increased in TLR3-deficient hOE cells compared to their wild-type counterparts. Our results indicate a role for TLR3 signaling in limiting the genital tract fibrosis, scarring, and chronic inflammation often associated with human chlamydial disease. Interestingly, we saw that Chlamydia infection induced the production of biomarkers associated with persistence, tumor metastasis, and autoimmunity, such as soluble CD163 (sCD163), chitinase-3-like protein 1, osteopontin, and pentraxin-3, in hOE cells; however, their expression levels were significantly dysregulated in TLR3-deficient hOE cells. Finally, we demonstrate using hOE cells that TLR3 deficiency resulted in an increased amount of chlamydial lipopolysaccharide (LPS) within Chlamydia inclusions, which is suggestive that TLR3 deficiency leads to enhanced chlamydial replication and possibly increased genital tract pathogenesis during human infection.


Assuntos
Chlamydia trachomatis/imunologia , Células Epiteliais/microbiologia , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/imunologia , Receptor 3 Toll-Like/imunologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Linhagem Celular Transformada , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Chlamydia trachomatis/crescimento & desenvolvimento , Chlamydia trachomatis/patogenicidade , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/imunologia , Células Epiteliais/imunologia , Tubas Uterinas/imunologia , Tubas Uterinas/microbiologia , Feminino , Deleção de Genes , Células HeLa , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/genética , Interleucinas/imunologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Transdução de Sinais , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética
10.
Anticancer Res ; 39(8): 4485-4490, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366549

RESUMO

BACKGROUND/AIM: Intraductal papillary mucinous neoplasm (IPMN) has a variety of histological and morphological appearances. Matrix metalloproteinases (MMPs) have been considered to be associated with tumor progression or poor prognosis. The aim of this study was to elucidate the molecular basis of IPMN variation in different types of lesions. MATERIALS AND METHODS: The expression of MMP-1,2,7,9 in 51 cases of IPMN were investigated. The MMP score was calculated as the sum of the score of staining distribution and the score of the intensity staining. RESULTS: MMP scores were correlated with histological grade, histological subtype, and type of invasion. MMP high expression groups (MMP score ≥5) had worse prognosis than low-expression groups. CONCLUSION: MMP expression varied between different types of IPMN, a result supporting differences in molecular basis of malignancies. These considerations may be helpful for optimal management or treatment according to various types of IPMN.


Assuntos
Metaloproteinase 1 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias Intraductais Pancreáticas/genética , Idoso , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Intraductais Pancreáticas/epidemiologia , Neoplasias Intraductais Pancreáticas/patologia
11.
Cell Physiol Biochem ; 53(1): 172-185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31264811

RESUMO

BACKGROUND/AIMS: MicroRNAs (miRs) are transcribed as stem-loop precursors harboring two different miRs on either side of the structure. Both miRs can modulate levels of cellular transcripts based on sequence complementarity between the miR and the mRNA target. The miR of the current study, miR-675, is encoded in the H19 gene with high expression in fetal/placental tissues but low levels in most adult tissues except for skeletal muscle and articular cartilage. miR-675 has a supportive role in expression of the major collagen component of articular cartilage (COL2A1) but it is unknown which arm contributes to this effect. Objectives: To determine the active arm of miR-675 in human articular chondrocytes. To evaluate effects of overexpression of both arms of miR-675 on MMP1 and MMP13, two enzymes involved in breakdown of COL2A1. To investigate whether abundance of both arms of miR-675 is dynamic. METHODS: miR-arm activity was determined by association with the AGO2 complex using immunoprecipitation with an AGO2 specific antibody. miR overexpression and inhibition was used to identify indirect downstream effects on two targets of the Matrix-Metalloprotease family, MMP1 and MMP13. Data was evaluated by qPCR and enzymatic activity assays. Early passage human articular chondrocytes (up to passage 2) obtained from cartilage from both healthy and osteoarthritis affected tissue were used. To evaluate miR-675 levels in a different model, myotube differentiation was employed. RESULTS: We show that both arms of miR-675 have opposing effects on MMP1 and MMP13; however only one arm, miR-675-3' is active in human articular chondrocytes. We demonstrate that during myotube differentiation, high expression of both arms of miR-675 is observed as well as an increase in expression of MMP1. CONCLUSION: We show that both arms of miR-675 result in opposing effects on two downstream molecules MMP1 and MMP13. We propose that miR abundance may arise as response to direct target transcript levels and are thus dynamic to meet the requirements of the cellular environment.


Assuntos
Condrócitos/metabolismo , Regulação da Expressão Gênica , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 1 da Matriz/genética , MicroRNAs/genética , Osteoartrite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/citologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Criança , Condrócitos/citologia , Condrócitos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/patologia , Regulação para Cima , Adulto Jovem
12.
Nutrients ; 11(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262076

RESUMO

Rice porridge containing Allium fistulosum (Welsh onion) root water extract (RAFR) has anti-inflammatory bioactive compounds. We examined whether the long-term administration of rice porridge with RAFR would prevent or delay the progression of osteoarthritis and menopausal symptoms in estrogen-deficient animals by ovariectomy. The rats consumed 40% fat energy diets containing 250 mg RAFR (rice: Allium fistulosum root = 13:1)/kg body weight (bw) (OVX-OA-RAFR-Low), 750 mg RAFR/kg bw (OVX-OA-RAFR-High) and 750 mg starch and protein/kg bw(OVX), respectively. After consuming the assigned diets for eight weeks, monoiodoacetate (OVX-OA) or saline (OVX) were injected into the knee joints of the rats for an additional three weeks. Sham rats were administered saline injections (normal-control). OVX-OA-RAFR improved oral glucose tolerance and also protected against decreases in bone mineral density and lean body mass in the legs and increases in fat mass in the abdomen, compared to the OVX and OVX-OA. OVX-OA-RAFR improved swelling and limping scores, normalized weight distribution between the osteoarthritic and normal limbs, and increased maximum running speeds compared to the OVX-OA. The OVX-OA deteriorated the articular cartilage by reducing the articular matrix and bone loss in the knee joint and it prevented knee joint deterioration when compared to the OVX. The improvement in osteoarthritis symptoms in OVX-OA-RAFR decreased the mRNA expression of matrix metallo-proteinase-1 and matrix metalloproteinase-13, tumor necrosis factor-α, and interleukin-1ß and interleukin-6 in the articular cartilage compared to OVX-OA rats. In conclusions, RAFR is effective in treating osteoarthritis symptoms and it may be used for a therapeutic agent in osteoarthritis-induced menopausal women.


Assuntos
Artrite Experimental/dietoterapia , Comportamento Animal , Glicemia/metabolismo , Densidade Óssea , Fêmur/fisiopatologia , Articulações/fisiopatologia , Cebolas , Oryza , Extratos Vegetais/farmacologia , Raízes de Plantas , Ração Animal , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Biomarcadores/sangue , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Ingestão de Energia , Feminino , Fêmur/metabolismo , Fêmur/patologia , Articulações/metabolismo , Articulações/patologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Atividade Motora , Valor Nutritivo , Ratos Sprague-Dawley , Fatores de Tempo
13.
Biomed Pharmacother ; 118: 109120, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302419

RESUMO

PROBLEM AND OBJECT: 5-fluorouracil (5-FU) is a pyrimidine-like antimetabolite. It has been widely used in human cancer therapies; however, the drug sensitivity can be very low and the survival outcome can be very poor dependent on tumor types and individual heterogeneity. This research was aimed to study the effects of matrix metalloproteinase 1 (MMP1) gene on nasopharyngeal carcinoma (NPC) cell proliferation, viability, invasiveness, apoptosis, and sensitivity to 5-FU. METHODS: Bioinformatics method was used to screen out the differentiated expressed genes in nasopharyngeal carcinomas compared with normal nasopharyngeal epithelial tissues. qRT-PCR was used to determine the expression of MMP1 mRNA, and western blot was used to determine the protein expression of MMP1, thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD). Colony foci formation assay, CCK8 assay, and BrdU incorporation assay were used to study the cell proliferation. Transwell invasion assay was carried out to determine cell invasion. Flow cytometry and caspase 3/7 activation assay were used to detect cell apoptosis. RESULTS: MMP1 gene was the most significantly upregulated gene in nasopharyngeal carcinomas according to the bioinformatics analysis. And the upregulation of MMP1 gene was confirmed in both NPC tissues and cell lines using RT-QPCR and western blot technique. When 5-FU was not a player, the forced overexpression of MMP1 gene led to enhanced growth and invasion of CNE1 and HNE1 cell lines, whereas MMP1 gene knockdown resulted in the opposite outcome. When 5-FU was added, MMP1 gene knockdown led to significantly suppressed cell proliferation and enhanced cell apoptosis. Also, MMP1 gene knockdown caused significantly lower level of TS and DPD enzymes. CONCLUSION: Not only the knockdown of MMP1 gene led to suppressed proliferation and invasion but also increased the sensitivity to 5-FU of CNE1 and HNE1 cells. Our results provided convincing evidence that MMP1 gene knockdown could offer a favorable sensitivity approach for NPC with 5-FU treatment.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Metaloproteinase 1 da Matriz/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Humanos , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/enzimologia , Regulação para Cima
14.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234539

RESUMO

Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and its underlying molecular mechanism. CAPE treatment suppressed UV-induced MMP-1 levels in both human dermal fibroblasts (HDF) and human skin tissues. While CAPE did not display any significant effects against the upstream regulatory pathways of MMP-1, CAPE was capable of reversing UV-mediated epigenetic modifications. CAPE suppressed UV-induced acetyl-histone H3 (Lys9) as well as total lysine acetylation in HDF cells. Similarly, CAPE also attenuated UV-induced lysine acetylations in human skin tissues, suggesting that the CAPE-mediated epigenetic alterations can be recapitulated in ex vivo conditions. CAPE was found to attenuate UV-induced histone acetyltransferase (HAT) activity in HDF. Notably, CAPE was able to directly inhibit the activity of several HATs including p300, CREP-binding protein (CBP), and p300/CBP-associated factor (PCAF), further confirming that CAPE can function as an epigenetic modulator. Thus, our study suggests that CAPE maybe a promising agent for the prevention of skin photoaging via targeting HATs.


Assuntos
Ácidos Cafeicos/farmacologia , Fibroblastos/enzimologia , Histona Acetiltransferases/antagonistas & inibidores , Metaloproteinase 1 da Matriz/genética , Álcool Feniletílico/análogos & derivados , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Humanos , Álcool Feniletílico/farmacologia , Pele/efeitos dos fármacos , Pele/enzimologia , Pele/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta
15.
Asian Pac J Cancer Prev ; 20(6): 1841-1847, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31244308

RESUMO

Objective: The association between matrix metalloproteinase1 (MMP1)-1607 1G>2G polymorphism and lung cancer risk is still inconclusive and inconsistent. We conducted a meta-analysis to estimate the potential relationship between MMP1-1607 1G>2G polymorphism and lung cancer risk. Methods: The comprehensive searches of the PubMed, Web of Science, Medline, CBM, CNKI, Weipu, and Wanfang databases, published up to Nov 10, 2018. Statistical analyses were performed with Review Manager 5.3 software. Results: A total of 14 relevant studies containing 6068 cases and 5860 controls were included in the study. The results indicated that MMP1-1607 1G>2G polymorphism was significantly associated with increased lung cancer risk under four models: 2G vs. 1G model (pooled OR = 1.19, 95% CI = 1.05-1.34, P < 0.0001); 2G/2G vs. 1G/1G (pooled OR = 1.34, 95% CI = 1.09-1.64, P = 0.003); 2G/2G vs. 1G/1G+1G/2G (pooled OR = 1.26, 95% CI = 1.06-1.49, P < 0.0001); 2G/2G+1G/2G vs. 1G/1G (pooled OR = 1.21, 95% CI = 1.05-1.40, P = 0.01). Subgroup analyses showed that there was a higher increase in smoking status under three models: 2G/2G vs. 1G/1G (pooled OR = 2.07, 95% CI = 1.14-3.77, P = 0.02); 2G/2G vs. 1G/1G+1G/2G (pooled OR = 1.71, 95% CI = 1.17-2.52, P = 0.006); 2G/2G+1G/2G vs. 1G/1G (pooled OR = 2.03, 95% CI = 1.14-3.62, P = 0.02). In addition, subgroup analyses by ethnicity further identified the significant association in Asians. Non-smoking population and ethnicity among Caucasian had no relationship with lung cancer susceptibility in four models. Conclusion: Our study suggested that MMP1-1607 1G>2G polymorphism was a risk factor for developing lung cancer risk.


Assuntos
Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metaloproteinase 1 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Humanos , Prognóstico , Fatores de Risco
16.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167359

RESUMO

Skullcapflavone II is a flavonoid derived from the root of Scutellaria baicalensis, a herbal medicine used for anti-inflammatory and anti-cancer therapies. We analyzed the effect of skullcapflavone II on the expression of matrix metalloproteinase-1 (MMP-1) and integrity of type I collagen in foreskin fibroblasts. Skullcapflavone II did not affect the secretion of type I collagen but reduced the secretion of MMP-1 in a dose- and time-dependent manner. Real-time reverse transcription-PCR and reporter gene assays showed that skullcapflavone II reduced MMP-1 expression at the transcriptional level. Skullcapflavone II inhibited the serum-induced activation of the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways required for MMP-1 transactivation. Skullcapflavone II also reduced tumor necrosis factor (TNF)-α-induced nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activation and subsequent MMP-1 expression. In three-dimensional culture of fibroblasts, skullcapflavone II down-regulated TNF-α-induced MMP-1 secretion and reduced breakdown of type I collagen. These results indicate that skullcapflavone II is a novel biomolecule that down-regulates MMP-1 expression in foreskin fibroblasts and therefore could be useful in therapies for maintaining the integrity of extracellular matrix.


Assuntos
Colágeno Tipo I/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Flavonoides/farmacologia , Metaloproteinase 1 da Matriz/genética , Transcrição Genética/efeitos dos fármacos , Biomarcadores , Células Cultivadas , Humanos , Metaloproteinase 1 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteólise/efeitos dos fármacos , Pele , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
J Biol Chem ; 294(26): 10266-10277, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31110047

RESUMO

The collagenase subfamily of matrix metalloproteinases (MMPs) have important roles in the remodeling of collagenous matrices. The proteinase-activated receptor (PAR) family has a unique mechanism of activation requiring proteolysis of an extracellular domain forming a neo-N terminus that acts as a tethered ligand, a process that has been associated with the development of arthritis. Canonical PAR2 activation typically occurs via a serine proteinase at Arg36-Ser37, but other proteinases can cleave PARs downstream of the tethered ligand and "disarm" the receptor. To identify additional cleavage sites within PAR2, we synthesized a 42-amino-acid peptide corresponding to the extracellular region. We observed that all three soluble MMP collagenases, MMP-1, MMP-8, and MMP-13, cleave PAR2 and discovered a novel cleavage site (Ser37-Leu38). Metalloproteinases from resorbing bovine nasal cartilage and recombinant human collagenases could cleave a quenched fluorescent peptide mimicking the canonical PAR2 activation region, and kinetic constants were determined. In PAR2-overexpressing SW1353 chondrocytes, we demonstrated that the activator peptide SLIGKV-NH2 induces rapid calcium flux, inflammatory gene expression (including MMP1 and MMP13), and the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 kinase. The corresponding MMP cleavage-derived peptide (LIGKVD-NH2) exhibited no canonical activation; however, we observed phosphorylation of ERK, providing evidence of biased agonism. Importantly, we demonstrated that preincubation with active MMP-1 reduced downstream PAR2 activation by a canonical activator, matriptase, but not SLIGKV-NH2 These results support a role for collagenases as proteinases capable of disarming PAR2, revealing a mechanism that suppresses PAR2-mediated inflammatory responses.


Assuntos
Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Receptor PAR-2/antagonistas & inibidores , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Condrossarcoma/genética , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 8 da Matriz/genética , Fragmentos de Peptídeos/metabolismo , Fosforilação , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
18.
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
19.
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
20.
J Gen Virol ; 100(6): 985-998, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31084699

RESUMO

Equine papillomavirus type 2 (EcPV2) was discovered only recently, but it is found consistently in the context of genital squamous cell carcinomas (SCCs). Since neither cell cultures nor animal models exist, the characterization of this potential disease agent relies on the analysis of patient materials. To analyse the host and viral transcriptome in EcPV2-affected horses, genital tissue samples were collected from horses with EcPV2-positive lesions as well as from healthy EcPV2-negative horses. It was determined by RNA-seq analysis that there were 1957 differentially expressed (DE) host genes between the SCC and control samples. These genes were most abundantly related to DNA replication, cell cycle, extracellular matrix (ECM)-receptor interaction and focal adhesion. By comparison to other cancer studies, MMP1 and IL8 appeared to be potential marker genes for the development of SCCs. Analysis of the viral reads revealed the transcriptional activity of EcPV2 in all SCC samples. While few reads mapped to the structural viral genes, the majority of reads mapped to the non-structural early (E) genes, in particular to E6, E7 and E2/E4. Within these reads a distinct pattern of splicing events, which are essential for the expression of different genes in PV infections, was observed. Additionally, in one sample the integration of EcPV2 DNA into the host genome was detected by DNA-seq and confirmed by PCR. In conclusion, while host MMP1 and IL8 expression and the presence of EcPV2 may be useful markers in genital SCCs, further research on EcPV2-related pathomechanisms may focus on cell cycle-related genes, the viral genes E6, E7 and E2/E4, and integration events.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Viral da Expressão Gênica/genética , Doenças dos Cavalos/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Processamento de RNA/genética , Transdução de Sinais/genética , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/virologia , DNA Viral/genética , Genes Virais/genética , Doenças dos Cavalos/virologia , Cavalos/genética , Cavalos/virologia , Interleucina-8/genética , Metaloproteinase 1 da Matriz/genética , Infecções por Papillomavirus/veterinária , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase/métodos , Transcrição Genética/genética
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