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1.
Medicine (Baltimore) ; 99(17): e19822, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332626

RESUMO

Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer (TNBC). More and more experts have noticed that AR signaling pathway plays an important role in the occurrence and development of TNBC. The purpose of this study is to detect the inhibitory efficacy and mechanism of Bicalutamide on the proliferation and invasion of TNBC cells.MDA-MB-231 cells of human breast cancer cells were treated with 0, 25, 100 µmol/L of Bicalutamide, cell proliferation assay was performed to assess cell proliferation viability by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide assay and cell invasion was evaluated by Transwell assay. Meanwhile, flow cytometric analysis and western blotting were performed to investigate the mechanism of Bicalutamide on the proliferation and invasion of MDA-MB-231 cells.Bicalutamide could efficiently inhibit the proliferation and invasion of MDA-MB-231 cells in a dose-dependent manner. In addition, Bicalutamide could significantly induce the cell cycle arrest at G0/G1 phase and decrease the protein expression of AR, cyclin D1, matrix metalloprotease-2 (MMP-2), and matrix metalloprotease-9 (MMP-9).The present study indicated the Bicalutamide inhibited the proliferation and invasion process of triple negative breast cancer cells by targeting AR signaling pathway and down-regulating MMP-2/-9 protein expression levels.


Assuntos
Anilidas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Nitrilos/uso terapêutico , Compostos de Tosil/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Anilidas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo/métodos , Humanos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Nitrilos/farmacologia , Sais de Tetrazólio , Compostos de Tosil/farmacologia , Neoplasias de Mama Triplo Negativas/fisiopatologia
2.
Biochim Biophys Acta Proteins Proteom ; 1868(6): 140412, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32179183

RESUMO

Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/antagonistas & inibidores , Cicloexanonas/antagonistas & inibidores , Metaloproteinases da Matriz/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Actinobacteria/metabolismo , Animais , Antineoplásicos/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cicloexanonas/síntese química , Glioxilatos/antagonistas & inibidores , Glioxilatos/metabolismo , Humanos , Metaloproteinase 11 da Matriz/efeitos dos fármacos , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Modelos Moleculares , Subunidade p50 de NF-kappa B/metabolismo , Invasividade Neoplásica , Neoplasias , Quinonas/química
3.
Rev Bras Ginecol Obstet ; 41(7): 449-453, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31344719

RESUMO

OBJECTIVE: To analyze the effects of estrogen alone or in combination with progestogens and tibolone (TIB) on the expression of the extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), of perlecan, and of heparanase (HPSE) of the vascular walls of the carotid arteries. METHODS: A total of 30 250-day-old ovariectomized Wistar rats were orally treated for 5 weeks with: a) 1 mg/kg of estradiol benzoate (EB); b) EB + 0.2 mg/kg of medroxyprogesterone acetate (MPA); c) EB + 0.2mg/kg of norethisterone acetate (NETA); d) EB + 2 mg/kg of dydrogesterone (DI); e) 1 mg/kg of TIB; f) placebo (CTR). Following treatment, the expression of mRNA for MMP-2, MMP-9, and HPSE was analyzed by real-time polymerase chain-reaction (PCR), and the expression of MMP-2, of MMP-9, of tissue inhibitor of metalloproteinase 2 (TIMP-2), and of perlecan was quantified by immunohistochemistry in the carotid arteries. RESULTS: The groups showed significant differences on mRNA HPSE expression (p = 0.048), which was higher in the EB, EB + MPA, and TIB groups. There was no statistically significant difference in mRNA MMP-2 or MMP-9 expression. The immunohistochemical expression of MMP-2, of TIMP-2, of MMP-9, of HPSE, and of perlecan showed no differences between groups. CONCLUSION: Estradiol alone or associated with MPA and TIB treatment can increase mRNA HSPE expression of the walls of the carotid arteries in ovariectomized rats.


Assuntos
Artérias Carótidas/enzimologia , Contraceptivos Hormonais/farmacologia , Estradiol/análogos & derivados , Heparina Liase/efeitos dos fármacos , Norpregnenos/farmacologia , Progestinas/farmacologia , Administração Oral , Animais , Artérias Carótidas/efeitos dos fármacos , Contraceptivos Hormonais/administração & dosagem , Estradiol/administração & dosagem , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteoglicanas de Heparan Sulfato/genética , Proteoglicanas de Heparan Sulfato/metabolismo , Heparina Liase/genética , Heparina Liase/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Modelos Animais , Norpregnenos/administração & dosagem , Ovariectomia , Progestinas/administração & dosagem , Ratos , Ratos Wistar
4.
Anticancer Agents Med Chem ; 19(13): 1633-1641, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31272362

RESUMO

BACKGROUND: Ginsenoside Rh2 (Rh2), which is extracted from ginseng, exerts antitumor activity. Here we would like to study the role of Rh2 on hypoxia-induced migration in lung adenocarcinoma. METHODS: Lung adenocarcinoma A549 and H1299 cells were cultured in 1% O2 condition to mimic the hypoxic tumor microenvironment. The migrations of cancer cells were measured by transwell assay and scratch assay. RESULTS: Rh2 could inhibit hypoxia-induced A549 and H1299 cell migration via increase of mir-491 expression. Further, mir-491 antisense oligonucleotide could repress hypoxia-induced migration and the expression of matrix metalloproteinase (MMP)-9 expression in Rh2-treated A549 cells. CONCLUSION: These findings suggest that Rh2 exerts anti-metastasis activity in the hypoxic tumor microenvironment in lung adenocarcinoma cells via mir-491.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Hipóxia Celular , Movimento Celular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Células A549 , Humanos , Metaloproteinase 9 da Matriz/efeitos dos fármacos
5.
Ann Hepatol ; 18(1): 40-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113607

RESUMO

INTRODUCTION AND AIM: Matrix metalloproteinase (MMP)-2 and MMP-9 are reported to participate in several pregnancy-related diseases, including intrahepatic cholestasis of pregnancy (ICP), which is a severe liver disorder in pregnant women. Meanwhile, ample evidences have demonstrated that celastrol inhibits the activity and expression of MMPs. The present study aims to examine the effect of celastrol to alleviate symptoms of ICP in rat model. MATERIAL AND METHODS: By inducing ICP with 17 - ethinylestradiol in pregnant female rats, we assessed the impact of celastrol administration on symptoms of ICP, such as the rate of bile flow, the level of total bile acids (TBA), and the activities of MMP-2 and -9. Furthermore, the correlations between the levels of MMPs with the examined ICP symptoms were investigated. RESULTS: In rats with ICP, both MMP-2 and -9 exhibited significantly elevated activities, which were inhibited by the administration of celastrol. Furthermore, ICP symptoms such as bile flow rate and total TBA were restored by celastrol. Lastly, there were strong correlations between levels of the two MMPs and TBA. CONCLUSION: Our findings described for the first time the effects of celastrol to attenuate ICP symptoms through an inhibition of both MMP-2 and -9, providing evidence for a potential role of celastrol as a new drug for the treatment of ICP.


Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Complicações na Gravidez/tratamento farmacológico , Prenhez , Triterpenos/uso terapêutico , Animais , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/enzimologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/enzimologia , Ratos , Ratos Sprague-Dawley , Tripterygium
6.
J Endod ; 45(7): 873-881, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109753

RESUMO

INTRODUCTION: During dental pulp healing, progenitor cells migrate to the injured site. This study investigated the effect of iloprost (an exogenous prostacyclin [PGI2]) on enhancing human dental pulp cell (HDPC) migration and its underlying mechanism. METHODS: HDPC migration was analyzed using a wound scratch assay. HDPCs were obtained from extracted teeth and cultured in the presence of iloprost for 24 and 72 hours. Immunofluorescent staining for matrix metalloproteinase 9 (MMP-9), quantitative polymerase chain reaction gene expression analysis, gelatin zymography, and enzyme-linked immunosorbent assay of MMP-9 expression were performed. A PGI2 (IP) antagonist, protein kinase A (PKA) inhibitor, and MMP-9 inhibitor were used to inhibit the IP receptor, PKA signaling pathway, and MMP-9 activity, respectively. RESULTS: A mechanically applied scratch in HDPC cultures closed more rapidly in the presence of iloprost. This result coincided with increased MMP-9 messenger RNA and protein expression and higher gelatinase activity. These iloprost-enhanced effects were inhibited by an IP receptor antagonist or a PKA inhibitor. Forskolin, a PKA activator, increased MMP-9 expression concomitant with increased migration. The application of a selective MMP-9 inhibitor resulted in decreased iloprost-induced migration. CONCLUSIONS: MMPs play an important role in cell migration by degrading components of the extracellular matrix. In this study, iloprost accelerated HDPC migration in a wound scratch assay. MMP-9 expression was increased concomitantly by iloprost and appeared to be mediated by the IP-PKA pathway. These observations suggest that iloprost may enhance dental pulp tissue healing by up-regulating MMP-9. The PGI2 analog might be a promising biomolecule in dental pulp regenerative treatment.


Assuntos
Movimento Celular , Polpa Dentária , Epoprostenol , Metaloproteinase 9 da Matriz , Células Cultivadas , Polpa Dentária/citologia , Epoprostenol/análogos & derivados , Humanos , Metaloproteinase 13 da Matriz , Metaloproteinase 3 da Matriz , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Regulação para Cima
7.
J Coll Physicians Surg Pak ; 29(6): 532-536, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133151

RESUMO

OBJECTIVE: To investigate inhibitory effect of semen litchi drug serum on proliferation of human hepatoma HepG2 cells and its effect on the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9). STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: College of Pharmacy, Guangxi University of Chinese Medicine, China, from June 2017 to January 2018. METHODOLOGY: Semen litchi drug serum with concentrations of 0 mg/kg (control group), 3 g/kg (low dose group), 6 g/kg (medium dose group) and 12 g/kg (high dose group) was used to act on HepG2 cells at the logarithmic phase. Inhibitory effect of semen litchi drug serum on cell growth, expression of VEGF and MMP-9 mRNA and protein was detected. RESULTS: Inhibitory effect of semen litchi drug serum on the proliferation of HepG2 cells significantly increased with the increase of drug concentration, which was dose-time dependent. Expression levels of VEGF and MMP-9 mRNA in HepG2 cells after 48 hours of treatment by semen litchi low-dose group, medium-dose group, and high-dose group were lower than those in control group (all p <0.001). After acting on HepG2 cells for 48 hours, relative expressions of VEGF and MMP-9 protein in semen litchi low-dose group, medium-dose group, and high-dose group were lower than those in control group (all p<0.001). CONCLUSION: Semen litchi drug serum can inhibit proliferation of hepatoma cells in vitro. The anti-hepatoma effect of semen litchi drug serum may be exerted through down-regulating the expression of VEGF and MMP-9 and inhibiting angiogenesis of hepatocellular carcinoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Litchi/química , Neoplasias Hepáticas/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Citometria de Fluxo , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Microscopia de Fluorescência , Coelhos , Distribuição Aleatória , Sementes/química , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Med Sci Monit ; 25: 1838-1847, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30855024

RESUMO

BACKGROUND Intracerebral hemorrhage (ICH) is associated with inflammation and disruption of the blood-brain barrier (BBB). Lipoxin A4 methyl ester (LXA4 ME), is a stable synthetic analog of lipoxin with anti-inflammatory properties. This study aimed to investigate the effects of LXA4 ME in a rat model of ICH. MATERIAL AND METHODS Male Sprague-Dawley rats (n=120), between 12-13 weeks of age, were divided into the sham group (sham-operated), the vehicle-treated group (ICH+vehicle), the LXA4 ME-L group (ICH+low-dose LXA4 ME, 10 ng/d), and the LXA4 ME-H group (ICH+high-dose LXA4 ME, 100 ng/d). The ICH model was created by injection of autologous blood into the right basal ganglia. LXA4 ME was injected into the ventricle 10 min after the development of ICH. A modified neurological severity score (mNSS), rotarod latencies, and brain water content were used to evaluate the rats. The TUNEL assay measured neuronal cell death. Western blot was used to measure protein expression of nuclear factor kappa B (NF-kappaB), matrix metalloproteinase-9 (MMP-9), zonula occludens-1 (ZO-1), and claudin-5. RESULTS In the rat model of ICH, treatment with LXA4 ME reduced the levels of proinflammatory cytokines, improved neurologic function, reduced neuronal apoptosis, and reduced cerebral edema associated with damage to the BBB, and reduced the expression levels of NF-kB, MMP-9, ZO-1, and claudin-5. CONCLUSIONS In a rat model of ICH, treatment with LXA4 reduced early brain injury and protected the BBB by inhibiting the NF-kappaB-dependent MMP-9 pathway.


Assuntos
Hemorragia Cerebral/metabolismo , Lipoxinas/metabolismo , Lipoxinas/farmacologia , Animais , Apoptose , Barreira Hematoencefálica , Encéfalo , Edema Encefálico , Lesões Encefálicas/tratamento farmacológico , Hemorragia Cerebral/tratamento farmacológico , Citocinas , Modelos Animais de Doenças , Inflamação , Masculino , Metaloproteinase 9 da Matriz/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
9.
Am J Physiol Endocrinol Metab ; 316(5): E940-E947, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30779630

RESUMO

IL-6 is secreted from muscles to the circulation during high-intensity and long-duration exercise, where muscle-derived IL-6 works as an energy sensor to increase release of energy substrates from liver and adipose tissues. We investigated the mechanism involved in the exercise-mediated surge in IL-6 during exercise. Using interval-based cycling in healthy young men, swimming exercise in mice, and electrical stimulation of primary human muscle cells, we explored the role of lactate production in muscular IL-6 release during exercise. First, we observed a tight correlation between lactate production and IL-6 release during both strenuous bicycling and electrically stimulated muscle cell cultures. In mice, intramuscular injection of lactate mimicked the exercise-dependent release of IL-6, and pH buffering of lactate production during exercise attenuated IL-6 secretion. Next, we used in vivo bioimaging to demonstrate that intrinsic intramuscular proteases were activated in mice during swimming, and that blockade of protease activity blunted swimming-induced IL-6 release in mice. Last, intramuscular injection of the protease hyaluronidase resulted in dramatic increases in serum IL-6 in mice, and immunohistochemical analyses showed that intramuscular lactate and hyaluronidase injections led to release of IL-6-containing intramyocellular vesicles. We identified a pool of IL-6 located within vesicles of skeletal muscle fibers, which could be readily secreted upon protease activity. This protease-dependent release of IL-6 was initiated by lactate production, linking training intensity and lactate production to IL-6 release during strenuous exercise.


Assuntos
Interleucina-6/metabolismo , Ácido Láctico/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Adulto , Animais , Quimiocina CXCL1/metabolismo , Citocinas/metabolismo , Estimulação Elétrica , Exercício Físico , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Ácido Láctico/farmacologia , Masculino , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Condicionamento Físico Animal , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
10.
Nutrients ; 11(2)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781353

RESUMO

Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice-a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8⁻20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.


Assuntos
Antineoplásicos/farmacologia , Curcuma , Neoplasias Pulmonares/prevenção & controle , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Extratos Vegetais/farmacologia , Receptores CCR7/efeitos dos fármacos , Animais , Feminino , Genes fos/efeitos dos fármacos , Genes jun/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Raízes de Plantas , Receptores CCR7/biossíntese
11.
Am J Physiol Renal Physiol ; 316(4): F660-F673, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30648910

RESUMO

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are serine/threonine kinases and function as regulators of cellular proliferation and differentiation. Recently, we demonstrated that inhibition of ERK1/2 alleviates the development and progression of hyperuricemia nephropathy (HN). However, its potential roles in uric acid-induced tubular epithelial-mesenchymal transition (EMT) and tubular epithelial cell injury are unknown. In this study, we showed that hyperuricemic injury induced EMT as characterized by downregulation of E-cadherin and upregulation of vimentin and Snail1 in a rat model of HN. This was coincident with epithelial cells arrested at the G2/M phase of cell cycle, activation of Notch1/Jagged-1 and Wnt/ß-catenin signaling pathways, and upregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. Administration of U0126, a selective inhibitor of ERK1/2, blocked all these responses. U0126 was also effective in inhibiting renal tubular cell injury, as shown by decreased expression of lipocalin-2 and kidney injury molecule-1 and active forms of caspase-3. U0126 or ERK1/2 siRNA can inhibit tubular cell EMT and cell apoptosis as characterized with decreased expression of cleaved caspase-3. Moreover, ERK1/2 inhibition suppressed hyperuricemic injury-induced oxidative stress as indicated by decreased malondialdehyde and increased superoxide dismutase. Collectively, ERK1/2 inhibition-elicited renal protection is associated with inhibition of EMT through inactivation of multiple signaling pathways and matrix metalloproteinases, as well as attenuation of renal tubule injury by enhancing cellular resistance to oxidative stress.


Assuntos
Butadienos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hiperuricemia/patologia , Hiperuricemia/prevenção & controle , Nefropatias/patologia , Nefropatias/prevenção & controle , Túbulos Renais/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nitrilos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Ciclo Celular/efeitos dos fármacos , Inativação Gênica , Lipocalina-2/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição da Família Snail/biossíntese , Vimentina/metabolismo
12.
Inflammation ; 42(2): 413-425, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30613914

RESUMO

It has been reported that matrix metalloproteinases (MMPs) are induced by many cytokines, and they are involved in various inflammatory processes, including periodontitis. However, the effects of interleukin-1ß (IL-1ß) on MMP-9 expression in cementoblasts, the cells responsible for cementum production, remain largely unknown. In this study, we used qPCR and gelatin zymogram analysis to show that IL-1ß upregulated MMP-9 expression in cementoblast-derived cell line. Several signaling pathways, such as ERK1/2, JNK, p38, and AP-1 (c-Fos and ATF-2), were activated in response to IL-1ß stimulation. Furthermore, enhancement of AP-1 activity by IL-1ß was further confirmed by the AP-1 reporter assay and the electrophoretic mobility shift assay (EMSA). Pretreatment with specific inhibitors of ERK1/2 (U0126), JNK (SP600125), and AP-1 (tanshinone IIA) attenuated IL-1ß-induced MMP-9 expression. In addition, inhibitors of ERK1/2 (U0126) and JNK (SP600125) attenuated IL-1ß-enhanced AP-1 activity. This suggested that IL-1ß stimulated AP-1 activation, at least partially, through ERK1/2 and JNK signaling pathways. Moreover, we found that IL-1ß also upregulated the expression of MMP-13 and enhanced MMP-mediated degradation of type I collagen. Collectively, these results suggested that IL-1ß induced MMP-9 expression by activation of AP-1 through the ERK1/2 and JNK signaling pathways in cementoblast-derived cell line and enhanced MMP-mediated collagen degradation possibly by MMP-13 and MMP-9.


Assuntos
Colágeno Tipo I/metabolismo , Cemento Dentário/metabolismo , Interleucina-1beta/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Linhagem Celular , Colágeno Tipo I/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo
13.
Hepatology ; 69(1): 314-328, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30019419

RESUMO

Recruitment of liver sinusoidal endothelial cell progenitor cells (sprocs) from the bone marrow by vascular endothelial growth factor-stromal cell-derived factor-1 (VEGF-sdf-1) signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP-9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or be detrimental. We found that liver-selective MMP-9 inhibition accelerated liver regeneration after partial hepatectomy by 40%, whereas systemic MMP inhibition impaired liver regeneration. Liver-selective MMP-9 inhibition largely abolished warm ischemia-reperfusion injury. In the extended hepatectomy model, liver-selective MMP-9 inhibition restored liver sinusoidal endothelial cell integrity, enhanced liver regeneration, and reduced ascites. Liver-selective MMP-9 inhibition markedly increased recruitment and engraftment of bone marrow sprocs, whereas systemic MMP inhibition impaired mobilization of bone marrow sprocs and their hepatic engraftment. Hepatic MMP-9 proteolytically cleaved VEGF after partial hepatectomy. Liver-selective MMP-9 inhibition prevented VEGF cleavage and doubled protein expression of VEGF and its downstream signaling partner sdf-1. In contrast, systemic MMP inhibition enhanced recruitment and engraftment of infused allogeneic progenitors. Conclusion: Liver-selective MMP inhibition prevents proteolytic cleavage of hepatic VEGF, which enhances recruitment and engraftment of bone marrow sprocs after liver injury. This ameliorates injury and accelerates liver regeneration. Liver-selective MMP-9 inhibition may be a therapeutic tool for liver injury that damages the vasculature, whereas systemic MMP inhibition can enhance the benefit of stem cell therapy with endothelial progenitor cells.


Assuntos
Regeneração Hepática/efeitos dos fármacos , Fígado/irrigação sanguínea , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/farmacocinética , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , Masculino , Metaloproteinase 9 da Matriz/fisiologia , Ratos , Ratos Endogâmicos Lew , Fatores de Tempo
14.
Ann Anat ; 222: 120-128, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30590121

RESUMO

Carthamus tinctorius L. (CT) has been widely used in Asian countries as a beverage and a folk medicine. The current study investigates the effect of CT extract on cardiac remodeling and possible mechanisms involved in Nw-nitro-l-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were administrated with L-NAME (40mg/kg/day) for five weeks to induce hypertension. Hypertensive rats were treated with CT extract (300mg/kg/day) or captopril (5mg/kg/day) or vehicle for a further two weeks. Treatment of hypertensive rats with CT extract or captopril significantly decreased systolic blood pressure, left ventricular (LV) hypertrophy and fibrosis, small intramyocardial coronary artery remodeling, and cardiac weight index. CT extract or captopril increased plasma nitric oxide metabolite (NOx) levels and reduced plasma transforming growth factor ß1 (TGF-ß1) level, together with downregulation of cardiac TGF-ß1 and matrix metalloproteinases-9 (MMP-9) expression. In addition, decreased plasma malondialdehyde (MDA) levels, consistent with downregulation of NADPH oxidase subunit gp91phox expression in heart tissue, was also observed after CT extract or captopril treatment. These findings suggest that CT extract alleviates cardiac remodeling in L-NAME-induced hypertensive rats, which is possibly related to inhibition of the NADPH oxidase-mediated TGF-ß1-MMP-9 pathway.


Assuntos
Anti-Hipertensivos/uso terapêutico , Carthamus tinctorius/química , Inibidores Enzimáticos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia , NADPH Oxidases/antagonistas & inibidores , NG-Nitroarginina Metil Éster , Extratos Vegetais/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Remodelação Ventricular/efeitos dos fármacos , Animais , Pressão Sanguínea , Captopril/uso terapêutico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-Dawley
15.
Gene ; 684: 30-38, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30315927

RESUMO

Anti-proliferative, anti-metastatic and anti-angiogenic effects of 17­allylamino­17­demethoxy geldanamycin (17-AAG) were studied alone and in combination with Capecitabine (Cap) and/or Irinotecan (IR) on HT-29 human colorectal carcinoma cells. Expression of MMP-9 (matrix metalloproteinase­9) and VEGF (vascular endothelial growth factor) mRNA was analyzed by real-time PCR method. The study was further followed by wound scratch assay for migration assessment. Nitric oxide content, Malondialdehyde generation and total anti-oxidant capacity were also assessed. Results showed significant differences between mono- and double therapy (p < 0.05). Combination of 17-AAG with IR or Cap resulted in synergistic effect (Combination Index < 1). Among double combination groups only Cap/17-AAG showed significant differences in MMP-9 and VEGF genes expression and wound healing assay. Moreover, a significant decrease of wound area in our triple combination group was obtained, indicating the antagonistic effect. IR/17-AAG and IR/Cap double combination groups resulted in down-regulation of MMP-9 and VEGF mRNA expression, respectively. Significant generation of MDA and decrease in TAC values have been observed in all our tested groups, however, the IR/17-AAG combination was the only group that could elevate NO concentration, significantly. Our findings demonstrated potent anti-angiogenesis and anti-metastatic effects for 17-AAG when it is provided in double combination especially with Cap, suggesting a new protocol in colorectal cancer combination therapy. These findings may indicate that down-regulation of VEGF and MMP-9 genes is directly related to angiogenesis and metastasis.


Assuntos
Benzoquinonas/metabolismo , Benzoquinonas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Camptotecina/análogos & derivados , Camptotecina/metabolismo , Capecitabina/metabolismo , Capecitabina/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Fluoruracila/análogos & derivados , Fluoruracila/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HT29 , Humanos , Irinotecano/metabolismo , Irinotecano/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
16.
Placenta ; 72-73: 62-73, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30501883

RESUMO

INTRODUCTION: Between 2 and 10% of pregnant women are treated with selective serotonin-reuptake inhibitors (SSRIs) for depression. The extravillous trophoblasts (evTBs), which migrate and invade maternal tissues, are crucial for embryo implantation and remodeling of maternal spiral arteries. Poor migration/invasion of evTBs can cause serious pregnancy complications, yet the effects of SSRIs on these processes has never been studied. To determine the effects of five SSRIs (fluoxetine, norfluoxetine, citalopram, sertraline and venlafaxine) on migration/invasion, we used JEG-3 and HIPEC cells as evTB models. METHODS: Cells were treated with increasing concentrations (0.03-10 µM) of SSRIs. Cell proliferation was monitored using an impedance-based system and cell cycle by flow cytometry. Migration was determined using a scratch test, and metalloproteinase (MMP) activities, by zymography. Invasion markers were determined by RT-qPCR. RESULTS: Fluoxetine and sertraline (10 µM) significantly decreased cell proliferation by 94% and by 100%, respectively, in JEG-3 cells, and by 58.6% and 100%, respectively, in HIPEC cells. Norfluoxetine increased MMP-9 activity in JEG-3 cells by 2.0% at 0.03 µM and by 43.9% at 3 µM, but decreased MMP-9 activity in HIPEC cells by 63.7% at 3 µM. Sertraline at 0.03 µM increased mRNA level of TIMP-1 in JEG-3 cells by 36% and that of ADAM-10 by 85% and 115% at 0.3 and 3 µM, respectively. In HIPEC cells, venlafaxine at 0.03 and 0.3 µM, increased ADAM-10 mRNA levels by 156% and 167%, respectively. DISCUSSION: This study shows that SSRIs may affect evTBs homeostasis at therapeutic levels and provides guidance for future research.


Assuntos
Inibidores de Captação de Serotonina/efeitos adversos , Trofoblastos/efeitos dos fármacos , Proteína ADAM10/genética , Secretases da Proteína Precursora do Amiloide/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Coriocarcinoma , Feminino , Fluoxetina/efeitos adversos , Fluoxetina/análogos & derivados , Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/genética , Modelos Biológicos , Gravidez , RNA Mensageiro/análise , Inibidores de Captação de Serotonina/uso terapêutico , Sertralina/efeitos adversos , Inibidor Tecidual de Metaloproteinase-1/genética , Trofoblastos/fisiologia , Cloridrato de Venlafaxina/efeitos adversos
17.
Stroke ; 49(11): 2743-2751, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30355205

RESUMO

Background and Purpose- Plasma levels of galectin-3-a matricellular protein-are increased after aneurysmal subarachnoid hemorrhage (SAH), but the functional significance remains undetermined. This study was conducted to evaluate whether modified citrus pectin (MCP; galectin-3 inhibitor) prevents post-SAH early brain injury, focusing on blood-brain barrier disruption. Methods- C57BL/6 male adult mice (n=251) underwent sham or filament perforation SAH modeling, followed by a random intracerebroventricular injection of vehicle or drug at 30 minutes post-modeling. First, vehicle-treated and 0.8, 4, 16, or 32 µg MCP-treated mice were assessed by neuroscore and brain water content at 24 and 48 hours post-modeling. Second, Evans blue extravasation, Western blotting, coimmunoprecipitation and immunostaining were performed in vehicle-treated or 4 µg MCP-treated mice at 24 hours post-modeling. Third, vehicle or R-galectin-3 (recombinant galectin-3) was administered to SAH mice simultaneously with vehicle or MCP, and neuroscore and Evans blue extravasation were evaluated at 24 hours post-modeling. Fourth, vehicle or R-galectin-3 was administered to MCP-treated SAH mice at 24 hours, and neuroscore and IgG immunostaining were evaluated at 48 hours post-SAH. Results- Among tested dosages, 4 µg MCP showed the best neuroprotective effects as to preventing neurological impairments and brain edema at 24 to 48 hours post-SAH. Four micrograms MCP attenuated post-SAH blood-brain barrier disruption and galectin-3 upregulation in brain capillary endothelial cells, associated with inactivation of ERK (extracellular signal-related kinase) 1/2, STAT (signal transducer and activator of transcription)-3, and MMP (matrix metalloproteinase)-9, and the consequent preservation of a tight junction protein ZO-1 (zonula occludens-1). Coimmunoprecipitation assay demonstrated physical interactions between galectin-3 and TLR (Toll-like receptor) 4. R-galectin-3 blocked the neuroprotective effects of MCP. Conclusions- MCP prevents post-SAH blood-brain barrier disruption possibly by inhibiting galectin-3, of which the mechanisms may include binding to TLR4 and activating ERK1/2, STAT-3, and MMP-9. This study suggests galectin-3 to be a novel therapeutic target against post-SAH early brain injury.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Galectina 3/antagonistas & inibidores , Pectinas/farmacologia , Hemorragia Subaracnóidea/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Western Blotting , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Galectina 3/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteína da Zônula de Oclusão-1/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
18.
Oncol Rep ; 40(5): 2515-2524, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226602

RESUMO

Mantle cell lymphoma (MCL) is an aggressive disease. MCL is associated with poor patient prognosis and limited survival. To identify key genes and explore targeting cyclic peptide inhibitors for the treatment of MCL, we downloaded two gene expression profiles (GSE32018 and GSE9327) from the Gene Expression Omnibus (GEO) database. We screened 84 differentially expressed genes (DEGs). Pathway analysis showed that DEMs were mainly enriched in the 'Pathway in cancer', 'PI3K­Akt signaling pathway', 'Cytokine­cytokine receptor interaction', 'Rap1 signaling pathway', 'NF­κB signaling pathway' and 'Leukocyte trans­endothelial migration'. We subsequently constructed a protein­protein interaction (PPI) network of DEGs. In addition, matrix metalloproteinase 9 (MMP9) with a high degree in the PPI network was identified as a hub gene in MCL. Meanwhile in the Molecular Complex Detection (MCODE) analysis, MMP9 was located in the important cluster. Thus, MMP9 can be used as a therapeutic target for MCL and we designed cyclic peptides as MMP9 inhibitors. MMP9 protein structure was gathered from the Protein Data Bank (PDB), with a PDB ID: 1L6J. MMP9 and cyclic peptides were docked using Molecular Operating Environment (MOE) software after structural optimization. It was revealed that cyclic peptide 2 bound deeply in the binding pocket of MMP9 and had interaction with the active­site Zn2+ ion in the catalytic domain. Cyclic peptides 1, 2, 4­6 also displayed potential interaction with active residues of MMP9; thus, these cyclic peptides can serve as potential drug candidates to block MMP9 activity and future studies are warranted to confirm their efficacy.


Assuntos
Inibidores Enzimáticos/química , Linfoma de Célula do Manto/genética , Metaloproteinase 9 da Matriz/química , Peptídeos Cíclicos/química , Domínio Catalítico , Biologia Computacional , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Simulação de Acoplamento Molecular , Peptídeos Cíclicos/uso terapêutico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/genética , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , Software , Zinco/química
19.
Behav Neurol ; 2018: 6470957, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018671

RESUMO

Background: Mammalian sterile 20-like kinase 1 (MST1), the key component of the Hippo-YAP pathway, exhibits an important role in the pathophysiological process of various neurological disorders, including ischemic stroke and spinal cord injury. However, during subarachnoid hemorrhage, the involvement of MST1 in the pathophysiology of early brain injury remains unknown. Methods: We employed intravascular filament perforation to establish the subarachnoid hemorrhage (SAH) mouse model. The MST1 inhibitor XMU-MP-1 was intraperitoneally injected at 1 h after SAH, followed by daily injections. MST1 in vivo knockdown was performed 3 weeks prior to SAH via intracerebroventricular injection of adeno-associated virus (AAV) packaged with MST1 shRNA. The SAH grade, behavioral deficits, TUNEL staining, Evans blue dye extravasation and fluorescence, brain water content, protein and cytokine expressions by Western blotting, immunofluorescence, and proteome cytokine array were evaluated. Results: Following SAH, the phosphorylation level of MST1 was upregulated at 12 h, with a peak at 72 h after SAH. It was colocalized with the microglial marker Iba1. Both XMU-MP-1 and MST1 shRNA alleviated the neurological deficits, blood-brain barrier (BBB) disruption, brain edema, neuroinflammation, and white matter injury, which were induced by SAH in association with nuclear factor- (NF-) κB p65 and matrix metallopeptidase-9 (MMP-9) activation and downregulated endothelial junction protein expression. Conclusions: The current findings indicate that MST1 participates in SAH-induced BBB disruption and white matter fiber damage via the downstream NF-κB-MMP-9 signaling pathway. Therefore, MST1 antagonists may serve as a novel therapeutic target to prevent early brain injury in SAH patients.


Assuntos
Fator de Crescimento de Hepatócito/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Lesões Encefálicas/complicações , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/prevenção & controle , Modelos Animais de Doenças , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Masculino , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
20.
Med Sci Monit ; 24: 4861-4868, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005060

RESUMO

BACKGROUND Lysophosphatidic acid (LPA) is an active compound of oxidized low-density lipoprotein that serves as an endogenous TLR4 ligand. Ligand activation of TLR4 activates nuclear factor-kappaB (NF-κB) and the transcription of NF-κB-regulated inflammatory cytokines, which are involved in the development of atherosclerosis. MMP9 is a member of the MMP family and can affect plaque stability. However, the mechanism responsible for the effect of LPA on the expression and activation of MMP9 has not been fully elucidated. In the present study we examined the effect of LPA on MMP9 expression and activity in THP-1 cells and the involvement of Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway in this effect. MATERIAL AND METHODS Human THP-1 cells were treated with 0-10 µM LPA for 4 h, or treated with 1 µM LPA for 0-8 h, and were then transfected with TLR4-specific siRNA or treated with 20 µg/ml cafestol acid phenethyl ester (CAPE, an NF-κB inhibitor). MMP9 mRNA and protein levels were measured by quantitative RT-PCR and Western blot analysis, respectively, and MMP9 activity was measured by zymography. RESULTS LPA upregulated MMP9 mRNA and protein levels and MMP9 activity in THP-1 cells in both concentration- and time-dependent manners. Transfection of cells with TLR4-siRNA-2 or treatment with CAPE significantly inhibited the upregulated MMP9 expression and activation. This inhibition was further enhanced by combining the TLR4-siRNA-2 transfection and CAPE pretreatment. CONCLUSIONS LPA can promote MMP9 expression and enhance MMP9 activity in THP-1 cells, in part via the TLR4/NF-kB signaling pathway.


Assuntos
Lisofosfolipídeos/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Humanos , Lisofosfolipídeos/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Regulação para Cima/efeitos dos fármacos
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