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1.
Anticancer Res ; 41(7): 3309-3315, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230126

RESUMO

BACKGROUND/AIM: Matrix metalloproteinase 9 (MMP9) is highly expressed in gastric cancer but the role of MMP9 is unclear. This study aimed at revealing the association of MMP9 promoter rs3918242 genotypes with gastric cancer risk. MATERIALS AND METHODS: MMP9 rs3918242 genotypes of 121 patients with gastric cancer and 363 healthy individuals were examined by polymerase chain reaction-restriction fragment length polymorphism methodology using serum samples. RESULTS: MMP9 rs3918242 TT genotype carriers had an elevated gastric cancer risk compared to wild-type CC carriers (odds ratio=3.92, 95% confidence interval=1.28-11.99; p=0.0103). Patients with CT/TT genotypes were at higher risk of metastasis (p=0.0178) than those with CC. No correlation was found between MMP9 rs3918242 genotype and gastric cancer risk with smoking or alcohol behavior, nor Helicobacter pylori infection. No correlation was observed for MMP9 rs3918242 genotypic distributions with age, gender, or body mass index. CONCLUSION: Carrying a T allele for MMP9 rs3918242 may be predictive for higher gastric cancer risk, and as a predictor for higher risk of metastasis.


Assuntos
Predisposição Genética para Doença/genética , Metaloproteinase 9 da Matriz/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Feminino , Genótipo , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Fatores de Risco
2.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072419

RESUMO

Although endometriosis is a benign disease characterized by the presence of endometrial tissues outside the uterus, ectopic endometrial cells can exhibit malignant biological behaviors. Retinol-binding protein4 (RBP4) is a novel adipocyte-derived cytokine, which has important roles in regulating insulin sensitivity and energy metabolism. RBP4 is a potent modulator of gene transcription, and acts by directly controlling cell growth, invasiveness, proliferation and differentiation. Here, we evaluated the possible role of RBP4 in the pathogenesis of endometriosis. We compared the levels of RBP4 in the tissues and peritoneal fluid (PF) of women with and without endometriosis and evaluated the in vitro effects of RBP4 on the viability, invasiveness, and proliferation of endometrial stromal cells (ESCs). RBP4 levels were significantly higher in the PF of the women in the endometriosis group than in the controls. RBP4 immunoreactivity was significantly higher in the ovarian endometriomas of women with advanced stage endometriosis than those of controls. In vitro treatment with human recombinant-RBP4 significantly increased the viability, bromodeoxyuridine expression, and invasiveness of ESCs. Transfection with RBP4 siRNA significantly reduced ESC viability and invasiveness. These findings suggest that RBP4 partakes in the pathogenesis of endometriosis by increasing the viability, proliferation and invasion of endometrial cells.


Assuntos
Suscetibilidade a Doenças , Endometriose/etiologia , Endometriose/metabolismo , Ovário/patologia , Proteínas Plasmáticas de Ligação ao Retinol/genética , Biomarcadores , Sobrevivência Celular , Endometriose/patologia , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunofenotipagem , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes/farmacologia , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/farmacologia
3.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063608

RESUMO

Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-ß-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis.


Assuntos
Senescência Celular/genética , Fumar Cigarros/efeitos adversos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Lesão Pulmonar/genética , Doença Pulmonar Obstrutiva Crônica/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Senescência Celular/efeitos dos fármacos , Fumar Cigarros/genética , Fumar Cigarros/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibronectinas/genética , Regulação da Expressão Gênica/genética , Humanos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Serpina E2/genética
4.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064140

RESUMO

Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure; however, the effects of MMP-9 on perioperative AV fistula remodeling remain unknown. Therefore, we created AV fistulas (end-to-side anastomosis) in wild-type (WT) and MMP-9 knockout mice with chronic kidney disease to further clarify this. Neointima progressively developed in the AV fistula venous segment of WT mice during the four-week postoperative course, and MMP-9 knockout increased the lumen area and attenuated neointima size by reducing smooth muscle cell and collagen components. Early perioperative AV fistula mRNA sequencing data revealed that inflammation-related gene sets were negatively enriched in AV fistula of MMP-9 knockout mice compared to that in WT mice. qPCR results also showed that inflammatory genes, including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were downregulated. In addition, Western blot results showed that MMP-9 knockout reduced CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation. In vitro, MMP-9 addition enhanced IL-6 and MCP-1 expression in vascular smooth muscle cells, as well as cell migration, which was reversed by an MMP-9 inhibitor. In conclusion, MMP-9 knockout attenuated AV fistula stenosis by reducing perioperative vascular inflammation.


Assuntos
Fístula Arteriovenosa/genética , Inflamação/genética , Metaloproteinase 9 da Matriz/genética , Neointima/genética , Animais , Movimento Celular/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Período Perioperatório , Remodelação Vascular/genética
5.
Arkh Patol ; 83(3): 20-29, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34041892

RESUMO

Investigation of features of expression of matrix metalloproteinases (MMPs) is important for both understanding the mechanisms of the pathogenesis of periodontal diseases, and determining the nature of their course in order to choose a correct and timely treatment strategy. OBJECTIVE: To establish the value of MMPs for the diagnosis and determination of the nature of the course of periodontitis at the stage of disease manifestation, by morphometrically assessing the expression of MMPs in the gingival biopsy material. MATERIAL AND METHODS: Gingival biopsy specimens from 82 patients with rapidly progressing (n=26), chronic simple (n=18), and chronic complex (n=38) periodontitis were analyzed. Morphometric and statistical analysis of the expression of MMPs was carried out using Aperio ImageScope v. 12.4.0.5043, Statistica 10.0, and MedCalc (p<0.05). RESULTS: Analysis of the nature of MMP expression in the gingival biopsy material of patients with periodontal diseases showed that MMP2 and MMP13 were approximately equally involved in the development and course of all the studied forms of periodontitis. An increase in the expression of MMP1, MMP8, and MMP14 and a decrease in that of MMP9 are of the greatest importance in the pathogenesis of a rapidly progressing process. The performed ROC analysis confirmed the significance of the parameters of general and stromal expression of MMP1, MMP9, and MMP14, and mainly stromal expression of MMP8 for the differential diagnosis of rapidly progressing periodontitis with chronic forms, including chronic complex periodontitis. CONCLUSION: The expression indicators of MMR1, MMR8, MMR9, and MMR14 are most informative in determining the course of periodontitis at the stage of disease manifestation and differential diagnosis of rapidly progressing periodontitis with chronic simplex and complex periodontitis.


Assuntos
Periodontite Crônica , Metaloproteinase 2 da Matriz , Diagnóstico Diferencial , Gengiva , Humanos , Metaloproteinase 9 da Matriz/genética
6.
Res Vet Sci ; 137: 30-39, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33932820

RESUMO

The aim of this study was to characterize the protein expression of matrix metalloproteinase-2 (MMP-2) and -- 9 and their inhibitors (TIMP-1 and -2) in mammary tissue of dairy cows with naturally occurring chronic S. aureus intramammary infections (IMI) during active involution. Moreover, the gelatinolytic activity of MMP-2 and -9 in mammary secretions was evaluated. Cows in late lactation that were either uninfected or with chronic naturally acquired S. aureus IMI were included in this study. Protein expression of MMP-2 and -9 in mammary tissues was significantly higher in S. aureus-infected than uninfected quarters at day 14 and 21 of involution. Protein expression of TIMP-1 and -2 was significantly higher in S. aureus-infected than uninfected quarters at day 7, 14 and 21 of involution. The MMP-2/TIMP-1, MMP-2/TIMP-2, MMP-9/TIMP-1 and MMP-9/TIMP-2 ratios were significantly higher in S. aureus-infected compared with uninfected quarters at day 14 of involution. The MMP-2 activity was significantly higher in mammary secretions from S. aureus-infected compared with uninfected quarters at day 1, 2, 7 and 14 of involution. The MMP-9 activity was significantly higher in mammary secretions from infected quarters compared with uninfected quarters at day 7, 14 and 21 of involution. The increased expression of MMP-2 and -9 in mammary tissue as well as the high levels of activity observed in mammary secretion from infected quarters compared with uninfected quarters during active involution, strongly suggests that these gelatinases could contribute to degradation of mammary tissue components during chronic S. aureus IMI. The MMPs/TIMPs imbalance could lead to greater proteolysis and potentially more damage to mammary tissue in S. aureus-infected quarters.


Assuntos
Mastite Bovina/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Staphylococcus aureus , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Animais , Bovinos , Feminino , Regulação Enzimológica da Expressão Gênica , Lactação , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/microbiologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Infecções Estafilocócicas/veterinária , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-2/genética
7.
Biomed Res Int ; 2021: 5553486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997006

RESUMO

Introduction: Microribonucleic acids (miRNAs) have short (approximately 18 to 25) nucleotides and are evolutionarily conserved and endogenously expressed RNAs belonging to a family of noncoding RNA molecules. miRNA-373 regulates cell proliferation, migration, apoptosis, invasion, and repairing damaged DNA after hypoxia stress. Neonatal hypoxic-ischemic encephalopathy (HIE) refers to perinatal asphyxia caused by partial or complete hypoxia, reduced or suspended cerebral blood flow, and fetal or neonatal brain damage. We aim to investigate the relationship between miRNA-373 and HIF-1α, between miRNA-373 MMP-9, and between miRNA-373 VEGF in the occurrence and development of HIE. Methods: Human (children) samples were divided into four groups (n = 15 in each group) according to HIE severity. The patient group was divided into middle, moderate, and severe HIE groups. The control group included healthy children or children with nonneurological diseases. The expressions of miRNA-373, HIF-1α, MMP-9, and VEGF were assayed in the serum samples. Results: Our study showed a strong relationship between miRNA-373 and HIF-1α, between miRNA-373 and MMP-9, and between miRNA-373 and VEGF. The expression levels of miRNA-373, HIF-1α, MMP-9, and VEGF in the HIE groups were much higher than those of the control group. Conclusion: The increased change in miRNA-373 expression has a certain diagnostic significance on neonatal HIE. In the occurrence and development of HIE, miRNA-373 is positively correlated with HIF-1α, MMP-9, and VEGF.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia-Isquemia Encefálica , Doenças do Recém-Nascido , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Biologia Computacional , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/fisiopatologia , Recém-Nascido , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/metabolismo , Doenças do Recém-Nascido/fisiopatologia , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/genética , MicroRNAs/sangue , MicroRNAs/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
In Vivo ; 35(3): 1521-1528, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33910830

RESUMO

BACKGROUND/AIM: This study aimed to investigate the usefulness of in vivo bioluminescence imaging (BLI) to examine the role of matrix metalloproteinases (MMP)-2 and MMP-9 activation in the development and healing of ethanol-induced damage in the cornea of mice. MATERIALS AND METHODS: Mouse corneal injury was induced by topical treatment with 20% ethanol. BLI was obtained from the ocular region of mice intravenously injected with an active-MMP-2/9 probe. In vivo results were validated in primary corneal epithelial cells. RESULTS: BLI indicated that treatment of the eye with 20% ethanol elevated MMP-2/9 activity, which was inhibited by the application of eye drops (hyaluronic acid and serum). Treatment of corneal epithelial cells with 20% ethanol-increased the activities of MMP-2 and MMP-9, which were also inhibited by eye drops. CONCLUSION: BLI can be applied in vivo in mice with corneal injury to examine the activity of MMPs and clarify the efficacy of eye drops.


Assuntos
Etanol , Metaloproteinase 2 da Matriz , Animais , Córnea , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinases da Matriz , Camundongos
9.
Molecules ; 26(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926142

RESUMO

In this novel study, we isolated 28 compounds from the leaves of Aquilaria sinensis (Lour.) Gilg based on a bioassay-guided procedure and also discovered the possible matrix metalloprotease 2 (MMP-2) and 9 (MMP-9) modulatory effect of pheophorbide A (PA). To evaluate the regulatory activity on MMP-2 and MMP-9, the HT-1080 human fibrosarcoma cells were treated with various concentrations of extracted materials and isolated compounds. PA was extracted by methanol from the leaves of A. sinensis and separated from the fraction of the partitioned ethyl acetate layer. PA is believed to be an active component for MMP expression since it exhibited significant stimulation on MMP-2 and proMMP-9 activity. When treating with 50 µM of PA, the expression of MMP-2 and MMP-9 were increased 1.9-fold and 2.3-fold, respectively. PA also exhibited no cytotoxicity against HT-1080 cells when the cell viability was monitored. Furthermore, no significant MMP activity was observed when five PA analogues were evaluated. This study is the first to demonstrate that C-17 of PA is the deciding factor in determining the bioactivity of the compound. The MMP-2 and proMMP-9 modulatory activity of PA indicate its potential applications for reducing scar formation and comparative medical purposes.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Thymelaeaceae/química , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Compostos Fitoquímicos/química , Extratos Vegetais/química
10.
J Stroke Cerebrovasc Dis ; 30(6): 105760, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33845422

RESUMO

Dentin matrix protein 1 (DMP1) is an extracellular matrix phosphoprotein that is known to facilitate mineralization of collagen in bone and promote osteoblast/odontoblast differentiation. Blood-brain barrier (BBB) disruption is the major pathogenesis in secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to investigate the expression pattern of DMP1 in the mouse brain and explore the role of DMP1 in BBB disruption and brain injury in a mouse model of ICH. Mice were subjected to autologous blood injection-induced ICH. Immunofluorescence staining, western blot analysis, neurobehavioral tests, brain water content measurements, Evans blue permeability assay, and transmission electron microscopy were performed. Small interfering RNA targeting DMP1 (DMP1 siRNA) was administered at 72 h prior to ICH. Results showed that DMP1 is expressed extensively in the mouse brain, and is upregulated in the ICH model. Administration of DMP1 siRNA effectively ameliorated BBB disruption, attenuated brain edema, and improved neurological function after ICH. Moreover, the expression of zonula occludens-1 (ZO-1) and occludin were upregulated, and matrix metalloproteinase-9 (MMP-9) was downregulated in the ICH model. DMP1 siRNA administration reversed the expression of ZO-1, occludin, and MMP-9. These results demonstrated that DMP1 upregulation plays an essential role in inducing BBB disruption and brain injury after ICH. The inhibition of DMP1 could be a potential therapeutic strategy for ICH treatment.


Assuntos
Barreira Hematoencefálica/metabolismo , Edema Encefálico/prevenção & controle , Hemorragia Cerebral/terapia , Proteínas da Matriz Extracelular/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Animais , Barreira Hematoencefálica/ultraestrutura , Edema Encefálico/genética , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Ocludina/genética , Ocludina/metabolismo , RNA Interferente Pequeno/genética , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
11.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920274

RESUMO

The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC-MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl- transport in CF.


Assuntos
Aminofenóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Metaloproteinase 9 da Matriz/genética , Quinolonas/farmacologia , Citoesqueleto de Actina/genética , Adulto , Biomarcadores/sangue , Movimento Celular/efeitos dos fármacos , Fibrose Cística/sangue , Fibrose Cística/genética , Fibrose Cística/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Proteoma/genética
12.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805784

RESUMO

Hepatocellular carcinoma (HCC) frequently shows early invasion into blood vessels as well as intrahepatic metastasis. Innovations of novel small-molecule agents to block HCC invasion and subsequent metastasis are urgently needed. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, orchid Dendrobium loddigesii. Although moscatilin has been reported to suppress tumor angiogenesis and growth, the anti-metastatic property of moscatilin has not been elucidated. The present results revealed that moscatilin inhibited metastatic behavior of HCC cells without cytotoxic fashion in highly invasive human HCC cell lines. Furthermore, moscatilin significantly suppressed the activity of urokinase plasminogen activator (uPA), but not matrix metalloproteinase (MMP)-2 and MMP-9. Interestingly, moscatilin-suppressed uPA activity was through down-regulation the protein level of uPA, and did not impair the uPA receptor and uPA inhibitory molecule (PAI-1) expressions. Meanwhile, the mRNA expression of uPA was inhibited via moscatilin in a concentration-dependent manner. In addition, the expression of phosphorylated Akt, rather than ERK1/2, was inhibited by moscatilin treatment. The expression of phosphor-IκBα, and -p65, as well as κB-luciferase activity were also repressed after moscatilin treatment. Transfection of constitutively active Akt (Myr-Akt) obviously restored the moscatilin-inhibited the activation of NF-κB and uPA, and cancer invasion in HCC cells. Taken together, these results suggest that moscatilin impedes HCC invasion and uPA expression through the Akt/NF-κB signaling pathway. Moscatilin might serve as a potential anti-metastatic agent against the disease progression of human HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Compostos de Benzil/farmacologia , Movimento Celular/efeitos dos fármacos , NF-kappa B/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
13.
Anticancer Res ; 41(4): 1803-1810, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813385

RESUMO

BACKGROUND/AIM: Sinusoidal obstruction syndrome (SOS) after neoadjuvant chemotherapy with oxaliplatin for colorectal liver metastases (CRLM) has been reported to lead to early recurrence. This study investigated the effects of SOS on the development of CRLM in a rat model. MATERIALS AND METHODS: RCN-H4 cells were injected into the spleen or liver of ten monocrotaline-treated (SOS group) and ten untreated (control group) rats. The number and size of liver tumors were compared between the groups. RESULTS: The number of liver tumors in the splenic RCN-H4 injection model was significantly higher in the SOS group than in the control group (332±213 vs. 16±5, p=0.029); however, the largest tumor diameter in the hepatic model was similar between groups (6.2±1.8 vs. 6.4±2.4 mm, p=0.87). CONCLUSION: SOS promotes CRLM development by splenic RCN-H4 cell injection. This might be due to the higher incidence of cancer cell implantation into the liver.


Assuntos
Neoplasias Colorretais/patologia , Hepatopatia Veno-Oclusiva/complicações , Neoplasias Hepáticas/secundário , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Hepatopatia Veno-Oclusiva/induzido quimicamente , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Monocrotalina , Ratos Endogâmicos F344 , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Int J Nanomedicine ; 16: 1405-1422, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33658780

RESUMO

Aim: Iridoid glycosides (IG) as the major active fraction of Syringa oblata Lindl. has a proven anti-inflammatory effect for ulcerative colitis (UC). However, its current commercial formulations are hampered by low bioavailability and unable to reach inflamed colon. To overcome the limitation, dual functional IG-loaded nanoparticles (DFNPs) were prepared to increase the residence time of IG in colon. The protective mechanism of DFNPs on DSS-induced colonic injury was evaluated in rats. Materials and Methods: We prepared DFNPs using the oil-in-water emulsion method. PLGA was selected as sustained-release polymer, and ES100 and EL30D-55 as pH-responsive polymers. The morphology and size distribution of NPs were measured by SEM and DLS technique. To evaluate colon targeting of DFNPs, DiR, was encapsulated as a fluorescent probe into NPs. Fluorescent distribution of NPs were investigated. The therapeutic potential and in vivo transportation of NPs in gastrointestinal tract were evaluated in a colitis model. Results: SEM images and zeta data indicated the successful preparation of DFNPs. This formulation exhibited high loading capacity. Drug release results suggested DFNPs released less than 20% at the first 6 h in simulated gastric fluid (pH1.2) and simulated small intestine fluid (pH6.8). A high amount of 84.7% sustained release from NPs in simulated colonic fluid (pH7.4) was beyond 24 h. DiR-loaded NPs demonstrated a much higher colon accumulation, suggesting effective targeting due to functionalization with pH and time-dependent polymers. DFNPs could significantly ameliorate the colonic damage by reducing DAI, macroscopic score, histological damage and cell apoptosis. Our results also proved that the potent anti-inflammatory effect of DFNPs is contributed by decrease of NADPH, gene expression of COX-2 and MMP-9 and the production of TNF-α, IL-17, IL-23 and PGE2. Conclusion: We confirm that DFNPs exert protective effects through inhibiting the inflammatory response, which could be developed as a potential colon-targeted system.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Glicosídeos Iridoides/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ácidos Polimetacrílicos/química , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Liberação Controlada de Fármacos , Fluorescência , Concentração de Íons de Hidrogênio , Glicosídeos Iridoides/sangue , Glicosídeos Iridoides/farmacocinética , Glicosídeos Iridoides/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos ICR , NADPH Oxidases/metabolismo , Nanopartículas/ultraestrutura , Tamanho da Partícula , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos
15.
Oxid Med Cell Longev ; 2021: 8839479, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33747350

RESUMO

Black berry (Syzygium cumini) fruit is useful in curing diabetic complications; however, its role in diabetes-induced cardiomyopathy is not yet known. In this study, we investigated the regulation of gelatinase-B (MMP-9) by S. cumini methanol seed extract (MSE) in diabetic cardiomyopathy using real-time PCR, RT-PCR, immunocytochemistry, gel diffusion assay, and substrate zymography. The regulatory effects of MSE on NF-κB, TNF-α, and IL-6 were also examined. Identification and estimation of polyphenol constituents present in S. cumini extract were carried out using reverse-phase HPLC. Further, in silico docking studies of identified polyphenols with gelatinase-B were performed to elucidate molecular level interaction in the active site of gelatinase-B. Docking studies showed strong interaction of S. cumini polyphenols with gelatinase-B. Our findings indicate that MSE significantly suppresses gelatinase-B expression and activity in high-glucose- (HG-) stimulated cardiomyopathy. Further, HG-induced activation of NF-κB, TNF-α, and IL-6 was also remarkably reduced by MSE. Our results suggest that S. cumini MSE may be useful as an effective functional food and dietary supplement to regulate HG-induced cardiac stress through gelatinase.


Assuntos
Anti-Inflamatórios/farmacologia , Hiperglicemia/patologia , Metaloproteinase 9 da Matriz/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Sementes/química , Syzygium/química , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucose , Hiperglicemia/genética , Inflamação/patologia , Interleucina-6/metabolismo , Metaloproteinase 9 da Matriz/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos , Especificidade por Substrato/efeitos dos fármacos , Termodinâmica , Fator de Necrose Tumoral alfa/metabolismo
16.
Trends Hear ; 25: 23312165211002140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33787399

RESUMO

Genetic biomarkers of neuroplasticity in deaf children treated with cochlear implantation (CI) might facilitate their clinical management, especially giving them better chances of developing proficient spoken language. We investigated whether carrying certain variants of the genes encoding matrix metalloproteinase MMP9 and neurotrophin brain-derived neurotrophic factor (BDNF), involved in synaptic plasticity, can be taken as prognostic markers of how well auditory skills might be acquired. Association analysis of functional MMP9 rs3918242 and BDNF rs6265 variants and the child's auditory development measured at CI activation and 1, 5, 9, 14, and 24 months post CI activation with LittlEARS Questionnaire (LEAQ) was conducted in a group of 100 children diagnosed with DFNB1-related deafness, unilaterally implanted before the age of 2 years. Statistical analysis in the subgroup implanted after 1 year of life (n = 53) showed significant association between MMP9 rs3918242 and LEAQ scores at 1 month (p = .01), at 5 months (p = .01), at 9 months (p = .01), and at 24 months (p = .01) after CI activation. No significant associations in the subgroup implanted before 1 year of life were observed. No significant associations between the BDNF rs6265 and LEAQ score were found. Multiple regression analysis (R2 = .73) in the subgroup implanted after 1 year of life revealed that MMP9 rs3918242 was a significant predictor of treatment outcome. In conclusion, C/C rs3918242 MMP9 predisposes their deaf carriers to better CI outcomes, especially when implanted after the first birthday, than carriers of C/T rs3918242MMP9.


Assuntos
Implante Coclear , Implantes Cocleares , Surdez , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Pré-Escolar , Surdez/diagnóstico , Surdez/genética , Surdez/cirurgia , Humanos , Metaloproteinase 9 da Matriz/genética , Plasticidade Neuronal/genética , Estudos Retrospectivos
17.
J Int Med Res ; 49(3): 300060521997718, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33752504

RESUMO

OBJECTIVE: C-X-C motif chemokine ligand 5 (CXCL5), a member of the chemokine family, is associated with remodeling of connective tissues. However, its role in formation of intrauterine adhesions (IUA) remains unclear. We aimed to investigate the expression and mechanism underlying the role of CXCL5 in IUA. METHODS: Expression of CXCL5 in IUA was detected by immunohistochemistry in a rat model of IUA and by real-time PCR and western blotting in patients with IUA. The protein levels of matrix metalloproteinase 9 (MMP9) and transcription factor p65 in human endometrial cells were assessed by western blotting after CXCL5 overexpression. RESULTS: Protein expression of CXCL5 was significantly decreased in the endometria of IUA rats compared with that of control and sham-operated rats. Real-time PCR and western blotting in patients with IUA showed similar results to those from the rat model. After overexpression, CXCL5 significantly upregulated expression of MMP9 and slightly upregulated expression of p65 in human endometrial cells. CONCLUSIONS: CXCL5 plays an important role in IUA formation after endometrial injury. We propose a molecular mechanism to explain formation of IUA, including downregulation of MMP9 by low CXCL5 expression. These findings provide valuable information for the prevention and targeted therapy of IUA.


Assuntos
Doenças Uterinas , Animais , Quimiocina CXCL5/genética , Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Metaloproteinase 9 da Matriz/genética , Ratos , Aderências Teciduais/patologia , Doenças Uterinas/patologia
18.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760180

RESUMO

Nasopharyngeal carcinoma (NPC) is an epithelial carcinoma originating from the nasopharyngeal mucosal tissue and is highly prevalent in southeast Asia. Galectin­3 (gal­3) serves crucial roles in many cancers but its role in NPC remains to be elucidated. The aim of the present study was to investigate the role of gal­3 in NPC. Immunohistochemistry and ELISA were used to determine the expression level of gal­3 in patients with NPC or chronic rhinitis (CR). Gal­3 short hairpin (sh)RNA was established to knockdown gal­3 in 5­8F and 6­10B cells, allowing for the evaluation of the roles of gal­3 in proliferation, migration and apoptosis in NPC cell lines. Immunohistochemistry staining of IL­6 and IL­8 was applied to access the inflammatory state of tumor tissues, and the correlation between the inflammatory state and gal­3 was analyzed. The results demonstrated that gal­3 was upregulated in patients with NPC compared with patients with CR. Knockdown of gal­3 inhibited proliferation and migration in 5­8F and 6­10B cells, as well as promoted apoptosis in these cells. The expression levels of MMP­9 and IL­8 were also decreased in 5­8F and 6­10B cells after transfection with gal­3 shRNA. A positive correlation was identified between the expression level of gal­3 and the inflammatory state of NPC. The phosphorylation levels of ERK1/2 and Akt were downregulated after knockdown of gal­3 in 5­8F and 6­10B cells. In conclusion, the expression level of gal­3 was upregulated in patients with NPC and was positively correlated with the inflammatory state of NPC. The results suggested that gal­3 promoted the proliferation and migration of 5­8F and 6­10B cells, while inhibiting the apoptosis of these cells. Moreover, activation of ERK1/2 and Akt may be the underlying mechanism of the effects of gal­3 on NPC.


Assuntos
Galectina 3/genética , Inflamação/genética , Interleucina-8/genética , Metaloproteinase 9 da Matriz/genética , Carcinoma Nasofaríngeo/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Galectina 3/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Proteína Oncogênica v-akt/genética , RNA Interferente Pequeno/farmacologia
19.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786621

RESUMO

The purpose of the present study was to evaluate whether tanshinone IIA (TIIA) could treat cardiac dysfunction and fibrosis in heart failure (HF) by inhibiting oxidative stress. An HF model was induced by ligation of the left anterior descending artery to cause ischemia myocardial infarction (MI) in Sprague­Dawley rats. Cardiac fibrosis was evaluated using Masson's staining, and the levels of collagen I, collagen III, TGF­ß, α­smooth muscle actin (α­SMA), matrix metalloproteinase (MMP) 2 and MMP9 were determined using PCR or western blotting. TIIA treatment reversed the decreases of left ventricular (LV) ejection fraction, fractional shortening (FS), LV systolic pressure and the maximum of the first differentiation of LV pressure (LV ± dp/dtmax), the increases of LV volume in systole, LV volume in diastole, LV end­systolic diameter and LV end­diastolic diameter in MI rats. TIIA administration also reversed the increases of expression levels of collagen I, collagen III, TGF­ß, α­SMA, MMP2 and MMP9 in the heart of MI rats and in angiotensin (Ang) II­treated cardiac fibroblasts (CFs). TIIA reversed the decreases of superoxide dismutase activity and malondialdehyde and the increases of superoxide anions and NADPH oxidase (Nox) activity in both MI rats and Ang II­treated CFs. Nox4 overexpression inhibited the effects of TIIA of improving cardiac dysfunction and fibrosis in MI rats and Ang II­treated CFs. These results demonstrated that TIIA improved cardiac dysfunction and fibrosis via inhibiting oxidative stress in HF rats. Nox4 could regulate the inhibitory effects of TIIA on HF and cardiac fibrosis.


Assuntos
Abietanos/uso terapêutico , Antioxidantes/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Estresse Oxidativo , Actinas/genética , Actinas/metabolismo , Animais , Colágeno/genética , Colágeno/metabolismo , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Masculino , Malondialdeído/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/complicações , Miocárdio/metabolismo , Miocárdio/patologia , NADPH Oxidases/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
20.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786635

RESUMO

Poor prognosis in patients with glioma is primarily due to rapid tumor growth and cell invasion and migration. In addition, microRNA (miR)­27b is decreased in metastatic glioma. The present study investigated whether sevoflurane inhibited glioma cell progression by targeting miR­27b. Cell proliferation was analyzed using a Cell Counting Kit­8 assay and a wound healing assay was used to detect cell migration. Western blotting and reverse transcription­quantitative PCR analysis were performed to determine the protein and mRNA expression levels. A dual luciferase assay was used to determine the relationship between vascular epithelial growth factor (VEGF) and miR­27b. VEGF was identified to be a direct target of miR­27b. Moreover, sevoflurane treatment increased the expression of miR­27b and decreased the expression of VEGF in U251 and U87 cells. Compared with the control group, sevoflurane inhibited the proliferation and migration of U251 and U87 cells, as well as the expression of matrix metalloproteinase (MMP)­2 and MMP­9, which were subsequently abolished by pre­treatment with an miR­27b inhibitor. The present results indicated the potential use of sevoflurane by anesthesiologists for the surgical resection of glioma, which may improve patient outcomes in the clinical setting.


Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioma/metabolismo , Sevoflurano/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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