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1.
Medicine (Baltimore) ; 99(40): e22544, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019464

RESUMO

BACKGROUND: Clinical studies have shown that celecoxib can significantly inhibit the development of tumors, and basic experiments and in vitro experiments also provide a certain basis, but it is not clear how celecoxib inhibits tumor development in detail. METHODS: A literature search of all major academic databases was conducted (PubMed, China National Knowledge Internet (CNKI), Wan-fang, China Science and Technology Journal Database (VIP), including the main research on the mechanisms of celecoxib on tumors. RESULTS: Celecoxib can intervene in tumor development and reduce the formation of drug resistance through multiple molecular mechanisms. CONCLUSION: Celecoxib mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenases-2/prostaglandin E2 signal axis and thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding, Akt, signal transducer and activator of transcription and the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. Meanwhile, it was found that celecoxib could promote the apoptosis of tumor cells by enhancing mitochondrial oxidation, activating mitochondrial apoptosis process, promoting endoplasmic reticulum stress process, and autophagy. Celecoxib can also reduce the occurrence of drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs.


Assuntos
Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Celecoxib/efeitos adversos , Celecoxib/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , 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 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
PLoS One ; 15(9): e0235824, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881898

RESUMO

Pulmonary hypertension due to left heart disease (PH-LHD) is a momentous pulmonary hypertension disease, and left heart disease is the most familiar cause. Mechanical stretching may be a crucial cause of vascular remodeling. While, the underlining mechanism of mechanical stretching-induced in remodeling of pulmonary vein in the early stage of PH-LHD has not been completely elucidated. In our study, the PH-LHD model rats were successfully constructed. After 25 days, doppler echocardiography and hemodynamic examination were performed. In addition, after treatment, the levels of matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA, immunohistochemistry and western blot assays in the pulmonary veins. Moreover, the pathological change of pulmonary tissues was evaluated by H&E staining. Our results uncovered that left ventricular insufficiency and interventricular septal shift could be observed in PH-LHD model rats, and the right ventricular systolic pressure (RVSP) and mean left atrial pressure (mLAP) were also elevated in PH-LHD model rats. Meanwhile, we found that MMP-9 and TGF-ß1 could be highly expressed in PH-LHD model rats. Besides, we revealed that stretch-activated channel (SAC)/mitogen-activated protein kinases (MAPKs) signaling pathway could be involved in the upregulations of MMP-9 and TGF-ß1 mediated by mechanical stretching in pulmonary vein. Therefore, current research revealed that mechanical stretching induced the increasing expressions of MMP-9 and TGF-ß1 in pulmonary vein, which could be mediated by activation of SAC/MAPKs signaling pathway in the early stage of PH-LHD.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Sistema de Sinalização das MAP Quinases , Metaloproteinase 9 da Matriz/metabolismo , Veias Pulmonares/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Masculino , Veias Pulmonares/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Remodelação Vascular , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/metabolismo
3.
Nat Commun ; 11(1): 4078, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843630

RESUMO

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.


Assuntos
Substitutos Sanguíneos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/metabolismo , Animais , Encéfalo/patologia , Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/patologia , Morte Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
4.
Life Sci ; 259: 118191, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777302

RESUMO

Numerous population studies conducted worldwide indicate that the prevalence of asthma is higher in obese versus lean individuals. It has been reported that sensitized lean mice has a better recovery of lung inflammation in asthma. Extracellular matrix (ECM) plays an essential role in the structural support of the lungs regulating the airways diameter, thus preventing its collapse during expiration. ECM renewal by metalloproteinase (MMPs) enzymes is critical for pulmonary biology. There seems to be an imbalance of MMPs activity in asthma and obesity, which can impair the lung remodeling process. In this study, we characterized the pulmonary ECM of obese and lean mice, non-sensitized and sensitized with ovalbumin (OVA). Pharmacological intervention was performed by using anti-TNF-α, and MMP-8 and MMP-9 inhibitors in obese and lean sensitized mice. Activity of MMPs was assessed by gelatinase electrophorese, western blotting and zymogram in situ. Unbalance of MMP-2, MMP-8, MMP-9 and MMP-12 was detected in lung tissue of OVA-sensitized obese mice, which was accompanied by high degradation, corroborating an excessive deposition of types I and III collagen in pulmonary matrix of obese animals. Inhibitions of TNF-α and MMP-9 reduced this MMP imbalance, clearly suggesting a positive effect on pulmonary ECM. Obese and lean mice presented diverse phenotype of asthma regarding the ECM compounds and the inhibition of MMPs pathway could be a good alternative to regulate the activity in ECM lungs of asthmatic obese individuals.


Assuntos
Asma/etiologia , Asma/metabolismo , Metaloproteases/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Matriz Extracelular/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Inibidores de Proteases/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
5.
Gene ; 762: 145044, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777528

RESUMO

OBJECTIVE: Gastric cancer is the most common malignant tumor. Most patients suffering from gastric cancer die of metastasis. The role of Atrial natriuretic peptide (ANP) in inhibiting and eliminating kinds of cancer cells has been reported. Aberrant activation of Hedgehog (Hh) signaling pathway contributes to initiation and progression of various malignancies. We have previously reported that the inhibitor of Hh, cyclopamine, reduces the metastatic activity of MGC-803 via inhibiting the expression of matrix metalloproteinases (MMP)-9. It remains to be further demonstrated that ANP has the suppressive effects on invasion and metastasis in gastric cancer via Hh-mediated MMP-9 production. METHODS: Transwell, western blot, qRT-PCR were used after application of ANP on MGC-803 gastric cancer cells to determine the levels of cell migration and invasion, protein levels of MMP-9 and Hh, as well as mRNAs of MMP-9 and Hh, respectively. RESULTS: It was demonstrated that the migration and invasion were significantly lower, MMP-9 and Hh as well as their mRNAs were lower as well, in ANP-treated MGC-803 gastric cancer cells than those in control. CONCLUSIONS: The expression of MMP-9 induced by aberrant activation of Hh in MGC-803 was inhibited by ANP, which may contribute to the inhibition of cell migration and invasion. These results suggested the potential of ANP to be used in gastric cancer therapy as an inhibitor targetting Hh signaling pathway to inhibit the proliferation as well as invasion and metastasis of gastric cancer.


Assuntos
Fator Natriurético Atrial/farmacologia , Proteínas Hedgehog/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteínas Hedgehog/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Transdução de Sinais/efeitos dos fármacos
6.
BMC Infect Dis ; 20(1): 505, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660552

RESUMO

BACKGROUND: Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM. METHODS: BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi. RESULTS: Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX. CONCLUSIONS: Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.


Assuntos
Antibacterianos/uso terapêutico , Ceftriaxona/uso terapêutico , Doxiciclina/uso terapêutico , Meningite Meningocócica/tratamento farmacológico , Neisseria meningitidis Sorogrupo C , Animais , Antibacterianos/administração & dosagem , Carga Bacteriana/efeitos dos fármacos , Ceftriaxona/administração & dosagem , Hemorragia Cerebral/tratamento farmacológico , Quimiocinas/análise , Quimiocinas/metabolismo , Modelos Animais de Doenças , Doxiciclina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/metabolismo , Meningite Meningocócica/mortalidade , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Resultado do Tratamento
7.
Cancer Sci ; 111(9): 3292-3302, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32644283

RESUMO

EphA10 (erythropoietin-producing hepatocellular carcinoma receptor A10) is a catalytically defective receptor protein tyrosine kinase in the ephrin receptor family. Although EphA10 is involved in the malignancy of some types of cancer, its role as an oncogene has not been extensively studied. Here, we investigated the influence of EphA10 on the tumorigenic potential of pancreatic cancer cells. Analysis of expression profiles from The Cancer Genome Atlas confirmed that EphA10 was elevated and higher in tumor tissues than in normal tissues in some cancer types, including pancreatic cancer. EphA10 silencing reduced the proliferation, migration, and adhesion of MIA PaCa-2 and AsPC-1 pancreatic cancer cells. These effects were reversed by overexpression of EphA10 in MIA PaCa-2 cells. Importantly, overexpression and silencing of EphA10 respectively increased and decreased the weight, volume, and number of Ki-67-positive proliferating cells in MIA PaCa-2 xenograft tumors. Further, EphA10 expression was positively correlated with invasion and gelatin degradation in MIA PaCa-2 cells. Moreover, overexpression of EphA10 enhanced the expression and secretion of MMP-9 in MIA PaCa-2 cells and increased the expression of MMP-9 and the vascular density in xenograft tumors. Finally, expression of EphA10 increased the phosphorylation of ERK, JNK, AKT, FAK, and NF-κB, which are important for cell proliferation, survival, adhesion, migration, and invasion. Therefore, we suggest that EphA10 plays a pivotal role in the tumorigenesis of pancreatic epithelial cells and is a novel therapeutic target for pancreatic cancer.


Assuntos
Carcinogênese/genética , Carcinogênese/metabolismo , Suscetibilidade a Doenças , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Neoplasias Pancreáticas/patologia , Transdução de Sinais
8.
Chem Biol Interact ; 329: 109202, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32717189

RESUMO

Triple-negative breast cancer (TNBC) is highly metastatic and lacks effective therapeutic targets among several subtypes of breast cancer. Cancer metastasis promotes the malignancy of TNBC and is closely related to the poor prognosis of the TNBC patients. We aim to explore novel agents that effectively inhibit cancer metastasis to treat TNBC. In our study, 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ), a CA-4 analogue, could inhibit cell motility and invasion in MDA-MB-231 cells, and the mechanism is closely associated to the inhibition of epithelial-to-mesenchymal transition (EMT). Meanwhile, SQ significantly inhibited the expression and secretion of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells. Moreover, the conditioned medium from SQ-treated MDA-MB-231 cells significantly inhibited the motility and invasion of human umbilical vein endothelial cells (HUVECs), which was correlated with the inhibition of EMT process in HUVECs. In addition, exogenous application of VEGF reversed the occurrence of EMT in HUVECs which stimulated by conditioned medium from SQ-treated cells. Furthermore, SQ inhibited vasculogenic mimicry (VM) formation in MDA-MB-231 cells, which was associated with VE-cadherin and EphA2 down-regulation. This study indicates that SQ inhibits MDA-MB-231 cell metastasis through suppressing EMT and VEGF, thereby implicating this compound might be a potential therapeutic agent against metastatic TNBC.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenóis/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Compostos Organosselênicos/química , Fenóis/química , Receptor EphA2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/genética
9.
Life Sci ; 257: 118096, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679150

RESUMO

AIMS: The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19. MATERIALS AND METHODS: The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations. KEY FINDINGS: A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs. SIGNIFICANCE: The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/metabolismo , Pneumonia Viral/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Antivirais/uso terapêutico , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Cloroquina/farmacologia , Biologia Computacional/métodos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Melatonina/farmacologia , Metaloproteases/metabolismo , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/fisiopatologia , Transporte Proteico
10.
Arch Biochem Biophys ; 690: 108460, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603715

RESUMO

BACKGROUND: Our previous research revealed that trypsin is abundantly expressed in atherosclerotic plaques and its distribution overlaps with that of matrix metalloproteinase-9 (MMP-9). This study was performed to explore the possible roles of trypsin in vulnerable atherosclerotic plaque formation. METHODS AND RESULTS: Twenty-four rabbits were randomly assigned to a normal (control) group, an atherosclerosis (experimental) group and a trypsin inhibitor (aprotinin) group. In the 13th feeding week, the aprotinin group was treated with 5 mg/kg/day aprotinin via ear vein for 4 weeks. At the end of the 16th week, coronary arterial and aortic expression of trypsin, proteinase-activated receptor-2 (PAR-2), activated MMP-9, and pro-inflammatory cytokines were significantly greater in the experimental group than in the control group. Aprotinin decreased trypsin expression and activation in plaques, blocked PAR-2 and MMP-9 activation, and decreased cytokine expression; it also increased fibrous cap thickness, decreased the intima-media thickness and intimal/medial ratio, thus significantly ameliorating plaque vulnerability. Upregulated trypsin, MMP-9 and PAR-2 were also found in coronary intimal atherosclerotic plaques of patients undergoing coronary artery bypass grafting. CONCLUSIONS: Ectopic trypsin was significantly upregulated in atherosclerotic plaques, which increased pro-inflammatory cytokine levels by activating PAR-2 and promoted plaque instability by activating proMMP-9, thereby promoting atherosclerosis and plaque vulnerability. In addition, the high trypsin expression in human coronary intimal atherosclerotic plaques suggests that targeting trypsin may be a new strategy for acute coronary syndrome prevention.


Assuntos
Aterosclerose/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Placa Aterosclerótica/química , Tripsina/metabolismo , Animais , Aorta/química , Aprotinina/administração & dosagem , Aprotinina/metabolismo , Espessura Intima-Media Carotídea , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Coelhos , Receptor PAR-2/metabolismo , Tripsina/genética , Inibidores da Tripsina/administração & dosagem , Inibidores da Tripsina/metabolismo
11.
Chem Biol Interact ; 328: 109144, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653415

RESUMO

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both ß-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Excitação Neurológica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Fosfato de Sitagliptina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Pentilenotetrazol , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
12.
PLoS One ; 15(7): e0235408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649686

RESUMO

The tear matrix metalloproteinase-9 (MMP-9) immunoassay (Inflammadry) exhibits variable results in dry eye (DE) patients. We investigated if the tear volume in DE patients affects the results of MMP-9 immunoassay in clinical and in vitro settings. This cross-sectional study enrolled 188 eyes of 188 DE patients. The clinical symptoms and signs of DE were assessed using the Ocular Surface Disease Index and visual analog scale, strip meniscometry, tear break-up time, and tear meniscus height (TMH), area (TMA), and depth (TMD) using swept-source optical coherence tomography and corneal and conjunctival staining scores. For quantitative evaluation, the bands produced by the InflammaDry test were analyzed with ImageJ. DE subjects were grouped according to MMP-9 positivity and TMH. The InflammaDry-positive group showed greater TMH, TMA, and TMD than the MMP-9-negative group (p < 0.05). InflammaDry test band density in the high TMH group was significantly greater than that in the low and normal TMH groups (p < 0.05). InflammaDry test band density correlated positively with TMH, TMA, and TMD (all p < 0.05). InflammaDry test results were influenced by tear volume. Low tear volume in aqueous tear-deficient DE may induce false-negative results, and reflex tearing during the test may induce false-positive results.


Assuntos
Síndromes do Olho Seco/diagnóstico , Imunoensaio/métodos , Metaloproteinase 9 da Matriz/metabolismo , Síndrome de Sjogren/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Córnea/metabolismo , Córnea/patologia , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/patologia , Olho/metabolismo , Olho/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Sjogren/genética , Síndrome de Sjogren/patologia , Lágrimas/metabolismo , Tomografia de Coerência Óptica/métodos , Adulto Jovem
13.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 45-50, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476372

RESUMO

OBJECTIVE: To investigate the probable roles of the novel C2H2 zinc finger transcription factor ZFP580 on all-transretinoic acid (ATRA)-regulated VSMCs migration and underlying mechanisms. METHODS: Rat aortic VSMCs were isolated, cultured and identified. VSMCs were treated with ATRA at the concentrations of 0, 5, 10 or 20 µmol/L for 24 hours. The migration ability of VSMCs was observed in each group and compared with control group which was treated by 0 µmol/L ATRA. The mRNA and protein expression levels of ZFP580 were detected by QPCR and Western blot. ZFP580 protein expression in VSMCs was detected under ATRA stimulation when ERK inhibitor PD98059 was used to inhibit the protein expression of ERK. Adenovirus transfection technology was used to obtain VSMCs with overexpression or low expression of ZFP580, and QPCR and Western blot were used to detect the mRNA and protein levels of MMP-2, MMP-9 and ZFP580. RESULTS: On the 10th day of VSMCs culture, immunofluorescence showed that SM22 alpha antibody, as a specific marker of smooth muscle cells, was positive. Compared to the control group, VSMCs migration was reduced by 32%, 43%, and 59% in the group of 5, 10, and 20 µmol/L ATRA pretreatment. Compared with the control group, VSMCs treated by 20 µmol/L ATRA reduced the cell migration by 49%, 36% and 22% at 24, 48 and 72 h. The mRNA and protein expression levels of ZFP580 were increased with the increase of ATRA stimulation solubility and the extension of stimulation time. ERK was increased significantly after 15 min of ATRA stimulation. Pretreatment with ERK inhibitor PD98059 (20 µmol/L) inhibited the expression of ERK protein and reduced the expression of ATRA-induced ZFP580 protein. Overexpression of ZFP580 inhibited the expressions of MMP-2 and MMP-9, whereas down-expression of ZFP580 promoted the expressions of MMP-2 and MMP-9. CONCLUSION: ATRA increased the expression of ZFP580 through the ERK signaling pathway, while ZFP580 was involved in ATRA's inhibition of VSMCs migration by affecting the expression of downstream MMP-2 and MMP-9.


Assuntos
Movimento Celular , Miócitos de Músculo Liso/citologia , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia , Animais , Células Cultivadas , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Ratos , Transdução de Sinais
14.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 39-47, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32538745

RESUMO

This study was designed to investigate the expressions and roles of MMP-9 and HMGB1 in peripheral blood of patients with epilepsy and their relationship with the cognitive function and to explore factors affecting the prognosis of epilepsy patients. A total of 127 patients with epilepsy were collected in the study group and 120 healthy subjects receiving a physical examination at the same time were collected in the control group. The MMP-9 and HMGB1 expressions and their diagnostic value for epilepsy were compared between the two groups. The relationship between MMP-9 and HMGB1 expression levels and the clinical-pathological features and the Mini-mental State Evaluation Scale (MMSE) of patients from the study group were also analyzed. The serum levels of MMP-9 and HMGB1 in the study group were significantly higher than those in the control group (P< 0.001), and were greatly decreased after the treatment (P<0.001). The ROC curve showed that MMP-9 and HMGB1 combined detection had a good diagnostic efficiency for epilepsy. MMP-9 was much related to the type and disease duration of epilepsy (P< 0.05). HMGB1 was significantly associated with disease duration, seizure, and previous treatment history of epilepsy (P< 0.050). According to the Pearson correlation coefficient analysis, the expressions of MMP-9 and HMGB1 were negatively correlated with MMSE scores of the study group (P< 0.001). Logistic regression analysis showed that the duration of disease, seizures, MMP-9, and HMGB1 were independent risk factors for the prognosis of epilepsy. The expression levels of MMP-9 and HMGB1 in peripheral blood of patients with epilepsy are significantly increased, and negatively correlated with neurological function scores. They have potential involvement in the occurrence and development of epilepsy, which makes them significant for the diagnosis and treatment of epilepsy in the future.


Assuntos
Epilepsia/sangue , Epilepsia/diagnóstico , Proteína HMGB1/sangue , Metaloproteinase 9 da Matriz/sangue , Adulto , Idoso , Cognição/efeitos dos fármacos , Cognição/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Feminino , Proteína HMGB1/metabolismo , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Análise de Regressão , Fatores de Risco , Convulsões
15.
Immunol Med ; 43(3): 121-129, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32546118

RESUMO

The roles of interleukin-22 (IL-22) in carcinogenesis have been proposed in various neoplasms. Increased expression of IL-22 has been observed in oral squamous cell carcinoma (OSCC) lesions as well as in other cancers. OSCC is still associated with poor prognosis and a high mortality rate because of its invasiveness and frequent lymph node metastasis. In the present study, we investigated the effects of IL-22 on OSCC cells. The human OSCC cell lines Ca9-22 and SAS were stimulated with IL-22 (1-10 ng/mL), and their migration abilities were examined using a cell scratch assay. A Matrigel invasion assay was performed to evaluate the invasion abilities of OSCC cells. Signal transducer and activator of transcription 3 (STAT3) phosphorylation, matrix metalloproteinase (MMP) and epithelial-mesenchymal transition (EMT)-related genes and proteins were also examined. IL-22 treatment promoted the migration and invasion abilities of OSCC cells without increasing their viability. IL-22 stimulation also induced STAT3 phosphorylation, MMP-9 activity and EMT-related genes and proteins. Our findings suggest that IL-22 has possible roles in the development of OSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular/efeitos dos fármacos , Interleucinas/efeitos adversos , Interleucinas/fisiologia , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Metástase Linfática/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Invasividade Neoplásica/genética , Fosforilação/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
16.
Environ Toxicol ; 35(11): 1194-1201, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32519806

RESUMO

Dioscorea nipponica Makino has been used for the treatment of chronic bronchitis, rheumatoid arthritis, cough, and asthma. Several studies have established the antitumor effect of D. nipponica Makino extract (DNE). However, no investigations have considered the antimetastatic potential of DNE in cervical cancer cells. The present study examined the effects of DNE on cervical cancer cells treated with 12-O-tetradecanoylphorbol-13-acetate and characterized the possible molecular mechanisms. MTT assay results indicated that DNE exhibited very low cytotoxicity, and DNE significantly reduced the invasion and migration abilities of cervical cancer cells. Gelatin zymography analysis revealed that DNE significantly inhibited matrix metalloproteinase-9 (MMP-9) activity. Reverse transcription-polymerase chain reaction assay results revealed that DNE treatment inhibited the MMP-9 mRNA levels of HeLa and SiHa cells. Western blot results revealed that DNE significantly diminished the ERK1/2 phosphorylation. In conclusion, we revealed that the antimetastatic effects of DNE on cervical cancer cells are due to its inhibition of MMP-9 expression through the ERK1/2 pathway.


Assuntos
Dioscorea , Metaloproteinase 9 da Matriz/metabolismo , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Acetato de Tetradecanoilforbol , Neoplasias do Colo do Útero/metabolismo
18.
Anticancer Res ; 40(5): 2725-2737, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366418

RESUMO

BACKGROUND/AIM: Glioblastoma (GB) is the most aggressive type of tumor in the central nervous system and is characterized by resistance to therapy and abundant vasculature. Tumor vessels contribute to the growth of GB, and the tumor microenvironment is thought to influence tumor vessels. We evaluated the molecular communication between human GB cells and human brain microvascular endothelial cells (HBMEC) in vitro. MATERIALS AND METHODS: We investigated whether GB-conditioned media (GB-CM) influenced HBMEC proliferation and migration, as well as the levels of MMP-9, CXCL12, CXCR4, CXCR7, VEGFs, VEGFR-2, and WNT5a in HBMEC. RESULTS: Although HBMEC proliferation was not modified, increased HBMEC migration was detected after GB-CM treatment. Furthermore, treatment of HBMEC with GB-CM resulted in increased levels of MMP-9 and CXCR4. The levels of WNT5a, VEGFs and VEGFR-2 were not affected. CONCLUSION: GB-secreted factors lead to increased endothelial cell migration and to increased levels of MMP-9 and CXCR4.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Movimento Celular , Células Endoteliais/patologia , Glioblastoma/patologia , Metaloproteinase 9 da Matriz/metabolismo , Receptores CXCR4/metabolismo , Neoplasias Encefálicas/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
19.
Life Sci ; 254: 117813, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428597

RESUMO

AIMS: This study aimed to investigate the effect of lymphocytes in wound healing and the underlying mechanisms, in diabetic and non-diabetic mice, using Balb/c recombination activating gene (Rag)-2 and interleukin 2 receptor gamma (IL-2Rγ) double knockout (KO) (RAG2-/- IL-2Rγ-/-) mice. MAIN METHODS: Wound healing in vivo was performed in control and STZ-induced diabetic mice, in both KO and WT mice. Inflammation and ROS production were evaluated by immunofluorescence microscopy analysis, antioxidant enzymes and angiogenesis were evaluated by quantitative PCR and immunofluorescence microscopy analysis, and wound closure kinetics evolution was evaluated by measurement of acetate tracing of the wound area. KEY FINDINGS: Wound closure was significantly delayed in KO mice, where the M1/M2 macrophage ratio and basal ROS levels were significantly increased, while antioxidant defenses and angiogenesis were significantly decreased. Moreover, the expected increase in matrix metallopeptidase (MMP)-9 protein levels in diabetic conditions was not observed in KO mice, suggesting that the mechanisms leading to the increase in MMP-9 observed in diabetic wounds may in part be lymphocyte-dependent. SIGNIFICANCE: Our results indicate that lack of lymphocytes compromises wound healing independent of diabetes. The lack of these cells, even in non-diabetic mice, mimics the phenotype observed in wounds under diabetic conditions. Moreover, the combination of diabetes and the lack of lymphocytes, further impair the wound healing conditions, indicating that when the innate regulatory function is lost in these KO mice, excessive M1 polarization, poor angiogenesis and impaired wound healing are worsen.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Linfócitos/fisiologia , Neovascularização Fisiológica/fisiologia , Cicatrização/fisiologia , Animais , Proteínas de Ligação a DNA/genética , Inflamação/metabolismo , Subunidade gama Comum de Receptores de Interleucina/genética , Ativação de Macrófagos/fisiologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Pele/irrigação sanguínea , Pele/metabolismo
20.
Nature ; 581(7806): 71-76, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376954

RESUMO

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.


Assuntos
Apolipoproteína E4/genética , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Capilares/patologia , Ciclofilina A/líquido cefalorraquidiano , Ciclofilina A/metabolismo , Feminino , Heterozigoto , Hipocampo/irrigação sanguínea , Humanos , Masculino , Metaloproteinase 9 da Matriz/líquido cefalorraquidiano , Metaloproteinase 9 da Matriz/metabolismo , Giro Para-Hipocampal/irrigação sanguínea , Pericitos/patologia , Tomografia por Emissão de Pósitrons , Receptor beta de Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano , Lobo Temporal/irrigação sanguínea , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo
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